The Role of Proper Insulin Injection Technique in the Treatment of Diabetes
Phase: NA
Conditions: Diabetes Mellitus, Type 2, Diabetes Mellitus, Type 1, Lipohypertrophy
Sponsor: Becton, Dickinson and Company

Cover Page 
 
 
Protocol Title: 
The role of proper insulin injection technique in the treatment of 
diabetes mellitus 
 
Document Type: 
Clinical Study Protocol 
 
Document Date: 
12-Jul-2019 
 
NCT number: 
NCT04120974 
 

 
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Clinical trial protocol 
 
«The role of proper insulin injection technique in the treatment of diabetes 
mellitus». 
 
Identification number BD-4MM 
Internal project number: DBC-19INJCTRU 
Current Version: version 04 of 12 July 2019  
(protocol design changes, see Protocol Revision Form for more details). 
 
Version history: version 01 of 27 February 2019 
Version 02 of 09 May 2019 
Version 03 of 27 May 2019 
 
 
 
Sponsor  
  
Becton, Dickinson and Company 
Dvintsev Str, No 12 
Building 1 
Moscow 127018 
Russia 
 
 
Sponsor’s Medical Monitor  
 
Stanislav Glezer, VP, Medical Affairs, 
Diabetes Care 
Email: Stanislav.Glezer@bd.com 
 
 
 
 
 
_______________________ 
(signature for protocol approval) 
 
 
 
 
«Becton, Dickinson and Company», Russia confirms that the proposed clinical trial will be 
conducted in accordance with the ethical principles of the WMA Declaration of Helsinki, and 
will not be started until the receipt of the approval by the Ethics Committee of research center or 
Independent Interdisciplinary Ethics Committee on Ethical Review for Clinical Trials (where 
applicable). During the conduct of clinical trial, any additional comments by the Ethics 
Committee of the research center will be taken note of, should such comments be provided.  
 
 

 
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CONFIDENTIALITY AGREEMENT AND INVESTIGATOR SIGNATURE PAGE 
 
I, the undersigned, NAME ________________________________________________________ 
_____________________________________________________________________________, 
agree to take personal responsibility for maintaining confidentiality with regard to the clinical 
trial protocol and any other related documents, and pledge not to disclose the documents to third 
parties bearing no relation to the Protocol. I accept the liability for conducting clinical trial 
procedures in accordance with the 1964 World Medical Association Declaration of Helsinki and 
its successive versions, also, in accordance with the National State Standard R ISO (GOST R 
ISO) 14155-2014. I affirm that the staff members of my research center understand and agree to 
comply with the protocol requirements, and are ready for participation in the clinical trial.  
 
Date_________________ Signature___________________ 
 
 
 
 
 
 

 
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Contents 
 
 
 
Confidentiality agreement and Investigator signature page………………………...…... 
2 
List of abbreviations …………………………………………………………………………... 4 
List of terms …………………………………………………………………………...……… 
5 
Brief description of clinical trial……………………………………......................................... 
7 
1. Identification and description of the medical device used in the trial ……...……...……. 
9 
2. Study sponsor ……………………………..……………………………………………… 
10 
3. Rationale of clinical trial plan (design)……… ………………………... 
10 
4. Summary about the training and experience of the medical staff needed to operate the 
device ………………………………………………...…………………………………… 
10 
5. Risks and benefits associated with the use of the device and the clinical trial………...... 
11 
6. Objectives of the clinical trial and the hypotheses to be tested………………………...... 11 
7. Clinical trial proposal (design)……………………...……………………………………. 12 
7.1.Standards for the clinical trial ………………………………………………...………....... 
12 
7.2.Outcome measures for the clinical trial …………………………………………………… 13 
7.3.Inclusion and exclusion criteria …………………………………………………………… 13 
7.4. Patient information and obtaining informed consent…………………………………………14 
7.5. Stages of the clinical trial …………………………………………………...………. 
14 
7.6. Patient training of correct injection technique…………………… 
22 
7.7. Patient safety …………………………………………………………………...…… 
23 
8. Monitoring design …………………………………………………………………..……. 
24 
8.1 Electronic data capture……………………………………………………..…... 
25 
8.2 Patient identification …………………………………………………..…... 
25 
9. Investigator’s range of responsibilities ……………………………………………...……. 
25 
10. Statistical analysis …………………………………………………………………...……. 
25 
10.1 Projected sample size ……………………………………………………………… 
25 
10.2 Statistical analysis plan …………………………………………………………... 
25 
11. Data management …………………………………………………………………………. 26 
12. Appendices to the clinical trial protocol……………………………………………...…… 
26 
13. Adverse events, unfavorable effects of the device and its disadvantages ……………… 
26 
13.1 Adverse Event (AE) Management………………………………………………….. 
27 
13.2 Assessment of Adverse Events (AEs)……………………………………………….. 
13.3 Incidents…………………………………………………………………………….. 
29 
29 
14. Sensitive populations ………………………………………………………………...……. 30 
15. CT suspension or premature termination……………………………………………..…… 
30 
16. Publication principles …………………………………………………………………..…. 30 
References ……………………………………………………………………………..……… 
32 
Appendix А: Accompanying regulatory documents……………………...…………………… 33 
Appendix B: Example of EQ-5D questionnaire ………………………………………………. 40 

 
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List of abbreviations 
ADE – adverse device effect 
AE – adverse event  
BD Micro-Fine Plus 4mm 32G pen needle – disposable BD Micro-Fine Plus 32G pen needle 
(0.23mm/32G x 4mm)  
BG- blood glucose value 
BGM – Blood Glucose Meter 
BMI – body mass index  
eCRF – electronic case report form  
CT – clinical trial  
DM – diabetes mellitus 
FITTER - Forum for Injection Technique Therapy Expert Recommendations 
GLP-1 – glucan-like peptide-1 
HbA1c – glycated hemoglobin  
ICF – informed consent form  
LEC – local ethics committee  
LH - Lipohypertrophy 
QOL – Quality of Life 
SAE – serious adverse event 
TDD – total daily dose 
USADE – unanticipated adverse device effect 
 
 
 
 

 
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List of terms 
Hypoglycemia is defined as the occurrence of ≥ 1 symptoms of low blood sugar (e.g., fast 
heartbeat, tiredness, sweating, extreme hunger, dizziness, tremors) and a blood glucose meter-
confirmed reading ≤ 3.9 mmol/L.  
Hypoglycemia of unknown etiology is defined as hypoglycemia occurring in the absence of a 
certain provoking event, such as a change in the administration of medications, diet or physical 
activity. 
Principal investigator is the qualified person responsible for the conduct of the clinical trial in 
the research center. 
Monitoring is the activity related to the supervision of the course of the clinical trial, in order 
to make sure that a given investigation is carried out and recorded, and the report is produced 
in accordance with the trial protocol, documented procedures, set standards and applicable 
regulatory requirements.  
Multicenter studies are clinical studies which are conducted according to a unique protocol in 
two or more research centers. 
Commissioner (Sponsor): An individual or organization bearing responsibility and having 
duties regarding the initiation or conduct of the clinical trial. For this trial, the Sponsor is the 
«Becton Dickinson and Company», Russia. 
Case report form, CRF: A set of documents in the form of a hard copy, electronic or optical 
data carrier recorded for each study subject, which, according to CT protocol, contains 
information that must be submitted to the study sponsor.  
Investigator (same as physician-investigator): The individual member of a research team 
appointed by and subordinate to the Principal Investigator in the research center, who will 
carry out the major procedures related to the clinical trial or take important decisions 
pertaining to all aspects of the clinical trial. 
Research center (Center): An institution or site where the clinical trial is conducted. 
Clinical trial: Systemic study with participation of one or more individuals as study subjects, 
aiming at evaluating the safety or functional characteristics of a medical device. 
Outcome measure (primary): The most important parameter(s) used to test the main 
hypothesis in the clinical trial. 
Outcome measure (objectives) (secondary): Parameter(s) used to test additional hypotheses 
in the clinical trial. 
Adverse Event (AE): : Any unfavorable medical manifestation, such as an unanticipated 
disease or trauma, as well as undesirable clinical signs, including abnormal laboratory values, 
in the subject, user, or any other individual who may not be associated with the studied 
medical device. 
Unanticipated Adverse Device Effect (UADE): Undesirable effect associated with the use of 
studied medical device. 
Serious Adverse Event (SAE)is  
An SAE is any AE occurring during study participation that results in any of the following 
outcomes: 
a) leads to a lethal outcome; 

 
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b) leads to the serious deterioration of the health of the subject, which, in turn, leads to either: 
1) disease or a life-threatening injury, or 
2) injury, or 
3) hospitalization or its extension, or 
4) medical or surgical intervention for the prevention of the life-threatening disease or 
injury; 
c) fetal injury, fetal death or abnormalities or defects of fetal development. 
 
Unanticipated Serious Adverse Device Effect (USADE):  Serious unfavorable effect of the 
device, of which the character, extent of effect, severity or consequences of its use have not 
been identified in the current working version of the risk analysis report. 
Deviation: Case(s) of departure, deliberate or accidental, from the protocol requirements. 
Clinical trial design (study protocol): The document which states the substantiation, 
objectives, study proposal (plan) and prospective analysis, method, monitoring, management 
and maintenance of the records pertaining to the clinical trial.  
Procedure of obtaining the informed consent: The process during which the subject is 
provided with complete information about the clinical trial, and he/she gives a voluntary 
consent for participation in the clinical trial.  
Sensitive subject is an individual whose preparedness to participate in the clinical trial can be 
unduly affected by anticipation, reasonable or not, participation-related benefit or negative 
reaction of the administration in case of the subject’s refusal to participate. 
Objective means the main objective of the clinical trial. 
Ethics committee; EC: An independent committee responsible for the analysis of the clinical 
trial aiming at protecting the rights and ensuring the safety and wellbeing of the subjects taking 
part in the clinical trial. 
 
 
 

 
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Brief description of the clinical trial 
Title 
The role of proper insulin injection technique in the treatment of diabetes 
mellitus  
Type  
A prospective, post-marketing, single-arm clinical study  
Duration  
Planned First patient in: end of June 2019 
Enrolment period: approximately 1 month 
Study duration per patient: 6 months 
Number and name 
of research centers 
Total number of centers - 6: 
1. Federal State-Funded Institution “National Medical Research 
Center of Endocrinology” of the Ministry of Healthcare of the 
Russian Federation.   
2. State-Funded Healthcare Institution of the Moscow Region 
“Moscow regional clinical scientific research institute named after 
M.F. Vladimirsky (MONIKI)”. 
3. State-Funded Healthcare Institution “Endocrinology Dispensary of 
the Health Department of Moscow City”.  
4. Federal State-Funded Educational Institution of advanced 
professional education of the Russian Medical Academy of 
continuous professional education of the Ministry of Healthcare of 
the Russian Federation.  
5. State-Funded Healthcare Institution of the Sverdlovsk region 
“Sverdlovsk regional clinical hospital №1".  
6.  Pavlov First Saint Petersburg State Medical University 
Rationale 
Insulin is the drug used in the treatment of diabetes mellitus, and it is 
administered via injection into subcutaneous adipose tissue. Proper 
technique of insulin injection in diabetic patients is a prerequisite for 
achieving good glycemic control, a reduction in the variability of insulin 
absorption, and reaching optimal efficacy of the anti-diabetic drugs [1]. 
Objective 
The study aims at testing the effect of training in optimal technique of 
insulin injection using a multimodal individual approach supplemented 
with a platform for personalized distance education of diabetic patients 
who are on insulin therapy, with regard to clinical outcomes and essential 
skills necessary for managing diabetes.   
Outcome measures 
- 
Reduction in glycated hemoglobin (HbA1c) (in %);  
- 
Insulin total daily dose (TDD);  
- 
Incidence of hypoglycemia;  

 
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- 
Incidence of severe hypoglycemia (which required assistance by 
others);   
- 
Change in Blood Glucose levels (measured by BGM) 
- 
Correct alternation of injection sites;  
- 
Cases of repeat needle use;  
- 
Changes in lipohypertrophy, its size (length and width, in mm) and 
localization (if applicable);  
- 
Cases of injection into lipohypertrophy areas (if applicable);  
- 
Quantitative experience with the use of distance-learning video 
lessons by patients. 
- 
Quality of Life assessments 
Number of 
participants 
At least 73, but not more than 90.   
Length of time of 
patients’ 
participation 
Total time of patient participation in the study is 6 months, which includes: 
- 
Three personal visits 
- 
Two phone calls  
Selection criteria 
Selection of patients will not be influenced by race, religion, socio-
economic and other factors. Approximately 50% of the subjects to be 
enrolled will have lipohypertrophy areas and 50% of the subjects will not.  
Inclusion criteria:  
1. Type 1 or type 2 diabetes mellitus; 
2. Patients (male and female) of 18 years of age and over; 
3. At least 1 year of experience with insulin self-administration;  
4. Use of insulin pen for insulin injections.  
5. HbA1c > 7.5 % measured at study entry or maximally 30 days  
prior to screening. 
6. BMI below 40 kg/m2 at study entry. 
7. Daily self-control of blood glucose level; 
8. Access to the internet for watching video lessons. 
9. Only outpatients are eligible for the study.  
10. Availability of signed informed consent of the patient for inclusion 
in the study. 
Exclusion criteria: 
1. Pregnant women or women planning to become pregnant during 
the time of study, breastfeeding women;  
2. Subjects using an insulin pump;  
3. Those using treatment with a GLP-1 receptor agonists alone; 
4. Subjects not fluent in Russian (reading and writing).  
5. Patients at high risk for ketoacidosis and/or hyperglycemia. 
6. Psychic, physical or any other reasons hampering patient 
participation in the study (based on the reasonable opinion of the 
physician-investigator). 
Name of medical 
Disposable BD Micro-Fine Plus 32G pen needle (0.23 x 4 mm). 

 
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device and its 
manufacturer 
Manufacturer: “Becton Dickinson and Company”, USA. 
Ancillary Products 
Blood Glucose Meter 
Interim analysis 
Will not be carried out.  
Statistical analysis 
The HbA1c and insulin total daily dose will be analyzed using linear 
models with mixed effects (with transformation or without it, whenever 
necessary) where lipohypertrophy will be a fixed effect. Analyses will be 
done overall and per lipohypertrophy sub-group (with or without LH) 
whenever the sub-group effect is significant. Generalized linear models 
with mixed effects will include logistic models for binomial responses  or 
Poisson models for count responses. 
Fixed effect models can be used when models with mixed effects cannot 
be employed. The effect of different covariates will be studied (including, 
but not limited to these), such as site, age, BMI, gender and diabetes type, 
as well as their interaction. The threshold to keep covariates in a model 
will be p <0.05. 
 
1. 
Identification and description of the medical device used in the trial. 
      Disposable BD Micro-Fine Plus 32G pen needles (0.23mm/32G x 4mm) will be used. The 
needles (Fig. 1) are made of stainless steel AISI 304, silicone, UV light curable adhesive, 
polypropylene, polyethylene and paper/copolymer film. The length of the needle is 4 mm, 
diameter 0.23 mm and weight 3 g. 
BD Micro-Fine Plus 4 mm 32G needles are intended for parenteral (subcutaneous) injection 
of medicines (insulin, hormonal medications and other drugs supplied in cartridges which, in 
turn, are enclosed in pen injectors [pre-filled syringes]).  
       BD Micro-Fine Plus 4 mm 32G needles are intended for self-injection of medications by the 
patient at home, using special injectors (pen injectors or pre-filled syringes). The same needles 
can be used in the hospital by skilled medical staff, provided the cartridges and injectors are used 
individually for each patient.  
        The needles are manufactured by the «Becton Dickinson and Company», USA. The 
manufacturing sites include Pottery Road, Dun Laoghaire Co Dublin, Ireland, and Donore Road 
Drogheda, Co Louth, Ireland.   
 
Fig. 1 Disposable BD Micro-Fine Plus 4 mm 32G needle (0.23mm/32G x 4mm): view of the 
open needle, individually packaged and in a carton box.  

 
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2. Study sponsor 
The study is sponsored by the «Becton, Dickinson and Company», Russia. Becton, 
Dickinson and Company is a manufacturer of different medical devices, including needles for 
insulin pen injectors. The company provides all necessary educational, instructional and 
supporting materials and provides assistance with the monitoring of studies, the  analysis of 
data, and the publication of results.  
For the period of the clinical trial, BD supplies all participating patients with 4 mm 32G 
needles free of charge.  
In the course of study, the required number of needles (depending on the number of insulin 
injections per patient and the number of patients in every center) will be supplied by the 
Sponsor to the research center. An entry will be made regarding the supplied needles (number 
of packages, date of receipt, batch №) by the investigator in a special log book (see Appendix 
А to the protocol). Upon study completion, the center must return all unused needles (if any) to 
the Sponsor and mark this in the needle log book.   
The needles will be used for insulin injection by patients with type 1 and type 2 diabetes 
mellitus who have been using insulin injections for more than a year. The injections will be 
done using pen injectors.   
BD will also supply, via the research center, a Blood Glucose Meter (BGM) as well as 
sufficient lancets and test strips to all study patients for use in the study. This BGM will need to 
be returned to the research center after the patient finished the study. This will also be 
documented in a log book. Upon study completion, the center must return all BGMs (used and 
unused) unused strips and lancets (if any) to the Sponsor and mark this in the corresponding 
log book.  
 
 
3. Rationale of clinical trial plan (design) 
To date, several clinical trials have been conducted [2,3,4] with the aim of evaluating the 
effect of proper insulin injection technique on such parameters as glycemic control, glycated 
hemoglobin, hypoglycemia, glycemic variability and TDD of insulin. The above mentioned 
studies attest to the fact that the use of proper injection technique yields tangible results, namely, 
a reduction in % of glycated hemoglobin, an improved control of blood glucose level and an 
overall improvement of patient satisfaction with treatment. A 6-month follow-up is considered a 
necessary and sufficient measure for the evaluation of the above parameters. In our study, we 
would also like to evaluate all the above mentioned parameters with regard to proper injection 
technique; in addition, physicians’ explanations on the injection technique will be reinforced by 
on-line video lessons, which will be recommended by the attending physician to patients for their 
own viewing.   
  
4. Summary about the training and experience of the medical staff needed to handle the 
device 
The experienced medical staff participating in this trial are in a position to handle the insulin 
pen needles. However, the Sponsor will run training classes for the medical specialists involved 

 
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in the study to familiarize them with the study protocol, including a briefing on how to find 
lipohypertrophy areas (using training phantoms).  Training will employ the “teach the teacher” 
method. Moreover, the Sponsor will run training classes on how to fill in the supporting 
documents required for the clinical trial, such as source worksheets, and the eCRF, the needle 
log book, etc. The site staff will also be instructed on how to deal with the subject diaries and 
how to administer the Quality of Life questionnaire EQ-5D.  
 
5. Risks and benefits associated with the use of the device and the clinical trial 
The risks associated with the use of disposable BD Micro-Fine Plus: 32G (0.23 x 4 mm) 
needles and the injection pen are the standard risks occurring during subcutaneous injections, 
which include the following: 
1) Hemorrhages and hematomas. Sometimes during an injection, the needle may damage blood 
vessels, causing hemorrhages or hematomas. Changes in needle length or other injection 
parameters do not seem to influence the rate of occurrence of bleeding or hematomas, 
although, according to some data, these complications may occur less frequently when short 
needles are used. Pressing on the injection site for 5-10 seconds should stop the bleeding [1].  
2) Leakage of the medication from the injection site. This can occur due to the following 
reasons:  
а) a one-time injection of a large insulin dose. In some cases, it would be preferable to divide 
large insulin doses into two doses and inject them one after another [1].  
b) individual skin properties (dermal structure) and its age-related changes may be the cause of 
medication leakage following an injection [1].  
3) Pain. Injections of insulin and GLP-1 receptor agonists do not usually cause pain, except for 
cases when the needle damages nerve ending fibers, which is a fairly rare event. However, some 
patients respond to injections in a rather sensitive way and describe their sensations as painful 
ones. Patient discomfort during injections was carefully studied and is attributed to three key 
factors: needle length, needle diameter and injection setting [1].  
 The benefit provided by this study is the demonstration of the fact that proper insulin 
injection technique used by patients is a prerequisite for achieving good glycemic control of 
diabetes, reducing the variability in the absorption of insulin preparations, and obtaining the 
optimal effect of their use [1].  Also, we expect that the proper technique of insulin injections 
will help to reduce the risks of injections: hemorrhages, hematomas cases and pain. 
 
6. Objectives of the clinical trial and the hypotheses to be tested 
The study aims at verifying the effect of teaching the optimal technique of insulin 
injection using the multimodal individual approach, supplemented with a personalized 
remote platform for the education of diabetic patients who are on insulin therapy, with 
regard to the clinical outcomes and essential skills necessary for managing diabetes.   
This is a prospective study conducted in Russia, with a subsequent progress review after 
a 6-month follow-up to assess the correctness of insulin injection technique. The study 
design represents a “before” and “after” comparison, where the patient is left under 

 
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his/her own control after the health worker-guided assessment of the existing technique, 
and is undergoing training in conjunction with the reinforcing video lessons. The study 
includes patients with and without lipohypertrophy. During the follow-up phase, the 
insulin total daily dose, extent of glycemic control (glycated hemoglobin, hypoglycemic 
episodes), repeat use of needles, insulin injection technique and practical use by patients 
of the taught hands-on skills will be reviewed and evaluated.    
 
Hypothesis 
• 
Proper insulin injection technique, which includes the single use of needles, alternating the 
injection sites, avoiding injection in lipohypertrophic areas and the use of short (4 mm-long) 
needles will allow us to improve glycemic control parameters (% glycated hemoglobin, 
hypoglycemia) and to reduce insulin TDD .  
 
Primary objective 
• 
Evaluation of the effect of personalized teaching of the optimal insulin injection technique 
in conjunction with the use of disposable BD Micro-Fine Plus 32G (0.23mm/32G x 4 mm) 
pen needles on the reduction in glycated hemoglobin (HbA1c in %) after 6 months follow 
up in patients with Type 1 or Type 2 diabetes .  
 
Secondary objective 
• 
Evaluation of the effect of optimal insulin injection technique on the total daily dose of 
insulin and clinical parameters of glycemic control (hypoglycemia and severe 
hypoglycemia requiring third party assistance).  
• 
Evaluation of the effect of optimal insulin injection technique on glucose blood levels 
(measured by BGM).   
 
 
Additional objective 
• 
Evaluation of the effect of education (especially distanced learning) on patients’ 
knowledge and their mastering insulin injection technique, including correctly 
alternating the injection sites, avoiding injecting the lipohypertrophy areas, and the 
single use of needles.  
 
 
7. Clinical trial proposal (design)  
This clinical trial is a prospective, post-marketing, single-arm clinical trial. 
 
7.1. Standards for the clinical trial 
To allow for 73 evaluable subjects at 6 months follow up, a total of up to 90 patients will be 
enrolled (the statistical power of the study is provided in a section below, dedicated to statistical 
analysis). Each center will be offered to supply a sufficient number of patients as study subjects 
(up to 15 patients). Approximately half of these patients will be with lipohypertrophy (LH), and 
half will be without. Ideally, each center should recruit half of their patients with and half of their 
patients without LH. The Sponsor will monitor if the overall balance of 50%/50% is maintained 

 
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and will advise study centers accordingly. The main goal is to have an equal distribution across 
the study, not necessarily per site, however, each study center should have at least a distribution 
of 1/3 versus 2/3 in each group.  The optimal injection technique and choice of needle length is 
based on the Russian Procedural Guidelines on injection techniques and infusions used in the 
treatment of diabetes mellitus [1]. These Guidelines, in turn, are based on recently published 
international guidelines by the Forum for Injection Technique Therapy Expert Recommendations 
(FITTER) [5].  
 
 
7.2. Outcome measures for the clinical trial 
• Reduction in glycated hemoglobin (HbA1c, in %);  
• Insulin total daily dose (TDD);  
• Incidence of hypoglycemia;  
• Incidence of severe hypoglycemia (which require assistance by others);  
• Change in Blood Glucose levels (measured by BGM) 
• Correct alternation of injection sites;  
• Cases of repeat needle use;  
• Change of lipohypertrophy, its size (length and width in mm) and localization (if 
applicable);  
• Cases of injection into lipohypertrophy areas (if applicable);  
• Patients’ quantitative experience with the use of distant video lessons. 
• Quality of Life assessments (EQ-5D) 
 
             
7.3.Inclusion/exclusion criteria.  
 
The selection of patients will not be influenced by race, religion, socio-economic and 
other factors. Approximately 50% of the subjects to be enrolled will have 
lipohypertrophy areas and 50% of the subjects will not. 
 
Inclusion criteria:  
1. Type 1 or type 2 diabetes mellitus; 
2. Patients (male and female) of 18 years of age and over; 
3. At least 1 year of experience with insulin self-administration;  
4. Use of insulin pen for insulin injections.  
5. HbA1c > 7.5% measured at study entry or maximally 30 days prior to study entry.. 
6. BMI below 40 kg/m2 at study entry. 
7. Daily self-control of blood glucose level; 
8. Access to the internet for watching video lessons. 
9. Only outpatients are eligible for the study.  
10. Availability of the patient’s signed informed consent for inclusion in the study. 
 
 

 
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Exclusion criteria: 
1. Pregnant women or women planning to become pregnant during the time of study, 
breastfeeding women;  
2. Subjects using an insulin pump;  
3. Those using treatment with a GLP-1 receptor agonists alone; 
4. Subjects not fluent in Russian (reading and writing).  
5. Patients at high risk for ketoacidosis and/or hyperglycemia. 
      6. Psychic, physical or any other reasons hampering patient participation in the study (based   
on the reasonable opinion of the physician-investigator). 
 
 
7.4. Patient information and obtaining informed consent 
       Before executing any study procedure, the informed consent of the patient must be obtained.  
The following steps must be taken in order to obtain the informed consent of the patient for participation 
in the study.   
1. Physician-investigator must ascertain whether patients understand and read Russian.  
2. Patient receives information about the study, its objectives, a brief description of the 
study design and the patient requirements in case he/she consents to participate in the 
study. Patients are informed that they meet the criteria required for study entry.  
3. Patient takes his/her time to ask questions, discuss the study with family members and 
take a decision about study participation before the next visit to the medical center. If the 
patient gives his/her consent to participate in the study, the next visit is scheduled within 
5 days from the moment of signing the inform consent form by the patient. 
4. Patients are informed that they are entitled to change their mind and withdraw from 
participation at any time, and this will not affect their treatment in any way. 
   
A patient is considered to be enrolled in the study when he/she signed the Informed Consent 
Form. 
 
7.5. Stages of the clinical trial.  
 
The enrolment period of the trial will be approximately 1 month, The follow-up period for 
each patient is 6 months. A total of maximally 90 patients will be included in the trial, to allow 
for 73 evaluable subjects at 6 months follow up, which is due to the statistical calculation of the 
required number of patients (see section 10 of this protocol).  
The study design and calendar of events, including all the necessary visits, their order, 
appointment time and manipulations carried out during the visits, are presented in Fig. 2 (Study 
Flow) Table 1 (Study design) and Table 2 (Calendar of events).

 
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Fig. 2. Study Flow 
 

 
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Table 1. Trial design  
 
Patient selection and start 
Interim control (telephone) 
Interim control (3 month FU visit) 
Completion and evaluation 
Visit 1 (Screening) duration - 5 working days) 
1 Patient evaluation in terms of 
his/her possible participation in 
the study. For female patients: 
perform a pregnancy test  
Follow-up visits – visit № 2,and 4 (by phone ) in 45 and 135  days +/-10 days after visit 1 
1 Make sure that patient follows 
study protocol: uses supplied 
needles only once, and watches 
recommended video lessons 
Follow-up visit – visit № 3 (personal ) in 90 days +/-10 days after visit 1 
1 Enter data regarding HbA1c and insulin 
TDD 
Visit 5 ( personal, final) in 180 days +/-10 days after visit 1
1  Enter data regarding HbA1c and 
insulin TDD 
2 Obtaining the informed consent 
2 Evaluate current level of glycemic 
control and cases of hypoglycemia 
2 Evaluate current level of glycemic control 
and cases of hypoglycemia. 
2  Evaluate current level of glycemic 
control and cases of hypoglycemia.  
3 Assignment of participant 
identification number (code) 
3 Find out about current level and 
frequency of measuring blood 
glucose and insulin TDD.  
3 Examine injection sites and injection 
technique, size and localization of 
lipohypertrophy 
3  Examine injection sites and injection 
technique, size and localization of 
lipohypertrophy  
4 Fill in the questionnaire, enter 
data regarding HbA1c and 
insulin TDD. 
Note: the HbA1c value may be 
measured at screening or the 
latest measured value (max. 30 
days prior to screening) may be 
taken.  
4 Make sure that the patient follows 
the recommended injection 
technique, correctly alternates 
injection sites and avoids 
injections into sites of 
lipohypertrophy. Remind the 
patient to use the BGM and 
complete the diary. 
4 Enter data regarding possible AE  
4  Collect diary and review completion 
5  Examine injection sites and 
injection technique, size and 
localization of lipohypertrophy 
(if applicable).  
5 Enter patient’s answers in the 
interim control form 
5 Review diary completion 
5 Request patient to complete the EQ-5D 
questionnaire 
6 Evaluate current level of blood 
glucose and cases of 
hypoglycemia. 
6 Remind patient about next 
personal visit 
6 Download the data from the BGM to a 
PC for further statistical analyses. 
6  Arrange subsequent medical follow-up 
for the patient, if required 
7 Carry out personalized training 
on correct injection technique 
7 Enter data regarding possible AE 
7 Provide new supply of BD Micro-Fine 
Plus 4 mm 32G needles (3 months’ 
supply) and additional strips and lancets 
for BGM.   
7  Release patient from participation in 
the study (fill in Exit from study form). 

 
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8 Familiarize patient with distance 
education resource and 
recommend independent studies 
using video lessons  
  
8 Schedule the HbA1c test and next 
personal visit in 90 days. 
Schedule next telephone follow up (visit 
4) 
8  Download the data from the BGM to a 
PC for further statistical analyses.  
9 Request patient to complete the 
EQ-5D questionnaire 
  
  
9   Enter data regarding possible AE  
10 Provide patient with required 
supply of BD Micro-Fine Plus 4 
mm 32G needles (3 months’ 
supply).   
  
  
10 Collect the BGM from the patients. 
Complete the log forms 
11 
 
 
 
 
Schedule the HbA1c test and 
next personal visits in 90 and 
180 days, and over-the-phone 
visits for interim control in 45 
and 135 days.  
  
  
 
 
12 Provide patients the diary and a 
Blood Glucose Meter  (BGM) 
with strips and lancets (3 
months’ supply). Explain how to 
complete the diary and use 
BGM.  
  
  
 
 
13 In a week +/-2 days after the 
screening visit, the investigator 
must ascertain if patient viewed 
recommended lessons.  
  
  
 
 
 

 
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Visit № 1 – screening visit (personal visit).  
1. For study purposes, prior to patient enrolment a physician will interview the patient about 
his/her condition in order to evaluate the effectiveness of current practices in terms of 
injection technique, the finding of gaps and possibilities for their improvement. Depending 
on the results of such an evaluation, the investigator will offer the patient familiarization 
with the corresponding distance learning modules.  
2. Information about study participation is provided, and the informed consent form is signed. 
3. Collection of the patient’s demographic data and medical history data is carried out. The 
patient undergoes a physical examination to make sure that he/she meets the 
inclusion/exclusion criteria. A urine pregnancy test must be done for the childbearing 
potential female patients.  
Examination of injection sites and injection technique is performed. The presence of 
lipohypertrophy is determined, and lipohypertrophy areas are marked on the diagram, 
indicating their number and size.  
4. A physician makes an arrangement for the glycated hemoglobin test (HbA1c), which is 
carried out in the laboratory of the center participating in a given clinical trial at 
investigator’s place of work.. To verify the inclusion criteria, the HbA1c value may be 
measured at screening or the latest measured value (max. 30 days prior to screening) may 
be taken.  The result should be entered in the eCRF. 
5. The current level of blood glucose and cases of hypoglycemia will be evaluated during the 
visit and the patient will be asked about his/ her condition and data will be completed in the 
eCRF. 
6. The insulin dose of the day prior to the visit (basal and boluses) will be captured in the 
eCRF. 
7.   A theoretical course is given on lipohypertrophy and the necessity of alternating the 
injection sites, followed by hands-on classes on insulin injection technique.  Also, patients 
are familiarized with other aspects of insulin therapy. Patients are given instructions that, in 
case of necessity, they can change the insulin dose during the clinical trial. The patient is 
not recommended to change the long-acting and intermediate-acting insulins, and not to 
change insulin subgroups, i.e., short-acting and ultra short-acting insulins.  
8. The patient is familiarized with the structure and scope of the distance learning program. 
The whole course of video lessons will be recommended to the all patients for individual 
studies independently from their insulin injection technique success.   
9.  Patients are requested to complete the EQ-5D questionnaire, see Appendix B for an 
example.  
10. Patients are supplied with an information package – booklet with instructions how to 
practice the right injection technique, rotation grid, the information letter for a physician in 
a local outpatient hospital to inform the patient is participating in the clinical trial. The letter 
should be formalized on the formal paper of the site.  Guidelines on video lessons and web 
access codes, if required.  
11. Patients will also receive:  
a. disposable BD Micro-Fine 32G (0.23mm/32G x 4 mm) needles in the amount 

 
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required for 3 months  (Table 3),  
b. Blood Glucose Meter (BGM), strips and lancets in the amount enough for 400 
measurements, which corresponds with 100 days (approx. 3 months) of 4 
measurements per day,  
c. a patient’s diary. Patients are requested to record their insulin doses and if they 
experienced any adverse effects, including hypoglycemia’s. 
12. Patients must be informed to return the BGM back to the site after the study. Boxes of 
needles, boxes of strips and lancets will be marked: “BD property. Only for clinical trial. 
Not for sale”. Glucometers will be marked: “BD property. Only for clinical trial. Not for 
sale. Must be returned”. 
13. Patients are instructed how to use the BGM and its accessories, how to complete the 
patient’s diary. BGMs will be calibrated if needed and the date and time will be set 
correctly. Patients will be recommended to make at least 4 measurements of glucose per 
day by the provided BGM regardless of the type of diabetes: 3 before meals (one of which 
is before breakfast) and one measurement before bedtime. More measurements may be 
performed in accordance with clinical practice. The recommended measurements as listed 
above should be performed during the following time periods:  
a. within 2 weeks after screening,  
b. the last 2 weeks before the visit of the 3rd month, and  
c. the last 2 weeks before the visit of the 6th month. 
The rest of the time, the patient may measure the level of glucose in the blood in 
accordance with accepted clinical practice.  
During the same 2 weeks periods the patient is asked to complete the diary with basal and 
bolus insulin doses on a daily basis. Also, the patient has to complete the diary with all 
episodes of hypoglycemia.  
14. The next meeting with the physician-investigator is scheduled in 90-100 days (visit № 3), 
as well as the interim visits, which include phone contacts in 45 +/-10 days (visit № 2)  and 
in 135 +/-10 days (visit № 4). 
15. A preliminary scheduled blood test for glycated hemoglobin takes place in 90 +/-10 days as 
well as in 180 +/- 10 days after the screening visit, to be carried out in the laboratory of the 
center participating in a given clinical trial at the investigator’s place of work. The test must 
be done not sooner than a week before the study completion visit or on the day of the 
completion visit. 
16. The Investigator informs the patient they have to visit the investigator before the next 
scheduled personal visit in case they do not have sufficient strips. Also, the patient can visit 
the investigator personally instead of the phone visit if the patient realizes they do not have 
enough strips to cover the period until the next scheduled personal visit. In this case, the 
patients have to bring the diary and his BGM for the visit and the Investigator will 
download the data from BGM and return it back to the patient. The diary will be kept by the 
investigator and the patient will receive the new diary. The patient also will receive the 
required number of strips in amount enough to the next scheduled personal visit. 
 
 

 
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1-week visit (optional, phone).  
In 1 week +/- 2 days after the visit № 1, the investigator must be sure that the patient has 
viewed the recommended video lessons. To this end, the Sponsor provides the investigator 
with the report on the patient’s use of the education resource. If the patient has not viewed 
recommended video lessons, then the investigator reminds him about the necessity of 
viewing the recommended video lessons. The information about video lesson viewing is 
marked in the patient’s eCRF. 
Visits № 2 and № 4- follow-up visits (over-the-phone visits, or personal visit).  
1. The interim contacts with the patient are maintained over the phone in 45 +/-10 days and 
135 +/-10 days from the first visit, with the view to evaluate the patient’s adherence to the 
study design, review diary completion and to provide recommendations on the correction 
of the injection technique, as well as to evaluate the progress of his/her distance learning.  
2. Information on the patient’s glycemic control (glucose level), total daily insulin dose (the 
day prior to the phone visits) and hypoglycemic events since the last visit is requested and 
the information is entered in the eCRF. 
3. To remind the patient to bring the BGM back on the next personal visit and to remind the 
patient on the appointment for having the HbA1c test, as was scheduled on the first and 
third visit  
4. Data regarding possible AEs is collected in a special form of the patient’s eCRF. 
5. In case of the occurrence of adverse events (AE) in the course of the study after the 
screening visit, the investigator will record these in a special form (eCRF). In case of 
serious adverse events (SAE), the corresponding eCRF must be filled in and the event 
reported to the Sponsor and to the corresponding Ethics Committee within 2 working days 
after the investigator has become aware of the event. 
6. The investigator has to remind the patient to measure their glucose levels upon the 
protocol requirements and complete the diary with insulin doses 2 weeks before the next 
personal visit. The same reminder will be also done 2 weeks before or even earlier the 
next personal visit.    
7. The Investigator informs the patient they have to visit the investigator before the next 
scheduled personal visit in case they do not have sufficient strips. Also, the patient can 
visit the investigator personally instead of the phone visit if the patient realizes they do not 
have enough strips to cover the period until the next scheduled personal visit. In this case, 
the patients have to bring the diary and his BGM for the visit and the Investigator will 
download the data from BGM and return it back to the patient. The diary will be kept by 
the investigator and the patient will receive the new diary. The patient also will receive the 
required number of strips in amount enough to the next scheduled personal visit. 
 
Visit № 3 – follow-up visit (personal).  
1. The physician-investigator enters the latest results of the glycated hemoglobin (HbA1c) 
measurements and insulin TDD (basal and boluses of the day prior to the visit) in the 
patient’s eCRF. 
2. The data, saved in the patients’ BGMs should be downloaded by the investigator. The 

 
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downloaded data will be transmitted to the Sponsor for analysis. The data will be 
transferred for analysis and storage to Becton, Dickinson and Company in the United States 
of America. 
3. The existing level of glycemic control and cases of hypoglycemia since the last visit are 
assessed. 
4. The physician conducts an examination of the injection sites and the injection technique, 
the size and localization of lipohypertrophy (if present).  
5. The physician will collect and review correct completion of the diary and will provide the 
patient with a new diary. 
6. Data regarding possible AEs is collected in a special form of the patient’s eCRF. If 
necessary, a subsequent medical follow-up is arranged for the patient.  
7. Patients will receive a new batch of 32G (0.23mm/32G x 4 mm) needles, BGM strips, and 
lancets for the next 3 months of the study. 
8. Confirm the telephone follow up at Day 135 +/-10 days (visit № 4). 
9. Confirm appointment to measure HbA1c for visit № 5 (6 months follow up). 
10. The Investigator informs the patient they have to visit the investigator before the next 
scheduled personal visit in case they do not have sufficient strips. Also, the patient can visit 
the investigator personally instead of the phone visit if the patient realizes they do not have 
enough strips to cover the period until the next scheduled personal visit. In this case, the 
patients have to bring the diary and his BGM for the visit and the Investigator will 
download the data from BGM and return it back to the patient. The diary will be kept by the 
investigator and the patient will receive the new diary. The patient also will receive the 
required number of strips in amount enough to the next scheduled personal visit. 
 
 
Visit № 5 – study completion visit (personal). 
1. The final patient examination is conducted by the physician-investigator, and, during this 
visit, the patient will be asked several questions, of which the answers are documented in 
the eCRF.   
2. The physician-investigator enters the latest results of the glycated hemoglobin (HbA1c) 
measurements and insulin TDD (basal and boluses, of the day prior to the visit) in the 
patient’s eCRF. 
3. The data, saved in the patients’ BGMs should be downloaded by the investigator. The 
downloaded data will be transmitted to the Sponsor for analysis. The data will be 
transferred for analysis and storage to Becton, Dickinson and Company in the United 
States of America. 
4. The BGM must be returned to the site and transferred to the Sponsor.  
5. The existing level of glycemic control and cases of hypoglycemia are assessed. 
6. The physician conducts an examination of the injection sites and the injection technique, 
the size and localization of lipohypertrophy (if present).  
7. The physician will review and collect the subject diaries. 
8. Patients are requested to complete the EQ-5D questionnaire, 
9. Data regarding possible AEs is collected in a special form of the patient’s eCRF. If 
necessary, a subsequent medical follow-up is arranged for the patient.  
10. The patient’s exit from the study form is filled in.  
 

 
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Table 2 Calendar of events 
Period 
Screening 
Follow-up 
Study 
completion 
Visit 
1 
2 and 4 
3 
5 
Time 
 
 
 
Actions 
5 working 
days  
In 45 and 135 +/-
10 days after visit 
№ 1 
In 90 +/-10 days 
after visit № 1 
In 180 +/-10 days 
after visit № 1 
Informed consent 
X 
 
 
 
Co-morbidities and medical history, 
demographic data 
X 
 
 
 
Pregnancy urine test for female patients 
in childbearing age 
X 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
Setting the dates for subsequent visits 
X 
 
X 
 
Setting the dates for blood HbA1c tests 
X 
 
X 
 
Patient questionnaire 
X 
X 
X 
X 
Quality of Life questionnaire (EQ-5D) 
X 
 
 
X 
Patient examination for lipohypertrophy 
X 
 
X 
X 
Glycated hemoglobin (HbA1c) 
X 
 
X 
X 
Collect information on occurrences of 
hypoglycemia 
X 
X 
X 
X 
Patient education classes, video lessons 
scheduling, provision of needles  
X 
 
 
 
Control of video lessons’ viewing 
X 
X 
X 
X 
Exit from the study 
 
 
 
X 
Collection of adverse event information 
X 
X 
X 
 
7.6.Patient training of correct injection technique  
At the beginning of the trial, the physician interviews the patient in order to evaluate the 
existing injection technique. The gaps and downsides found are sorted out for each patient in 
terms of the correct injection technique practice, as set forth in the Russian Procedural 
Guidelines on injection techniques and infusions used in the treatment of diabetes mellitus [1] 
and in the international guidelines FITTER [5].  The physician-investigator recommends that 
patients view the video lessons which best suit their specific needs.  Video lessons highlight the 
following topics: 
1. How to deliver an injection with an insulin pen 
2. Insulin delivery to the right place/injection sites 
3. Using the right length of needles 
4. Injection site swelling or induration 
5. Injection site care 

 
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6. Insulin is absorbed differently by your body 
7. Injections, possible problems and their solutions, idiopathic hypoglycemia and 
blood glucose spikes.  
8. How to store insulin and safely dispose of injection devices       At study entry, patients 
receive a 3-month supply of BD Micro-Fine Plus 4 mm 32G injection pen needles, depending on 
the type of their injection therapy, in order to secure their single use, as well as access to on-line 
education. Moreover, patients receive an extra package of BD Micro-Fine Plus 4 mm 32G 
injection pen needles (100 items per package) to cover losses or other contingencies (Table 3).  
At visit No. 3 patients will receive another 3-month supply of BD Micro-Fine Plus 4 mm 32G 
injection pen needles. 
Table 3.  
Total 
number of 
injections 
per day 
Number of packages 
(3-month supply), 
given that each needle 
is used only once 
Number of packages 
to cover losses or 
other contingencies 
Total number of 
packages per  
patient 
1 
1 
1 
2 
2 
2 
1 
3 
3 
3 
1 
4 
4 
4 
1 
5 
5 
5 
1 
6 
6 
6 
1 
7 
 
Depending on patient’s condition, insulin TDD and other factors, the physician can 
recommend that the patient reduces insulin TDD after visit № 1.   
The physician must recommend to the patient not to change the insulin preparations (for 
intermediate- and long-acting insulins) and/or the insulin subgroup (for short- and ultra short-
acting insulins) throughout the period of the patient’s participation in the study. 
 
7.7.Patient safety 
      The trial will be carried out in accordance with Russian law, the regulatory requirements for 
quality clinical studies, and the WMA Declaration of Helsinki in so far as relevant to research 
ethics. Patients will be entitled to forego participation or pull out of the study for any reason and 
at any stage, which will not affect the quality or availability of their health care. 
       Participation in the study does not put patients at any significant risk, but encourages them to 
adopt the correct injection technique, including the avoidance of insulin injection in 
lipohypertrophic areas.  Patients who stop injecting insulin in lipohypertrophic areas and start to 
inject into healthy tissue often note the necessity to reduce insulin TDD (sometimes up to 20%) 
in order to avoid hypoglycemia. This information is made available to the investigators, who 
instruct patients accordingly. 
        Strict confidentiality is guaranteed for all patients. Patients are not paid for their 
participation in the study; however, during the study, the Sponsor provides the participants free 

 
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of charge with a sufficient supply of BD Micro-Fine Plus 4 mm 32G needles for pen injectors. 
Also, the Sponsor provides the participants free of charge blood glucose meters, with sufficient 
amount of strips and lancets. Blood glucose meters must be returned to the sites by the patients 
on the 6 months follow up (completion) visit.  
8. Monitoring plan 
Clinical monitoring of this clinical trial will be carried out by the Sponsor, the «Becton 
Dickinson and Company», Russia. Study monitoring will be conducted by a clinical monitor 
with an appropriate background and experience. The duties of the clinical monitor include the 
maintenance of regular contacts with every research center by phone and/or during personal 
visits to the research center to make sure that:   
• The study is carried out in accordance with the requirements of GOST R ISO 14155-
2014 [6]; 
• Study design is adhered to;  
• Complete, timely and accurate data are provided;  
• Problems with discordant or incomplete data are being solved;  
• Cases of complications and unforeseen undesirable effects are brought to the 
attention of the Sponsor and the research center ethics committee;  
• Technical abilities of the research center keep complying with the study 
requirements.  
       The clinical monitor will start the conduct of the study in the research center during the site 
initiation visit or in the course of the study activation visit, and continue the monitoring visits to 
the research center at the required frequency. The first monitoring visit can usually be made 
immediately after the start of a patient’s enrollment. At this visit and all other monitoring visits, 
the clinical monitor will compare data entered in the eCRF with that from the medical documents 
(primary documents) in the center. The primary documents include the medical card, the filled in 
laboratory analysis form, physician’s notes, the patient’s medical history, recorded data from 
automated instruments or any other documents prepared and supported by the 
investigator/medical staff or support services which contain records of patient monitoring and 
other data pertaining to the trial. For the purpose of confirming the correctness of the obtained 
informed consent, adherence to the protocol requirements, the adequacy of reporting adverse 
events (AE) and subsequent AE follow-up, and information about procedures, the primary 
documents must be available to the clinical monitor and kept at the research center. Data from 
the analysis of the eCRF and the primary documents will be discussed with the investigator 
during the monitoring visits. The dates of the monitoring visits will be entered in the registration 
book (Appendix A) kept at the research center. The Sponsor assumes that during the monitoring 
visits the principal investigator and investigator must be available for contacts, the primary 
documents must be available for  viewing, and the required site conditions provided for the 
assessment of documents pertaining to the trial. 
The research centers must get in touch with all patients, making every endeavor to make 
sure that they turn up for consequent follow up visits. The research centers must have log books 
with records of patient contact dates and the results of such contacts. After 3 unsuccessful 
attempts of contact (e.g., by phone or e-mail) to arrange a patient’s visit, the patient will be 
considered as lost to subsequent follow-up.   

 
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8.1. Electronic data capture and storage.  
Data management will be carried out by Becton, Dickinson and Company in the United 
States of America. Data will be collected electronically, and electronically entered records 
present on the website will be entered directly into the controlled database. Data safety is secured 
by password protection, restricted access, control books and regular data backup. Upon 
completion of the data investigation and verification, the data will be checked for accuracy and 
completeness, after which the database will be blocked to prevent any additional modification. A 
copy of the blocked database will be passed on to the BD Corporate Statistics Department (USA) 
for statistical analysis. 
Electronic data collection in the eCRF is based on the use of Oracle software, and is 
developed, supported and allocated by Becton, Dickinson and Company in the United States of 
America..  
 
8.2.Patient identification  
In order to rule out a prejudiced attitude and preconception, each patient will be assigned a 
participant identification code which is filled in the individual registration card (IRC) and study 
participant information sheet. The code consists of six digits, which designate the following:   
 - , the first three digits are the number of the research center, e.g. 001, 
002, 003 etc., which will be assigned in the course of a trial depending on the time of the study 
entry of each center, and the other three digits indicate the consecutive number of the study 
participant in a given center.  
 
9. Investigator’s range of responsibilities 
    All research centers will have to sign an agreement with the Sponsor. All principal 
investigators and investigators will undergo training in study protocol, data entry in the 
electronic database and the use of disposable BD Micro-Fine Plus: 32G (0.23 x 4 mm) needles 
for the pen injector.  
 
10. Statistical analysis 
     It is of the utmost importance that patients invited to participate in the study comprise a 
representative sample of Russian patients receiving insulin injections. For this reason, the 
chosen eligibility criteria are as comprehensive as possible.  
        
10.1. 
Projected sample size  
Based on data observed in internal studies with similar designs, assuming an HbA1c decrease of 
0.4% between baseline and 6 months and a standard deviation of paired differences of 1.2%, a 
sample size of 73 subjects would be needed to demonstrate statistical significance using a one 
sample t-test with a power of 80% and alpha equal to 0.05. 
 
10.2. 
Statistical analysis plan 
     For descriptive statistics and conclusive statistics,   R 3.4.4 or more recent version and 
Rstudio will be used. The HbA1c and insulin total daily dose will be analyzed using linear 
models with mixed effects (with transformation or without it, whenever necessary) where 

 
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lipohypertrophy will be a fixed effect. Analyses will be done overall and per lipohypertrophy 
sub-group (with or without LH) whenever the sub-group effect is significant.. Generalized linear 
models with mixed effects will include logistic models for binomial responses or Poisson models 
for count responses.  
Fixed effect models can be used when models with mixed effects cannot be employed. The 
effect of different covariates will be studied (including, but not limited to these), such as site, age, 
BMI, gender and diabetes type, as well as their interaction. The threshold to keep covariates in a 
model will be p <0.05. 
Non-parametric tests will be used if basic assumptions do not hold for the models. 
McNemar’s test will be used, when necessary, for contingency tables.  
Statistical methods will be detailed in a Statistical Analysis Plan. Additional analyses may be 
performed and will be defined in the Statistical Analysis Plan. 
 
11. Data management 
All documents containing personal information of the study participants must be stored at the 
trial conduct site.  
The data collected during the course of the study will be entered in the eCRF. The study 
participants will be identified by the study participant code which is generated by the eCRF. 
Patient confidentiality will be maintained throughout the study, including the publication of the 
study results. The principal investigator or sub-investigator will review and sign each form 
(eCRF, AE), the system will record the date when it was signed. The investigator’s signature is 
the confirmation that clinical and laboratory data entered in the form are complete, accurate and 
veracious.   
The data obtained and entered in the eCRF are the property of Becton, Dickinson and 
Company.    
The study data, copies of the study materials and the medical documents will be provided to 
the Ethics Committee of the research center, the authorized bodies for internal audit should it be 
conducted, and on the audit demand. All data obtained in the course of the study will be stored 
confidentially for at least 3 years after the end of this trial.  
 
12. Appendices to the clinical trial protocol 
In case of the introduction of amendments or additions to the protocol, an amended protocol 
of the clinical trial will be created, which will be assigned a new version number.  A list of 
introduced amendments and additions indicating their containing pages will be attached to the 
amended protocol. The protocol will be used in the study only after its approval by the Ethics 
Committee of the research center.  
 
13. Adverse events, unfavorable effects of the device and its disadvantages 
     In this study, the Sponsor does not anticipate the occurrence of adverse events, except for 
those listed in paragraph 5 of this protocol.  
All adverse events (defined below) are recorded, and serious adverse events (defined below) are 
reported to the principal investigator, the Ethics Committee and the Sponsor.  

 
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Adverse event (AE) is any unfavorable and involuntary event (including non-typical data of 
laboratory investigation), symptom or disease diagnosed in a subject and associated with his/her 
participation in the study. Such events imply the ones which were not seen at the baseline and/or 
deteriorated as compared with the baseline level. An undesirable event does not necessarily have 
to be causally related to the patient’s participation in the study.   
Serious adverse event (SAE) is an unfavorable event occurring in the course of study which 
leads to any of the following outcomes:  
a) a lethal outcome; 
b) a serious deterioration of the health of the subject, which, in turn, leads to either: 
1) disease or a life-threatening injury, or 
2) injury, or 
3) hospitalization or its extension, or 
4) medical or surgical intervention for the prevention of the life-threatening disease or 
injury; 
c) a fetal injury, fetal death or abnormalities or defects of fetal development. 
 
  All AE (related and unrelated to injections) which meet the criteria for SAE must be 
immediately reported to the Sponsor and LEC, followed by filling in forms provided by the 
Sponsor to give a full description of the course of the event, the treatment conducted, and the 
final outcome.  The first SAE reporting to the Sponsor must be carried out not later than two (2) 
working days after the Principal investigator has become aware of the event.  
 
     Unanticipated serious adverse device effect (USADE)s any serious undesirable and 
unanticipated effect on the state of health state or safety of the patient, or any life-threatening 
problem or death caused by or related to the injection needle if this event, problem or death has 
not been mentioned in the study design or in the application to conduct a research study 
(including additional plan or application) with an indication of its nature, severity or frequency 
of occurrence, or any other unforeseen serious problem related to the device and pertaining to the 
rights, safety or wellbeing of the patients.    
     Any USADE will be immediately reported to the Sponsor and LEC. That said, this report 
must be received by the Sponsor and LEC not later than two (2) working days from the moment 
when the Principal investigator has become aware of it.    
 
     In case of an occurrence of a SAE or USADE, the patient must contact the Principal 
investigator or investigator, whose contact phone numbers are given in the patient information 
leaflet.  
 
13.1. 
Adverse Event (AE) Management 
At each study contact, subjects will be questioned in an open-ended manner regarding 
any new or worsening undesirable signs or symptoms they may have experienced since 
the previous contact.  Elicited signs and symptoms must be comprehensively documented 
on the appropriate source documentation.  

 
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Each sign, symptom, disease or illness reported must be evaluated by the Investigator or 
designee to determine if it meets the definition of an Adverse Event.  
The clinical course of the event will be followed according to accepted standards of 
medical practice until the event resolves, stabilizes, or in the opinion of the Investigator, 
is no longer considered clinically significant.  The Investigator must supply the Sponsor 
with information concerning the follow up and/or resolution of the AE.  
Some reported or observed signs and symptoms are inherent to subcutaneous injection 
and are likely to occur transiently for nearly all subjects in this study.  Such signs or 
symptoms will not be considered AEs as long as they are mild (transient, easily tolerated, 
no interference with daily activities) and the Principal Investigator agrees. The following 
will not be not be considered AEs: 
• Mild, self-limited pain, swelling at the injection site 
• Mild bruising at the injection site 
• Mild self-limited bleeding at the injection site 
 
However, these signs and symptoms must be considered AEs and documented on the 
Adverse Event eCRF  should any of them occur in such a way that the extent or nature of 
the experience exceeds that normally associated with the procedure, as judged by the 
Subject to be excessive pain, bruising or bleeding. 
Some signs and symptoms are inherent to the conditions under study (i.e. diabetes) and 
are likely to occur transiently for nearly all subjects in this study. Episodes of 
hyperglycemia and hypoglycemia occurring after subject enrollment and exposure to 
study product and/or study procedures, should be reported based on the following criteria: 
• All blood glucose values <2.8 mmol/L (hypoglycemia) or >22.2 mmol/L 
(hyperglycemia) that require 3rd party (defined as, assistance of another person to 
administer carbohydrates or glucagon) or medical assistance for recovery will be 
recorded as an AE and assessed for seriousness. 
• Any self-identified hypoglycemia or hyperglycemia without a BG reading or with 
any BG reading that requires 3rd party or medical assistance for recovery will be 
recorded as an AE and assessed for seriousness. 
• All blood glucose values >22.2 mmol/L (and no symptoms of ketosis) will not be 
considered an AE. 
o 
Signs of ketosis are elevated BG along with nausea but individual has the 
ability to drink fluids and nausea is resolved with additional insulin and 
oral fluids, this may be considered an AE per the discretion of the PI or 
designee. 
All blood glucose values <2.8 mmol/L, or self-identified as hypoglycemia that resolves 
with standard carbohydrate administration will not be recorded as an AE unless otherwise 
determined by the Principal Investigator. However, these signs and symptoms must be 
considered AEs and documented on the Adverse Event eCRF  should any of them occur 
in such a way that the extent or nature of the experience exceeds that normally associated 
with the procedure, as judged by the PI, or the event meets the criteria for a Serious 
Adverse Event (SAE). 
 

 
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13.2. 
Assessment of Adverse Events (AEs) 
All AEs must be assessed for Seriousness, Severity, and Relationship. All AEs, 
regardless of classification, must be comprehensively documented in the eCRF and on 
the SAE form, if applicable, and reported to BD.  This includes AEs related to marketed 
study products. The following information about the event is to be reported on the AE 
eCRF: 
• Seriousness, classified as: Non-Serious or Serious 
• Severity,  classified as: 
o Mild: Transient symptoms, easily tolerated, no interference with daily 
activities 
o Moderate: Marked symptoms, moderate interference with daily activities, 
tolerable 
o Severe: Considerable interference with daily activities, intolerable 
• Relationship, to the study product or study procedures:  
o Not Related: Evidence suggests absolutely no possible causal relationship 
between the event and the investigational study device (or procedures). 
o Unlikely Related: Evidence suggests that other possible causes or 
contributing etiological factors may have caused the event other than the 
investigational study device (or procedures). 
o Possibly Related: Evidence suggests a causal relationship between the 
event and the investigational study device (or procedures) cannot be ruled 
out 
o Definitely Related: Evidence suggests a reasonable causal relationship 
between the event and the device (or procedures) is likely 
In addition, the following should be recorded for each AE: 
• Action(s) taken to remedy the AE, including change in study treatment or 
participation, or medical/surgical treatments 
• Duration of the AE from onset through resolution, as applicable 
• Cause (including suspected product/procedure and/or other cause) 
• Outcome of the event, including resolution and sequelae, as applicable 
 
13.3. 
Incidents 
A Clinical Study Incident is defined as any problem or issue involving the study device(s), 
reference methods, associated procedures or equipment, or represents a product-related 
injury (or potential for injury) to study subjects or personnel as a result of execution of 
this protocol.   Clinical Study Incidents may adversely (or potentially adversely) affect 
human safety, the integrity of the evaluation data, or the operation of devices or systems, 
and warrant prompt attention.  
Incidents involving injury to study subjects will also be reported as Adverse Events (as 
explained above).   Examples of Clinical Study Incidents that are not Adverse Events 
might be mislabeling or adulteration of the study device, device malfunctions, errors in 
the device instructions, damage to devices caused by shipping or handling or improper 

 
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storage, or injury to study personnel due to execution of the protocol.  If appropriate, an 
Incident may also be documented and reported as a protocol deviation.  
The Monitor should be contacted immediately when site becomes aware of or suspects 
any defective or malfunctioning product. This includes: 
• 
BD Micro-Fine Plus 4mm 32G pen needles that are involved in Study Incidents, 
• 
BD Micro-Fine Plus 4mm 32G pen needles that are found to be expired, damaged  
or defective, 
• 
BD Micro-Fine Plus 4mm 32G pen needles that are possibly the cause of an  
adverse effect, regardless of whether the product was believed to be damaged, 
defective or malfunctioning.  
The Study Monitor should be contacted with any questions regarding return of study 
products.  
 
14. Sensitive populations 
    According to GOST R ISO 14155-2014, a sensitive subject is an individual whose 
preparedness to participate in the clinical trial can be unduly affected by anticipation, 
reasonable or not, participation-related benefits or negative reaction of administration in case 
of his/her refusal to partake. In this study, only non-sensitive populations will be enrolled, and 
all procedures will be carried out under Compulsory Medical Insurance and subsidized 
pharmaceutical provision. Based on the definition of a sensitive subject,  research center staff    
and Sponsor employees cannot be enrolled in the trial as study subjects.  
 
15. CT suspension or premature termination 
The Sponsor can suspend or terminate the trial in case of substantial and documented reasons, 
including cases of occurrence of serious AE. The Sponsor can also stop participation in the trial 
of the research center or the investigator should any breach of, and deviation from the protocol 
on the part of the investigator be found. Disqualification of the investigator can be done if the 
following violations by the investigator have been revealed: 
-repeated and deliberate violation of the protocol, 
- repeated and deliberate communication of incorrect, incomplete and inaccurate information to 
the Sponsor (in eCRF, reports, etc.).  
     The principal investigator or Ethics Committee of the research center can suspend or 
terminate the participation of the center which they are responsible for. In order to suspend or 
terminate the study, the party initiating the suspension must notify, in writing, all parties about 
the decision taken (including the Sponsor, the investigator and the Ethics Committee of the 
research center) and provide substantiation of such a decision. When necessary, the investigator 
must notify patients, in writing, about study suspension or termination. Trial resumption may be 
possible only after approval by the Ethics Committee of the research center.   
 
16. Publication principles  
    We intend to publish the study results obtained at the premises of all the participating 

 
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research centers.  The publication media will be chosen by the Principal investigator jointly 
with the Sponsor.  
 
 
 
 

 
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References 
1. Majorov A.Yu., Melnikova O.G., Koteshkova О.М., Misnikova I.V., Chernikova N.A. 
The injection and infusion technique in the treatment of diabetes mellitus. Procedure 
manual, 64 pp. LLC “ART INFO” Publisher (in Russian), Moscow. 
2. Grassi G, Scuntero P, Trepiccioni R, Marubbi F, Strauss K. 
Optimizing insulin injection technique and its effect on blood glucose control. J Clin 
Transl Endocrinol. 2014 Jul 23;1(4):145-150.  
3. Blanco M, Hernández MT, Strauss KW, Amaya M.  Prevalence and risk factors of 
lipohypertrophy in insulin-injecting patients with diabetes.  Diabetes Metab. 2013 
Oct;39(5):445-53. 
4. Ji L, Li Q, Wei G.  Lipohypertrophy - prevalence, risk factors and clinical characteristics 
of insulin-requiring patients in China.  Submitted, J. Diabetes. 
5. Frid, Anders H. et al.  New Insulin Delivery Recommendations.  Mayo Clinic 
Proceedings , Volume 91 , Issue 9 , 1231 – 1255. 
http://www.mayoclinicproceedings.org/article/S0025-6196(16)30321-4/fulltext   
6. “GOST R ISO 14155-2014 Clinical investigations. Good Clinical Practice” (in Russian). 
 
 

 
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Appendix А: Accompanying regulatory documents 
«The role of proper insulin injection technique in the treatment of diabetes mellitus» 
 
Principal investigator: 
 
Name of research center:   
 
 
 
Research center number: 
ACCOUNTING FORM FOR RECORDING NEEDLE SUPPLY 
For disposable BD Micro-Fine Plus: 32G (0.23 x 4 mm) needles 
for injection pen 
 
PAGE _____ OF _____ 
 
Dates of needle receipt, 
number of packages, № 
and batch 
       Packages _____Batch №  ________ 
day   month        year      
      Packages _____Batch №  _________ 
day   month        year      
      Packages _____Batch №  _________ 
 day   month        year      
      Packages _____Batch №  _________ 
 day   month        year      
      Packages _____Batch №  _________ 
 day   month        year      
      Packages _____Batch №  _________ 
day   month        year      
Dates of return of unused 
needles, number of 
packages, № and batch 
      Packages _____Batch №  _________ 
 day   month        year      
      Packages _____Batch №  _________ 
 day   month        year      
      Packages _____Batch №  _________ 
 day   month        year      
      Packages _____Batch №  _________ 
day   month        year      
 
 
 
  
 
 
 
 
 
 
Investigator’s signature 
 
Date  
 

 
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«The role of proper insulin injection technique in the treatment of diabetes mellitus» 
 
Principal investigator: 
 
Name of research center:   
 
 
 
Research center number: 
ACCOUNTING FORM FOR RECORDING GLUCOMETERS, 
STRIPS and LANCETS SUPPLY 
 
 
PAGE _____ OF _____ 
 
Dates of glucometers 
receipt, number of 
packages, № and batch  
       Packages _____Batch №  ________ 
day   month        year      
      Packages _____Batch №  _________ 
day   month        year      
Dates of strips receipt, 
number of packages, № 
and batch 
      Packages _____Batch №  _________ 
 day   month        year      
      Packages _____Batch №  _________ 
 day   month        year      
Dates of lancets receipt, 
number of packages, № 
and batch 
      Packages _____Batch №  _________ 
 day   month        year      
      Packages _____Batch №  _________ 
day   month        year      
Dates of return of unused 
glucometers, number of 
packages, № and batch 
      Packages _____Batch №  _________ 
 day   month        year      
Dates of return of unused 
strips, number of packages, 
№ and batch 
      Packages _____Batch №  _________ 
 day   month        year      
Dates of return of unused 
lancets, number of 
packages, № and batch 
      Packages _____Batch №  _________ 
 day   month        year      
Dates of return of USED 
glucometers, number of 
packages, № and batch 
      Packages _____Batch №  _________ 
day   month        year      
 
 
  
 
 
 
 
 
Investigator’s signature 
 
Date  
 

 
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«The role of proper insulin injection technique in the treatment of diabetes mellitus» 
 
Principal investigator: 
 
Name of research center:   
 
 
 
Research center number: 
NEEDLE USE LOG BOOK 
For disposable BD Micro-Fine Plus: 32G (0.23 x 4 mm) 
needles for injection pen 
 
PAGE _____ OF _____ 
Patient code 
Number of packages of 100 items 
each 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigator’s signature  
 
Date  
 

 
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«The role of proper insulin injection technique in the treatment of diabetes mellitus» 
 
Principal investigator: 
 
Name of research center:   
 
 
 
Research center number: 
STRIPS USE LOG BOOK 
PAGE _____ OF _____ 
Patient code 
Number of packages of 100 items 
each 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigator’s signature  
 
Date  
 

 
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«The role of proper insulin injection technique in the treatment of diabetes mellitus» 
 
Principal investigator: 
 
Name of research center:   
 
 
 
Research center number: 
LANCETS USE LOG BOOK 
PAGE _____ OF _____ 
Patient code 
Number of packages of 100 items 
each 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigator’s signature  
 
Date  
 

 
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«The role of proper insulin injection technique in the treatment of diabetes mellitus» 
 
Principal investigator: 
 
Name of research center:   
 
 
 
Research center number: 
CT PATIENT ACCOUNTING LOG BOOK 
Page _____of ______ 
Patient’s 
initials 
Patient code 
Date of signing the informed consent (dd. mm. 
yy) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
________________________________________________ 
 
_________________________ 
Investigator’s signature  
 
 
 
             
  Date 
 
 
 
 

 
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«The role of proper insulin injection technique in the treatment of diabetes mellitus» 
 
Principal investigator: 
 
Name of research center:   
 
 
 
Research center number: 
 
RECORDS OF MONITOR SITE VISITS 
Page _____of _____ 
 
Date of 
visit 
dd/mm/yy 
 
Signature 
 
Purpose of visit 
 
Initials of center staff 
member 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigator’s signature 
Date 
    
 
 

 
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Appendix B: EQ-5D (English and Russian version) 
 
 
 

 
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