a randomized controlled trial comparing (fgms)...
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A RANDOMIZED CONTROLLED TRIAL COMPARING (FGMS) FLASH
GLUCOSE MONITORING SYSTEM + SMBG VS SMBG (SELF
MONITORING OF BLOOD GLUCOSE) ALONE FOR GLYCEMIC
CONTROL IN ADOLESCENTS OF 12- 18 YEARS OF AGE WITH TYPE 1
DIABETS MELLITUS
A DISSERTATION SUBMITTED IN PARTIAL FULFILLMENT OF THE REGULATION FOR THE
AWARD OF THE DEGREE OF MD PAEDIATRICS (BRANCH VII)
THE TAMIL NADU DR. MGR MEDICAL UNIVERSITY
CHENNAI, TAMIL NADU
MAY -2018
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CERTIFICATE
This is to certify that the dissertation titled “A RANDOMIZED CONTROLLED
TRIAL COMPARING (FGMS) FLASH GLUCOSE MONITORING
SYSTEM + SMBG VS SMBG (SELF MONITORING OF BLOOD
GLUCOSE) ALONE FOR GLYCEMIC CONTROL IN ADOLESCENTS OF
12- 18 YEARS OF AGE WITH TYPE 1 DIABETS MELLITUS” is the bona
fide work done by Dr. VINOD KUMAR.P. under my supervision in the
Department of Pediatrics, Christian Medical College and Hospital, Vellore, in
partial fulfilment of the requirements for the degree of MD Pediatrics of The Tamil
Nadu MGR Medical University, Chennai, to be held in April 2018.
Dr. Anna Simon MD, DCH, FRCP (Edin)
Professor and head,
Division of Child Health, Unit – 1,
Christian Medical College,
Vellore, Tamil Nadu,
India- 632004.
3
CERTIFICATE
This is to certify that the dissertation titled “A RANDOMIZED CONTROLLED
TRIAL COMPARING (FGMS) FLASH GLUCOSE MONITORING
SYSTEM + SMBG VS SMBG (SELF MONITORING OF BLOOD
GLUCOSE) ALONE FOR GLYCEMIC CONTROL IN ADOLESCENTS OF
12- 18 YEARS OF AGE WITH TYPE 1 DIABETS MELLITUS” is the bona
fide work done by Dr. VINOD KUMAR. P in the Department of Paediatrics,
Christian Medical College and Hospital, Vellore in partial fulfilment of the
requirements for the degree of MD Paediatrics Examination of The Tamil Nadu
MGR Medical University, Chennai, to be held in April 2018. This work was
carried out under the guidance of Dr. Anna Simon, Professor and head, Division of
Child Health, Unit-1, Christian Medical College, Vellore.
Dr. Indira Agarwal MD FISN
Professor and Head,
Department of Paediatrics,
Christian Medical College,
Vellore, Tamil Nadu,
India- 632004.
4
CERTIFICATE
This is to certify that the dissertation titled “A RANDOMIZED CONTROLLED
TRIAL COMPARING (FGMS) FLASH GLUCOSE MONITORING
SYSTEM + SMBG VS SMBG (SELF MONITORING OF BLOOD
GLUCOSE) ALONE FOR GLYCEMIC CONTROL IN ADOLESCENTS OF
12- 18 YEARS OF AGE WITH TYPE 1 DIABETS MELLITUS” is the bona
fide work done by Dr. VINOD KUMAR P. in the Department of Paediatrics,
Christian Medical College and Hospital, Vellore in partial fulfilment of the
requirements for the degree of MD Paediatrics Examination of The Tamil Nadu
MGR Medical University, Chennai , to be held in April 2018.
Dr. Anna B. Pulimood MD
Principal
Christian Medical College
Vellore, Tamil Nadu
India, 632004
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DECLARATION CERTIFICATE
This is to certify that the dissertation titled “A RANDOMIZED CONTROLLED
TRIAL COMPARING (FGMS) FLASH GLUCOSE MONITORING
SYSTEM + SMBG VS SMBG (SELF MONITORING OF BLOOD
GLUCOSE) ALONE FOR GLYCEMIC CONTROL IN ADOLESCENTS OF
12- 18 YEARS OF AGE WITH TYPE 1 DIABETS MELLITUS”, submitted in
partial fulfilment towards the MD Paediatrics examination of The Tamil Nadu Dr
MGR Medical University, Chennai to be held in April, 2018, comprises my
original work and due acknowledgements have been made in the text for all the
materials used.
Dr. VINOD KUMAR.P
PG Registrar, Department of Paediatrics,
Christian Medical College,
Vellore, 632004
India
6
7
CERTIFICATE -II
This is to certify that this dissertation work titled “A RANDOMIZED
CONTROLLED TRIAL COMPARING (FGMS) FLASH GLUCOSE
MONITORING SYSTEM + SMBG VS SMBG (SELF MONITORING OF
BLOOD GLUCOSE) ALONE FOR GLYCEMIC CONTROL IN
ADOLESCENTS OF 12- 18 YEARS OF AGE WITH TYPE 1 DIABETS
MELLITUS” by Dr Vinod Kumar. P with the registration number 201617458 for
the award of Degree of MD Paediatrics. I personally verified the urkund.com
website for the purpose of plagiarism Check. I found that the uploaded thesis file
contains from introduction to conclusion pages and result shows ONE percentage
of plagiarism in the dissertation.
Guide & Supervisor sign with Seal.
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ACKNOWLEDGEMENTS
I thank God Almighty for giving me the opportunity to do this study and giving me the
grace to complete it successfully.
In the selection of topic and preparation of this dissertation I am deeply indebted to my
guide Dr Anna Simon, professor and head, Division of Child Health, Unit- 1, who guided
me with grace and truth. She gave me suggestions for improvement and made alterations
in the presentation. Without her help, I would not have been able to complete this
assignment in time.
Dr Sophy Korula, Associate Professor, Child Health, Unit -1 who as co-investigator
brought valuable insights into the study.
I am grateful to the nursing staff of department of endocrinology for their
cooperation and help.
I am thankful to Mrs.Hepsy, Department of Biostatistics for her help and advice.
I thank my parents for this life and my in laws for their loving and sacrificial support in
taking care of my children.
I owe thanks to my wife Annie and children Liza and Jamy who bore the pain of my
absence yet showered me with their love.
I thank the children who were part of this study.
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TABLE OF CONTENTS
1. INTRODUCTION 11
2. AIMS AND OBJECTIVES 14
3. MATERIALS AND METHODS 16
4. LITERATURE REVIEW 25
5. RESULTS 49
6. DISCUSSION 76
7. CONCLUSION 89
8. LIMITATIONS 92
9 BIBLIOGRAPHY 95
10 ANNEXURES 101
10
INTRODUCTION
11
INTRODUCTION
Type 1 diabetes is a most common endocrine disorder of childhood. Strict glycemic
control was proven to improve the quality of life and prevent the long term complications.
Self monitoring of blood glucose by finger prick method is commonly practiced to
monitor blood sugars and glycemic control is assessed by HbA1c once in 3months.
However self monitoring of blood glucose can miss the glucose excursions that vary
according to activity and food intake. Continuous glucose monitoring in achieving the
better glycemic control is well established. However cost and need for finger pricks for
machine calibration is cumbersome. FGMS is a novel method of continuous glucose
monitoring which is cost effective and did not require finger pricks. We propose that
FGMS in addition to SMBG will improve the glycemic control compared to self
monitoring of blood glucose alone and will also help in better identifying the
hypoglycemic events which otherwise might go unnoticed with SMBG alone.
12
RESEARCH QUESTION
Comparing FGMS (Flash Glucose Monitoring System) + SMBG Vs SMBG (Self
Monitoring of Blood Glucose) alone for glycemic control in adolescents of 12-18years
age with Type 1 diabetes mellitus.
HYPOTHESIS
1) Flash glucose monitoring system offers continuous and frequent monitoring of
glucose once in 15minutes for 14days. Therefore it will allow the clinician for more
appropriate insulin dosing schedule and thereby help in reduction of HbA1c.
2) FGMS helps in improved detection of hypoglycemic episodes when compared to
self monitoring of blood glucose alone in children (12-18years) with type 1
diabetes mellitus.
13
AIMS & OBJECTIVES
14
AIMS AND OBJECTIVES
PRIMARY OUTCOMES
1) To compare the flash glucose monitoring system + self monitoring of blood glucose
with self monitoring of blood glucose alone in terms of glycemic control as assessed by
reduction in HbA1c in adolescents with type 1 diabetes.
2) To identify the hypoglycemic events not identified with self monitoring of blood
glucose alone.
SECONDARY OUTCOMES
1. To assess the correlation of FGMS interstitial glucose recordings with
glucometer capillary recordings.
2. To assess the feasibility and acceptability of FGMS
15
METHODOLOGY
16
MATERIALS AND METHODS
Setting
Paediatric endocrinology- division of Child Health Unit-I, Christian Medical
College, Vellore which is a tertiary care centre which caters to an average of 7000
children with endocrine and metabolic issues per year.
Study period: 1 year January 2017 till December 2017
Study design: Prospective, Open label randomized control study
Participants
Inclusion Criteria:
1) Adolescents of 12-18years age with type 1 diabetes for at least 1 year who are
registered in pediatric endocrinology department
2) Residing in and around Vellore.
3) Patients on basal bolus or split mix regimen insulin with 3-4 injections per day
and doing SMBG at least 3-4 times per day for 3 consecutive days once in every 2
weeks.
4) Hba1c >8% and <14%.
17
Exclusion Criteria:
1) Patients age less than 12 and more than 18years.
2) Patients residing far from Vellore.
3) New onset Type 1 diabetics for less than 1 year duration.
4) Patients with HbA1c <8% and >14%.
5) Patients on corticosteroid therapy or any other major systemic illness.
Sample size calculation
Sample size was calculated with 1:1 randomization ratio based on assumption of a
common SD of 1% and an absolute difference of 1% in HbA1c between study
groups. This can be detected with an alpha error of 0.05(two sided) and beta error
of 0.20. So by using the formula n=2 x {Z (1-α/2) + Z (1-β)}2
xσ2/d
2. Sample size of
15.68 participants in each in the intervention and control group was required. For
convenience 15 was chosen.
Randomization
Participants were randomized to intervention (FGMS + SMBG) or control (SMBG
alone) arms. Randomization was done by using computer generated random
number list.
18
Allocation concealment
Group allocation was concealed from the investigator and participants with opaque
sealed envelopes prepared by a third person from biostatistics department who was
not part of the design and analysis of study.
Blinding
Randomization and allocation was concealed from the subjects and the
investigator. Post allocation blinding was not possible because the study design
was open label randomized study.
Definition of hypoglycemia
Cut off for hypoglycemia in all subjects was taken as any value less than 70mg/dl.
However for FGMS recordings, this cut off was reduced to 60mg/dl allowing for
the difference of 10-15mg/dl between interstitial and blood glucose values.
Asymptomatic hypoglycemia is defined as blood glucose value less than 70mg/dl
presenting without symptoms of hypoglycemia. Symptomatic hypoglycemia is
defined as blood glucose value less than 70mg/dl associated with clinical
symptoms viz headache, palpitation, dizziness, sweating, abdominal pain and
mood changes. Severe hypoglycemia is defined as when the patient has altered
sensorium (coma or convulsions) with concomitant blood glucose value less than
70mg/dl.
19
Implementation
The primary investigator had distributed envelopes to the subjects after obtaining
consent. Subjects were asked to open the covers and were allotted to respective
groups. After the sealed cover was opened neither the primary investigator nor the
patient were blinded to further interventions.
As per the protocol followed in the endocrinology unit self monitoring of blood
glucose was done throughout the study period for all the participants in both
groups for 4 consecutive days at two weekly intervals. At the end of every 2 weeks
of home blood glucose monitoring, insulin adjustment and dietary recommendation
were done by the treating physician over phone or in person.
FGMS apparatus installation and monitoring
Flash glucose monitoring sensor was placed for 14 days for participants in
intervention (FGMS+SMBG) group at the beginning of the study period and at
end of 2nd
and 4th
month. The FGMS sensor was placed by the diabetes nurse
educator in the presence of the primary investigator. The participants were sent
home after giving all the necessary precautions about the sensor and advised to
continue the usual way of monitoring of blood glucose by finger pricks as
followed in the unit. Patients were encouraged to follow their regular lifestyle and
treatment during this monitoring period. Participants were not asked to come in
20
between 14days of sensor placement. Patients were given contact phone number
available 24 hours throughout the study period to ask and resolve queries about
FGMS maintenance at home. At the end of 14 days, the FGMS sensor was
collected from patients and the information from sensor was downloaded to the
computer using FGMS sensor reader. Insulin adjustments were done as per the
FGMS and SMBG readings. Patients were informed about the changes in insulin
adjustments at the time of sensor removal or over phone.
Hba1c was done at the beginning of the study and at end of 3rd
and 6th
month.
Control group
All other procedures were same except that control group was not placed
intermittent FGMS for glucose monitoring. Treatment modifications were solely
based on SMBG records.
Statistical methods
Statistical analysis was performed using SPSS statistical software. Categorical
variables were summarized using counts and percentages. Quantitative variables
were summarized using mean and standard deviation or median and IQR. Chi
square test was used to compare the proportions between the groups and two
sample t tests were used to compare means between the two groups. For all the
analysis, 5% level of significance was considered to be significant.
21
Ethical clearance & Funding
The institutional review board of Christian Medical College, Vellore had reviewed
and accepted the study design (See annexure).The study was registered with
clinical trials registry of India with registration number CTRI/2017/05/008628.
Funds for procuring FGMS sensors were released from the Office of Research,
Institutional Review Board, Christian Medical College, Vellore. Study was
monitored by data safety monitoring board and an interim report was presented to
DSMB.
22
LITERATURE REVIEW
23
LITERATURE REVIEW
EPIDEMIOLOGY OF TYPE 1 DIABETES MELLITUS
Type 1 diabetes mellitus is one of the commonest metabolic and endocrine
disorders of childhood. Earlier, because of poor socio-economic status of the
communities’ infectious diseases like viral infections, pneumonia, diarrhea, and
nutritional deficiencies resulted in significant childhood morbidity and mortality.
In the present postmodern era these communicable diseases are replaced by non-
communicable diseases like diabetes, overweight and obesity. (1–3)
Type 1diabetes is often diagnosed in children and adolescents. Unlike type 2
diabetes which can be managed primarily with oral hypoglycemic agents T1DM
requires lifelong requirement of exogenous insulin. The incidence of childhood
T1DM is rising all over the world, with reported increases of 2 to 5% per year in
Europe, the Middle East, and Australia.(4–7) T1DM is on a rising trend in
Finland, India, Sweden, Colorado and Germany. There has been an increase in
incidence of almost 10/100,000 children to 60/100,000 children in Finland in the
last five decades. Around 78,000 children under the age of 15 years are estimated
to develop T1DM yearly worldwide. Of the existing 49lakh children living with
T1DM, 24% are from European region and 23% from the South‑East Asian
region. In South‑East Asia India have most of the children with T1DM. According
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to 6th edition of the IDF diabetes atlas, India has 3 new cases of T1DM/1lakh
children of 0–14 years.(8) The prevalence of diabetes in India as a whole is not
available, data available from hospital based studies showed variable prevalence.
Three studies from metropolitan cities of India showed, 3.2 cases/100,000 children
in Chennai, 17.93 cases/100,000 children in Karnataka and 10.2 cases/100,000
children in Karnal (Haryana).(9–11)
DEFINITION AND TYPES OF DIABETES
As per American diabetic association criteria 2011 diabetes is diagnosed when
fasting plasma glucose is more than 126mg/dl (or) HbA1c >6.5% (or) in a patient
with symptoms of hyperglycemia , a random plasma glucose >200 mg/dl.(12)
T1DM is the most common cause of diabetes in childhood and adolescence. Other
types include Type 2 diabetes and monogenic forms. T1DM often presents with
poydipsia, polyuria and weight loss. It is characterized by the lifelong dependence
on exogenous insulin.(13)
COMPLICATIONS
Chronic hyperglycemia results in multiple complications which includes
microvascular complications (Neuropathy, nephropathy and retinopathy) &
macrovascular complications (cerebrovascular disease, peripheral vascular disease
and coronary artery disease).(14,15) Impaired performance of mathematical tasks
can also occur during periods of hyperglycemia(16)
25
Other serious and potentially life threatening complication of diabetes is
hypoglycemia. Hypoglycemia is often a result of intensive insulin therapy.
Children and their caretakers may not be able to identify low blood glucose levels
solely based on symptoms. Gonder et al compared glucometer results with self-
reporting of hypoglycemia. They found >50% of parents and >40% of children
failed to recognize hypoglycemic events.(17) Hence, regular and frequent blood
glucose monitoring is necessary to prevent hypoglycemic episodes and to optimize
glycemic control. In children with T1DM, blood glucose level <70 mg/dl is used as
a threshold for identifying and initiating intervention for hypoglycemia. (18,19) A
lower level <65 mg/dl defined as hypoglycemia. Normal physiologic responses to
hypoglycemia include release glucagon, growth hormone, epinephrine and cortisol
which are counter regulatory hormones. Counter regulatory hormone response
often becomes blunted over time in individuals with T1DM. In these individuals
glucagon response is impaired and the epinephrine rise decreased. This blunting of
responses increases the risk of hypoglycemia.30% of children and adolescents have
impaired epinephrine response in whom diabetes is well controlled.(20)
“Hypoglycemic unawareness” is a state defined by a lack of alarming symptoms of
hypoglycemia because of blunting of counter regulatory hormone response.
Hypoglycemic unawareness is commonly seen in children &adolescents with long
duration of diabetes. This increases the risk of recurrent and severe hypoglycemia.
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Any event of hypoglycemia can further lower the glucose threshold at which
counter regulatory hormone discharge and symptoms occur, increasing the risk for
further severe hypoglycemia. Hypoglycemia when prevented for few weeks can
lead to restoration of hypoglycemia awareness. Night time hypoglycemia is
common to occur in children. The incidence of nocturnal hypoglycemia in children
at any given night is up to 47 percent. (21,22)
Symptoms of hypoglycemia can be non specific which include behavioral changes
nightmares, disturbed sleep, headache and confusion. Blunted counter regulatory
hormone response to hypoglycemia can result in nocturnal hypoglycemia.(23)
MANAGEMENT
Successful management of T1DM in children and adolescents includes maintaining
a balance of strict glycemic control, which minimizes the risk of chronic
hyperglycemic complications, avoid severe hypoglycemia which can happen with
strict glycemic control, to achieve the recommended goals of glycemic control and
to identify & treat hypoglycemia by educating the patient and care takers to
provide necessary care and to maintain normal growth, and emotional
development, and self-care of diabetes as the adolescent enters into adulthood.(24–
26) American Diabetes Association (ADA) set higher targets in the past for
HbA1C for young children as compared with adolescents and adults. This is of the
concern that strict glycemic control can increase the risk for hypoglycemic
27
episodes. (27) However, ADA and ISPAD in 2014 stated that it is possible to
improve glycemic control by stringent HbA1C targets without much increase in the
risk for severe hypoglycemia. For this reason ADA and ISPAD currently
recommend HbA1C of <7.5 percent for all children. Pre meal level of 90-130mg/dl
and overnight glucose level of 90-150mg/dl are to be maintained to achieve
recommended target of HbA1c <7.5%.(24)
Self monitoring of blood glucose
Daily blood glucose levels are used to monitor glycemic control and adjust insulin
accordingly. Irrespective of age group of the patient, the goal of management in
diabetes is to maintain glucose control as near to normal as possible so as to
balance the risks of long-term complications of hyperglycemia and hypoglycemia.
The lower the HbA1c value, the lower the risk for development of long term
hyperglycemic complications. However, the risk of hypoglycemia is more.
Diabetes is a chronic disease state which requires regular and frequent monitoring
of sugars and insulin adjustment. Regular and frequent monitoring of blood sugars
not only improves glycemic control in children but also decrease the frequency of
serious hypoglycemic events(28–30). Hence self monitoring of blood glucose
monitoring daily is very much needed for management and decreasing the
complications. As per American diabetes association and International society for
pediatric and adolescent diabetes consensus guidelines (ISPAD) self monitoring of
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blood glucose should be done a minimum of four times a day (Early morning
fasting, pre lunch, pre dinner and at bedtime). More frequent monitoring is
recommended during times of increased physical activity and sick days.(21,22)For
self monitoring the most widely used investigation to evaluate long-term glycemic
control is blood glycosylated hemoglobin (Hemoglobin A1C). Newly formed red
blood cells are released into circulation with minimal glucose attached to them. As
red blood cells are permeable to glucose, glucose continues to get attached to
hemoglobin depending on the availability in the blood. Temporary elevation in
glucose in blood forms large amounts of aldamines. This reaction is reversible
because when the glucose concentration of body falls. Another reaction by which
glucose gets attached to hemoglobin leads to formation of ketoamines. Formation
of ketoamines is an irreversible reaction unless the protein to which glucose
attached is metabolized. Majority of commercially available HbA1c assays test for
ketoamines and not aldamines. Hence it reflects long term glycemic control and
mostly unaltered by acute fluctuations in sugar levels.(33,34)
Three useful ways for defining glycemic control includes, firstly estimation of
mean of different values obtained by measuring blood sugars 6 times a day. The
simpler way of doing this is measurement of HbA1c. Second way is to measure
mean daily differences which estimates fluctuation of glucose concentrations day
29
to day. Thirdly measurement of mean amplitude of glycemic excursions to
estimate glucose fluctuations occurs within a day. (35,36)
Estimation of mean blood glucose received much importance in clinical trials.
However at a given mean blood glucose value there may be day to day and within
a day fluctuations. The limitation of Hba1c is that it cannot give any information
about day to day and within a fluctuation in glucose levels. Though frequent self
monitoring of blood glucose monitoring is recommended very few perform it that
frequently.
Continuous glucose monitoring (CGMS)
A new landmark in glucose monitoring called CGMS received FDA approval in
1999. In children who are at increased risk of hypoglycemia and in individuals on
intensive therapy who have multiple snacks and meals in a day and require glucose
measurements before administration of insulin needs frequent monitoring of blood
glucose values. Monitoring at expected peaks of insulin action and during times of
exercise is needed to safeguard against hypoglycemia. In case of nocturnal
hypoglycemia there is no other way to identify a low sugar value except to check
glucose by finger prick. Solely depending on finger prick method for estimation of
hyper and hypoglycemic episodes puts enormous emotional, financial stress upon
families. In addition either home monitoring of blood glucose or Hba1c cannot
30
correctly identify day to day or within a day glucose fluctuations. Intermittent
glucose monitoring by finger prick method of blood glucose provides only limited
information about glycemic profile and often misses asymptomatic hypoglycemia
and overnight glycemic excursions. These limitations led to the development of
continuous blood glucose monitoring (CGM) systems. In a motivated patient and
also patients with hypoglycemic unawareness continuous glucose monitoring
system was found useful to optimize glycemic control. (24)
In a retrospective study Frederico et al studied CGMS utility, accuracy and
complications in children and adolescents with T1DM. They found CGMS is a safe
and well tolerated by all the study participants. CGMS measurements were also
found to be accurate and procedure had low complications.(37) Invasive and
noninvasive CGMS are available for clinical use. Non invasive CGMS uses a
technology of measuring the blood glucose without breaching skin barrier. Non
invasive CGMS is worn like a wrist watch which extracts glucose by reverse
ionotophoresis.(38)
Invasive CGMS measures interstitial blood glucose via an indwelling sensor
placed in subcutaneous tissue. CGMS machine needs calibration by at least three to
four finger stick glucose values every day. Real time CGMS are also available
commercially which provide a continuous information about glucose levels, these
can be accessed by patients so as to make a change in meal and insulin dosage.
31
Real time CGMS are also available with alarms to indicate hyper and
hypoglycemic events.(39,40)
Many systematic reviews and metanalysis published till date proved that real time
CGMS with good compliance improves glycemic control by reduction of HbA1c
and helps in identifying hypoglycemic events when compared to self monitoring of
blood glucose alone.
In a systematic review and metanalysis, Golicki et al studied the effectiveness of
CGMS compared to self monitoring of blood glucose on glycemic control in type 1
diabetic children. This study included 5 randomized controlled trials involving 131
children with type 1 diabetes. Data from these studies showed no significant
reduction in HbA1c in CGMS group as compared to SMBG group. They
concluded that CGMS is not superior to SMBG in glycemic control among
Children with type 1 diabetes. (41)
Gunjan Y Gandhi et al conducted a systematic review and meta-analysis to assess
the efficacy of CGMS in improving glycemic control and hypoglycemia reduction
compared to self monitoring of blood glucose. 19 randomized controlled trials
were included in the study. CGMS has resulted in significant reduction in mean
Hba1c reduction in adults with both type 1 and type diabetes [WMD – 0.50%(95%
CI -0.69 to -0.30) and -0.70 (95% CI, -1.14 to -0.27) respectively]. In children and
adolescents there was no significant effect observed. The study concluded that
32
CGMS helps in improving the glycemic control in type 1 and type 2 diabetic
adults, however the effect of CGMS on identification of hypoglycemia is
unclear.(42)
The usefulness of real time continuous glucose monitoring system compared to self
monitoring of blood glucose on glycemic control in patients with type1 diabetes
was studied by A.szypowskai et al in a systematic review and metanalysis.7
randomized controlled studies involving 948 subjects were included in the study.
This study showed that reduction in HbA1c in subjects using RT-CGM compared
with SMBG (MD –0.25; 95% CI: – 0.34 to – 0.17; p<0.001). Subjects used Real
time CGMS with insulin pump had lower HbA1c levels when compared with
subjects on insulin pump and self monitoring of blood glucose. RCTs, n=497; MD
– 0.26; 95% CI: – 0.43 to – 0.10; p=0.002). Real time continuous glucose
monitoring was not associated with a heightened rate of major hypoglycemic
episodes. Subjects who used CGMS for more than 60-70 percent of time had
significantly lowered HbA1c levels.(43)
Nalinee Poolsup et al conducted a systematic review and metanalysis to study the
effects of continuous glucose monitoring system on glycemic control in Type 1
diabetic children and Type 2 diabetic adults compared to self monitoring of blood
glucose. 10 RCTs involving 817 children with type 1diabetes, 5 RCTs involving
161 adults with type 2 diabetes was studied. They found, in children with type 1
33
diabetes, CGMS use was not superior to SMBG in HbA1c reduction [mean
difference – 0.13% (95% CI -0.38% to 0.11%,].Within group analysis showed that
retrospective CGMS was not beneficial than SMBG [mean difference -0.05%
(95% CI -0.46% to 0.35%)]. However real-time CGMS resulted in reduction of
HbA1c level when compared with SMBG [mean difference -0.18% (95% CI -
0.35% to -0.02%, p = 0.02)]. In adults with type 2 diabetes, significant lowering of
HbA1c level was noticed with CGMS as against self monitoring of blood glucose
[mean difference – 0.31% (95% CI -0.6% to -0.02%, p = 0.04)]. They concluded
that real-time CGMS will be more effective than SMBG in children with type
1diabtes, but not retrospective CGMS. In adults with type 2 diabetes CGMS results
in better glycemic control compared to SMBG.(44)
Another systematic review and metanalysis by VT Chetty et al studied effect of
CGMS and SMBG on HbA1c levels in patients with type 1 diabetes. 7 randomized
controlled trials were included involving 335 patients with type 1 diabetes. This
study found CGMS resulted in reduction of HbA1c, however the difference was
not statistically significant (0.22%, 95% CI -0.439 to 0.004). In pediatric patients
they observed a significant decrease in HbA1c associated with continuous glucose
monitoring system (0.37% (95% CI -0.71 to -0.02). With respect to nocturnal
hypoglycemia, patients on CGMS showed reduced number of such episodes.(45)
34
Cochrane data base of systematic reviews by Miranda Langendam et al, studied 22
randomized control trials published till June 2011. They found that the patients on
CGMS compared to SMBG had reduction in HbA1c after 6 months period. Mean
difference in HbA1c level was -0.7%, 95% (CI) -0.8% to -0.5%, 2 RCTs, 562
patients, I2=84%). Most improvement in glycemic control was seen in patients on
sensor-augmented insulin pump therapy. The severe hypoglycemia risk was not
increased significantly in CGMS patients. This study also found that higher
compliance of wearing the CGMS results in reduction of HbA1c. (46)
35
Table 1 Systematic reviews and metanalysis done on continuous glucose monitoring system in Type 1 and Type 2 diabetics
AUTHOR STUDY
TYPE
DATA BASE TIME
PERIOD
No
Of
RCT
Study
population
Age
group
Study question Conclusion Limitation
D. T.
Golicki
Systematic
review and
metanalysis
MEDLINE
EMBASE
CENTRAL
1966-2007 5 Type 1 DM Children CGMS Vs SMBG on
glycemic
Control
CGMS is not superior
to SMBG for glycemic
control
Small number of study
population, methodological
limitations of studies involved.
V T
Chetty
Systematic
review and
metanalysis
MEDLINE
EMBASE
CENTRAL
1996 to
March
2007
7 Type 1 DM Children
Adults
CGMS Vs SMBG on Hba1c
levels CGMS might be
beneficial in children,
It Improves detection
of night time
hypoglycemia
Small number of trials
Gunjan Y Systematic
review and
metanalysis
MEDLINE
EMBASE
CENTRAL
Web Ofscience
SCOPUS
1996-2010 19 Type1 DM
Type 2 DM
Children
Adults
CGMS vs. SMBG in
improving glycemic control
and reducing hypoglycemia
CGMS improves
glycemic control in
adults with T1DM and
T2DM.The effect on
hypoglycemia
incidence is unclear
Heterogeneous documentation
of hypoglycemia
Small number of studies
ASzypow
ska
Systematic
review and
metanalysis
MEDLINE
EMBASE
CENTRAL
1996-2011 7 Type 1 DM Children
Adults
RT CGM Vs SMBG in type
1 DM
RT CGM is more
beneficial in Hba1c
reduction
Heterogenous documentation
of hypoglycemia
Small number of studies
Nalinee
Poolsup
Systematic
review and
metanalysis
MEDLINE
SCOPUS
CINAHL
CENTRAL
Web ofScience
Till may
2013
7 Type 1 DM Children
Adults
Effects of CGMS in Type1
DM pediatrics, Type 2 DM
adults
RT CGM is more
effective than SMBG
in pediatric population
Small number of studies
Miranda
Langenda
m1a
Cochrane
data base of
systematic
reviews
MEDLINE
CINAHL
CENTRAL
EMBASE
Till June
2011
22 Type 1 DM Children
Adults
Effects of CGM compared
to (SMBG) in patients with
Type 1 DM.
Higher compliance of
wearing the CGM
device improves
Hba1c
Limited details on quality of
life assessment
36
Challenges with adolescents
Adolescence is a unique period where an individual journey from semi dependency
to fully independent adult. Physical and physiological changes of adolescence pose
significant challenge for the management of T1DM. As diabetes is a chronic
condition it places great deal of demands on psychology of adolescent. Minimal or
no intervention by care takers results in poor glycemic control if sole responsibility
of diabetes management is on adolescent. Responsibility shared among care takers
and adolescents result in a better glycemic control. (24,31) Apart from the
management issues other factors that influence glycemic control are risk taking
attitude ( Alcohol, substance abuse), behavioral and eating disorders which can
happen during transition from adolescence to adult.
Limitations of SMBG and CGMS
Though self monitoring of blood glucose by finger prick method is widely
practiced the main disadvantages in using them is the cost of the glucometer and
reagent strips. Commercially available strip cost ranges from Rs 15 to 35 per strip.
If an individual has to do 4-6 readings per day then the cost would be ranging from
Rs90-210 per day which is a major financial burden on families. The other limiting
factor of finger prick method is pain. Pain caused by finger pricks is underrated
and overlooked. There is paucity of literature regarding self monitoring of blood
glucose and pain. Development of thin and sharp lancets has considerably reduced
37
the pain of the procedure but not completely eliminated it. (47) In a child with
difficult to treat diabetes with night time hypoglycemia monitoring of blood sugars
in the night would not only cause stress and sleep disturbance for child or
adolescent but also to the care takers. Apart from these there is a chance of
infection secondary to use of strips from multi use vials with highly virulent
organisms. Chance of infection is less with strips from individually packed
vials.(48)
To overcome the limitations of self monitoring of blood glucose novel continuous
glucose monitoring system is developed. CGMS also needs a minimum of 4 finger
prick glucose recordings for calibration of the machine. Another major limiting
factor for use of CGMS is high cost. CGMS sensor, monitor and battery together
cost around $ 2000.
Flash glucose monitoring system (FGMS)
When initially introduced in the year 2013 free style libre pro flash glucose
monitoring system by Abbott’s is a glucose-monitoring device indicated for
detecting trends and tracking glucose patterns in diabetics who are aged above 18
years. In the year 2016 Abbott received CE Mark approval for use of the system
in children aged above four years. (49)
38
Alike continuous glucose monitoring system, flash glucose monitoring system
collects glucose data continuously from interstitial fluid. Glucose data thus
collected is generated as an advanced software report called the ambulatory
glucose profile (Fig 1&2). The FGMS sensor is placed over the back of the
patient's arm and an adhesive applied over it. Sensor is left in place for up to 14
days. Sensor measures glucose from interstitial fluid every 15 minutes through a
small filament that is inserted in subcutaneous tissue. Patients activities like
outdoor games, bathing and swimming are unhindered by the presence of devise.
After 14days, the sensor is removed and data from the sensor is scanned by
practice-owned reader, thereby downloading the glucose data and generating a
report.
Unlike CGMS sensor, Flash Glucose Monitoring system will be calibrated at the
factory, which means users need not to enter any glucose values by fingerstick for
sensor calibration. This is a major difference between CGMS and FGMS in that
CGMS needs four fingerstick glucose values a day for sensor calibration. Other
difference is FGMS device will not have alarms, reason being data is not
continuously sent to the reader device. To avail the data from the sensor the user
has to scan the reader over the sensor patch to obtain real-time glucose data. The
flash glucose monitoring system is designed as an improvement over traditional
blood glucose monitoring.
39
Figure: 1. How the FGMS system works
Figure: 2. Ambulatory glucose profile obtained from FGMS sensor (Sample)
40
It also overcomes some of the limitations of continuous glucose monitoring system
viz need for calibration and cost. The Flash glucose monitoring system can be
particularly valuable for children, who experience the pain of fingersticks more
than adults. (50)
(Direcnet) Diabetes research in children network study group studied the accuracy
of FGMS with home glucose recordings from venous blood samples. It concluded
that FGMS achieved high percentage of accuracy when compared with laboratory
reference over wider range of concentrations of glucose in T1DM children.(51)
FGMS sensor measures blood glucose from interstitial fluid. Interstitial fluid is a
reasonable alternative for blood. Glucose can be measured in the interstitial fluid
where freely diffusion of glucose occurs from capillaries into interstitial space.
Rebrin et al studied the feasibility of replacing interstitial fluid as a replacement for
plasma blood glucose and concluded that glucose differences between interstitial
fluid and plasma are not significant.(52)
In Italy a study performed by Corradinin et al studied clinical and analytical
accuracy of FGMS in dogs with diabetes and found flash glucose monitoring
system was 93, 99, and 99% precise at low, normal, and high concentrations of
blood glucose. (53)
41
So far many studies were conducted in adults with diabetes demonstrating the
utility feasibility and accuracy of flash glucose monitoring system. But similar
studies in children were sparse. One reason for this was till year 2016 FGMS was
not licensed for use in children.(54–56)
Arndis et al studied the accuracy and treatment experience of the FGMS in Fifty-
eight adults with type 1 diabetes mellitus. All these patients did 6times of home
blood glucose monitoring simultaneously with along FGMS. Mean absolute
relative difference calculated was 13.6% (95% CI 12.1%–15.4%) in 1st week and
12.7% (95% CI 11.5%–13.9%) in 2nd
week. The mean absolute difference was
19.8mg/dl (95% CI 17.8–21.8 mg/dl).Correlation coefficient was 0.96. For sugar
values <72, 72–180, and >180mg/dl, the mean absolute relative difference was
20.3% (95% CI17.7%–23.1%), 14.7% (95% CI 13.4%–16%), and 9.6% (95% CI
8.5%–10.8%). Mean absolute difference values were 12.3, 17.8, and 23.6 mg/dl.
They concluded that flash glucose monitoring system had similar overall MARD
when compared to other CGMS when studied in same at home conditions.(54)
Larry A. Distiller et all studied characterization of glycemic control by using
ambulatory glucose profile (AGP) with flash glucose monitoring system. Amongst
50 adult patients with type 1 and Type 2 diabetes included in the study they found
similar HbA1c values among both groups (8.4 ± 2 Vs 8.6 ± 1.7%) however
patients with type 2 diabetes had low mean glucose levels (166 ± 54 Vs 185
42
mg/dl]) and reduced indices of glucose fluctuations (54 ± 27 vs 90 ± 34.2 mg/dl]).
This study concluded that without much input from either provider or patient much
data was obtained from AGP regarding glucose exposure, fluctuations, and
information regarding incidence and risk of hypoglycemia.(57)
Maya Ish-Shalom et al conducted a study in 31 adults with type 1 and type 2
diabetes with difficult to control diabetes who were treated with multiple daily
insulin injections with an HbA1C ≥7.5% .They studied the beneficial effects of
FGMS in achieving desired target glucose levels and minimizing episodes of
hypoglycemia. FGMS resulted in major improvement in glycemic control in both
type 1 and type 2 diabetic patients. HbA1C was reduced 1.33 ± 0.29% at 8 weeks
(mean ± SE respectively, P < .0001) and then plateaued. But those patients who
continued to use device (n = 27), the change in HbA1c was maintained for 24
weeks,–1.21 ± 0.42% (P =.009) .No events of major hypoglycemia was noticed. At
the end of 3-6 months of follow-up all patients (n = 31) were greatly satisfied and
reported that they would like to use FGMS in future. All the patients reported that
use of FGMS was easy and painless.(58)
An open label randomized controlled study by Thomas Haak et al studied FGMS
as a replacement for SMBG in adults with type 2 diabetes mellitus on intensive
insulin therapy. Intervention group only used FGMS for glucose monitoring where
as control group used self monitoring of blood glucose for the same for initial 6
43
months. Next 6 months period was open access phase. At end of open-access
period (12months), time spent in hypoglycemia [sensor glucose 70 mg/dl] was
reduced by 50% compared to baseline [-0.70 ± 1.85/24 h (mean ± SD); p =
0.0002]. Night time hypoglycemia [2300 to 0600 hours, (70 mg/dl)] was reduced
by 52%; p = 0.0002. SMBG testing fell from a mean of 3.9 times/day at baseline to
0.2, with an average frequency of sensor scanning of 7.1 times/day at 12 month.. 9
patients reported 16 events of sensor-related adverse events and 28 patients
experienced 134 events of erythema, itching and rash. This study concluded that
use of FGMS in patients with type 2 DM on intensive insulin therapy over 1 year
period resulted in sustained reduction in hypoglycemic events and replaced
conventional SMBG effectively and safely(56).
44
Table 2 - Studies previously done on FLASH GLUCOSE MONITORING SYSTEM in adults with Type 1 and Type 2 diabetes
First author,
year
Study
Group
Sample
size
Type of
study
Aim of study Results Conclusion
Arndı´s F. et
al 2017
Adults with
Type 1 DM
58 Clinical
experience
study
To evaluate the
accuracy and
treatment experience
FGMS
MARD was 13.6% (95% CI 12.1%–
15.4%) during week 1 and
12.7% (95% CI 11.5%–13.9%)
during week 2.
overall correlation coefficient was
0.96
FGMS had similar MARD as CGMS in
earlier studies( Studies done at home
conditions)
Larry A.
Distiller et al
2016
Adults with
Type 1 & Type 2
DM
50 Clinical
experience
study
Glycemic Control
with Ambulatory
Glucose Profile by
FGMS
Type 2 DM pts had lower mean
glucose levels (9.2 ± 3 vs 10.3 mmol/l
[166 ± 54 vs 185 mg/dl]) & low
glucose variability (3.0 ± 1.5 vs 5.0 ±
1.9 mmol/l [54 ± 27 vs 90 ± 34.2
mg/dl])
With in short period AGP provides
information regarding glucose exposure,
variability, & risk of hypoglycemia risk and
incidence with minimal patient input.
Maya Ish-
Shalom et al
2016
Adults, Type 2
DM
31 Clinical
experience
study
Reduction in HbA1c
in Difficult-to-
Control -Diabetes
Using FGMS
HbA1C reduced by −1.33 ± 0.29% at
8 weeks (mean ± SE respectively, P <
.0001) & plateaued thereafter.
Continued use of device change in
Hba1c was maintained for 24 weeks,–
1.21 ± 0.42% (P =
.009)
FGMS use greatly
improved glucose control in difficult-
to-control diabetes
Thomas Haak et al 2017
Adults, Type 2
DM
139 Open
labeled RCT
Impact of FGMS
as a replacement for
SMBG
After 12 months , time in
hypoglycemia [sensor glucose (70
mg/dl)] was reduced by 50%
compared to baseline [-0.70 ± 1.85/24
h (mean ± standard
deviation); p = 0.0002]
FGMS use was associated
with reduction in hypoglycemia and
safely and effectively replaced SMBG
45
Identification of night time hypoglycemia is more convenient with FGMS than
with self monitoring of blood glucose. Jan Bolinder et al studied the effect of
FGMS on reduction of time spent in hypoglycemia in adults with well controlled
diabetes. They found mean time of hypoglycemia changed from 3.38 hours at the
beginning of study to 2.03 hours after 6 months of study period when compared to
3.44 hours to 3.27 hours in control group. They concluded that glucose monitoring
by FGMS reduced the time spent in hypoglycemia in adults with type 1 diabetes
mellitus.(59)
Another study by Al Agha et al studied the effect of flash glucose monitoring
system in children and adolescents with T1DM during Ramadan fasting. They
found patients were able to maintain fast for 67.0% of the total days meant for
fasting. They concluded that the risk of serious complications of severe
hypoglycemia during Ramadan fast could be avoided in T1dm children and
adolescents with the use of FGMS. (60)
Julie Edge et al conducted a prospective single arm study to assess the accuracy,
safety and acceptability of the FGMS in the pediatric age group. 89 participants
between 4-17 years of age with type 1 diabetes were included in the study. Glucose
recordings from the sensor were compared with self monitoring of blood glucose
recordings. Participants were blinded to glucose recordings from sensor. All the
study participants were followed up for 2 times after sensor placement. Overall
46
mean absolute relative difference was found to be13.9%. Accuracy of the sensor
was unaffected by body weight, age, gender, method of insulin administration and
time of insulin use. All the study participants were found to be in target glucose
range for 50% of the time (mean 12.1 hours/day). Average duration of
hypoglycemia and hyperglycemia was 2.2 hours/day and 9.5 hours/day
respectively. Application of sensor and use of devise was rated favorable by both
caregivers and participants. This study reported five device related adverse
events(61). Till date there is no published data available from India regarding
effectiveness of flash glucose monitoring in children and adolescents with T1DM.
Advantage of FGMS over CGMS
It is proven beyond doubt that continuous glucose monitoring system will help in
better glycemic control and helps in identifying life threatening hypoglycemia.
However CGMS sensors because of their high cost are not practically feasible for
developing nations like India. Cost of FGMS sensor is Rs 2000 for 14days. If self
monitoring of blood glucose is done daily for four times with currently available
glucose strips the cost ranges from Rs 840-1960 which is almost the same. But the
amount of data on glycemic fluctuations with meals and activity and night time
continuous monitoring by FGMS is cost effective. In addition to these FGMS
needs no calibration unlike CGMS sensor. CGMS sensor records glucose values
47
for 3-4days where as FGMS can record glucose values once every 15 minutes for
14days.
Hence we aimed to study the effectiveness of FGMS in T1DM adolescents in
terms of glycemic control and identification of hypoglycemic episodes.
48
RESULTS
49
RESULTS
A total of 330 children with type 1 DM, on treatment and follow-up from pediatric
endocrinology clinic were screened for eligibility from January – March 2017. Out
of 330 subjects screened, 202 subjects did not meet pre-defined inclusion criteria.
81 subjects who met exclusion criteria were excluded. Remaining 47 subjects who
met eligibility criteria were eligible for enrollment in the study. Among the
subjects eligible to participate in the study, 24 subjects declined to participate in
the study. So, a total of 23 patients were enrolled in the study with 12 in
intervention and 11 in control group.
50
Figure3. STUDY FLOW DIAGRAM
ASSESSED FOR ELIGIBILITY n=330
2) Change in insulin dosage from baseline to 6 months in both groups. ( Epidata file only has total dose of insulin..but in excel sheet i made it for UNITS/ KG/DAY
3)In FGMS group what is the inference on hypoglycemic events
Total duration of hypoglycemia
No of hypoglycemic episodes
duration of daytime and night time hypoglycemia
Effect of BMI, age ,sex and socioeconomic status on hypoglycemia IN FGMS group( with in group analysis)
MY PRIMARY AIM
IS EFFECT OF FGMS ON Hba1c ( whether its use reducing Hba1c in type1 diabteics or not), and ITS EFFECT IN IDENTIFYING HYPOGLYCEMIA
For this i have taken 2 groups 1 group who does conventional finger prick glucose checking alone Once in every 2weeks for 6 months period....and other group along with conventional finger prick + FGMS machine ( which i placed for 14 days at the begining, 2 months and 4 months later).
Is there any better way of reporting the data.
If you need any clarification please call
RANDOMIZED n = 23
Excluded n = 307
Not meeting inclusion
criteria-202
Meeting exclusion
criteria-81
Declines participation-
24
Allocated to control group
n= 11
Received standard care
(SMBG) only
Allocated to intervention
group n= 12
Received intervention
(FGMS) + standard care
(SMBG)
ALLOCATION
Excluded = 2
[1.Withdrew consent for academic reason
2. Sensor failure]
Lost to follow up = 0
Excluded = 0 FOLLOW UP
Total analyzed - 10 Total analyzed - 11 ANALYSIS
51
Base line characteristics
There were 12 participants enrolled in the intervention group of which only 10
were included in the final analysis. Of the 2 patients who were excluded from
intervention group one had withdrew consent and lost to follow up and the other
missed the FGMS sensor for second time and the 3rd
FGMS sensor data was
incomplete for analysis.
Of the 10 children who were included in the final analysis 2 participants missed the
2nd
FGMS placement but they were included in the study to retain the strength of
the sample size. Of the 10 participants 4 were boys and 6 were girls.
There were 11 children in the control group who were included in the final
analysis. Of which 5 were boys and 6 were girls.
The age at the time of diagnosis in intervention and control groups was 8.3±3.6
(Mean ± SD) years and 12.1 ± 2.1(Mean ± SD) years respectively. The mean
duration of diabetes in intervention cohort was 5.1 ± 3 years (Mean ± SD) and the
mean duration of diabetes in control cohort was 3.2 ± 1.5 years (Mean ± SD).
Of the 10 children in intervention group 6 and of 11 children in control group 8
had previous episodes of diabetic ketoacidosis. All the children in both groups
reported to have hypoglycemic awareness as experienced by sweating, dizziness,
reeling, weakness, palpitation. 1 child in intervention group had eventful
52
hypoglycemia in the form of seizures requiring admission for 5 times at 5, 6, 7, 9,
11 years respectively. None of the other participants in either group had similar
events. None of the children in both the cohorts had documented end organ
involvement (Eye, kidney and CNS)
Anti islet antibody was positive in 2 children from control and 3 children from
intervention group. Anti GAD antibody was positive in 3 and 6 children from
control and intervention group respectively. 2children in control group were
positive for anti thyroid antibodies whilst none from intervention group.
Hypovitaminosis D was present in 1child in control and 4 children in intervention
group. One patient in control group had nephrotic syndrome in the past treated
with steroids and levamisole and was off medications for more than one year at th
e time of beginning of study. Anti TTG antibody was positive in 1 child in control
group and 2 children in intervention group.
Average HbA1c 6 months prior to study was 10.2% ± 1.58 (Mean ± SD) in control
group and 10.74% ± 1.7(Mean ± SD) in intervention group. Baseline HbA1c was
10.3% ± 1.9 and 10.32 ±1.27 (Mean ± SD) in control and intervention groups
respectively.
Baseline average insulin intake was1.29 ± 0.44 units/ kg/day in control group and
1.32 ± 0.34 units/kg/day in intervention group. All the baseline characteristics were
53
comparable between control and intervention groups except age of the patient and
age at the time of diagnosis as mentions in table3. More number of younger
children was present in intervention group.
Figure: 4. Gender and group distribution in control and intervention cohorts
0
1
2
3
4
5
6
SMBG FGMS + SMBG
Male 5 4
Female 6 6
Gender & group distribution
Male Female
54
Table: 3. Baseline parameters of the participants in control (SMBG) and
intervention (FGMS+SMBG) groups
S. No Baseline parameter FGMS+ SMBG
N= 10
n (%)
SMBG alone
N = 11
n (%)
P value
1 Age ( years), Mean ± SD 13.1 ± 1.12 15.4 ± 1.8 0.003
2
Gender
Male 4 (40.0) 5 (45.5)
0.80 Female 6 (60.0) 6 (54.5)
3 BMI 17.94 ± 1.46 18.83 ± 4.5 0.56
4 Socio
economic
state
Upper 2 (20.0) 1 (9.1)
Upper middle 3 (30.0) 3 (27.3)
Lower Middle 5 (50.0) 6 (54.6) 0.71
Upper Lower 0 (0) 1 (9.1)
Lower 0 (0) 0
5 Age at diagnosis(years) Mean
± SD
8.3 ± 3.6 12.1 ± 2.1 0.007
6 Duration of illness, Median
(IQR)
5 (3-8) 4 (1-4) 0.16
7 Previous DKA present (n) 6 (60.0) 8 (81.8) 0.27
9 Hypoglycemia awareness 10 (100.0) 11 (100.0) -
10 GAD antibody positive (n) 3 (30.0) 6 (54.6) 0.27
11 IA2 antibody positive (n) 2 (20.0) 3 (27.3) 0.70
12 Thyroid Ab positive (n) 0 (0.0) 2 (18.2) 0.16
13 Anti TTG positive (n) 2 (20.0) 1 (9.1) 0.48
14 Hypovitaminosis D (n) 4 (40.0) 1 (9.1) 0.09
15 Nephrotic syndrome in past 0 (0.0) 1 (9.1) 0.34
16 End organ damage present(n)
)
0 (0) 0 (0) -
17 HbA1c 6 months prior),
Mean ± SD
10.7 (1.7) 10.2 (1.6) 0.46
18 HbA1c Baseline),
Mean ± SD
10.3 (1.3) 10.3 (1.9) 0.99
19 Baseline total insulin
(U/kg/day) ), Mean ± SD
1.3 ± 0.3 1.2 ± 0.4 0.87
Note: Values are reported as n(%) for categorical variables, Mean ± SD for continuous normally
distributed variables, Median (IQR) for skewed variables.
55
FGMS FINDINGS IN INTERVENTION (FGMS + SMBG) GROUP
In our trail, we enrolled 12 patients into intervention group. Of the 12 one patient
withdrew consent after 1st FGMS sensor and were lost to follow up for rest of the
study period, other patient missed FGMS placement for second time and the 3rd
time sensor recording was incomplete (only 6 hours of glucose recordings) for
analysis and hence was excluded from the final analysis.
2 other patients missed FGMS sensor placement for second time. Both of them
were included in the final analysis. Finally a total of 10 patients were analyzed in
intervention group.
FGMS sensor was removed after 14 days of insertion and the data was downloaded
on to the computer using the reader device. Interstitial glucose values recorded for
every 15 minutes for a period of 14days (average of 96 glucose recordings per day
{1344 recordings /14days}) was shown as ambulatory glucose profile. Glucose
patterns over 14days period were depicted as within range (70mg/dl -180mg/dl),
below the range (<70mg/dl) and above the range (>180mg/dl).
Individual recordings of FGMS sensor data done at baseline, end of second month
and at the end of 4th month for 10 participants in the intervention group is shown in
table 4.
56
Table: 4. FGMS data in each individual in intervention group (n=10)
Patient
S no Time in range (%) GRBS - 70-180mg/dl
Time below range
(%) GRBS - < 70mg/dl
Time above range
(%) GRBS - >180mg/dl
FGMS 1 FGMS 2 FGMS 3 FGMS 1 FGMS 2 FGMS 3 FGMS 1 FGMS 2 FGMS 3
1 35 21 19 34 4 14 31 75 67
2 13 14 4 3 3 3 84 83 93
3 10 13 2 3 3 1 87 84 97
4 27 * 27 15 * 26 58 * 57
5 10 30 8 2 12 3 88 58 89
6 11 26 19 8 9 7 81 65 74
7 18 * 21 25 * 19 57 * 60
8 1 22 3 1 6 0 98 72 97
9 17 27 14 5 17 9 78 56 77
10 21 30 17 13 19 9 66 51 74
*Missed 2nd
FGMS sensor placement
From baseline to third sensor placement the percentage of glucose values within
the range was decreased in 7, increased in 2 and unchanged in one participant.
Percentage of glucose values below the range was decreased in 7 participants
where as increased in 2 and unchanged in 1 participant. Percentage of glucose
values above the range increased in 5 participants, decreased in 1 and unchanged in
4 participants.
All the participants in intervention group had hypoglycemic recordings while on 1st
and 2nd
FGMS. During 3rd
FGMS of the 10 participants 9 had hypoglycemic
recordings. Only one participant had no recorded hypoglycemia however the same
57
participant had hyperglycemic recordings above 97% and had within range glucose
values only for 3% of time.
Comparison of FGMS and SMBG data in intervention group
All the participants in intervention group had performed self monitoring of blood
glucose once in 2 weeks all throughout the study period even while on FGMS
sensor. SMBG data was also calculated as within range and below range and above
range. When compared to FGMS data obtained for 14days, SMBG data over 3-4
days showed no major difference in glucose ranges
Table: 5. Simultaneous individual SMBG recordings (For 3days) during
FGMS sensor placement in intervention group
Patient
S no
Time in range (%) Time below range (%) Time above range (%)
SMBG 1 SMBG 2 SMBG 3 SMBG 1 SMBG 2 SMBG 3 SMBG 1 SMBG 2 SMBG 3
1 27 30 30 0 0 0 73 70 70
2 78 53 47 0 0 0 22 47 53
3 16 72 66 2 22 16 72 5 16
4 39 45 32 5 0 0 56 55 68
5 27 27 30 0 0 5 73 73 65
6 47 33 60 5 5 10 38 61 30
7 14 16 71 0 0 0 86 84 29
8 39 45 28 0 0 0 61 55 72
9 55 50 61 0 0 0 45 50 39
10 47 15 24 0 5 0 53 80 76
58
While all the participants during 1st and 2
nd FGMS sensor placement and 9 of 10
participants during 3rd
FGMS sensor placement showed hypoglycemic recordings,
simultaneous glucose monitoring by SMBG showed hypoglycemic recordings only
in 3 participants. During the 3rd
FGMS sensor placement one participant did not
had any hypoglycemic recordings, SMBG data also showed no hypoglycemic
recording in this participant. Simultaneous SMBG data for intervention group
while on FGMS sensor is shown in table 5.
For the 10 participants in intervention group mean percentage of glucose values
within the range (GRBS-70-180mg/dl) below the range (GRBS- <70mg/dl) and
above the range (GRBS- >180mg/dl) for 1st, 2
nd and 3
rd FGMS and simultaneous
SMBG is depicted in tables 6 and 7.
Table: 6. Average time in different ranges by FGMS sensor data {each sensor
for 14days (n=10)}
Parameter FGMS 1 FGMS 2 FGMS 3
Within range 14.8% 22.8% 13.4%
Below range 10.9% 9.1% 9.1%
Above range 72.8% 68% 78.5%
59
Table: 7. Average time in different ranges by SMBG data in intervention
group (3days) n=10
Parameter SMBG 1 SMBG 2 SMBG 3
Within range 38.9% 38.6% 44.9
Below range 1.2% 3.2% 3.2%
Above range 57.9% 58% 51.8%
Hypoglycemia description in intervention group by FGMS report
Hypoglycemic recordings
FGMS sensor considers glucose value <70mg/dl as hypoglycemia and gives the
ambulatory glucose profile which comes as a graph. However FGMS sensor also
gives continuous report of glucose values as a separate report (Annexure). FGMS
sensor records glucose from the interstitial fluid. Because of 10-15mg/dl difference
in glucose value from blood to interstitial fluid, glucose value of less than 60mg/dl
was taken as hypoglycemia when manual evaluation of recording was done. The
total number of hypoglycemic recordings in FGMS data (GRBS less than 60mg/dl)
for individual patients is shown in table 8.
60
Table: 8. Individual Hypoglycemic recordings in intervention group (GRBS
<60mg/dl) during FGMS sensor for 14days
Patient S. No FGMS 1 FGMS 2 FGMS 3
1 30 33 120
2 18 11 17
3 15 4 0
4 136 * 125
5 2 73 9
6 44 53 34
7 143 * 196
8 0 34 0
9 18 160 56
10 75 127 75
*Patient missed FGMS sensor
Compared to the hypoglycemic recordings recorded during 1st and 2
nd FGMS the
number of hypoglycemic recordings in FGMS 3 reduced in 8 patients. While in 2
patients there were increased number of hypoglycemic recordings.
The mean number of hypoglycemic recordings among all 10 participants in the
intervention group during the placement of FGMS sensor for first time was 48
(range 0-143), during second and third FGMS sensor placement the mean number
of hypoglycemic events were 62 (4-160) and 63(0-196) respectively.
61
Table: 9. Mean of hypoglycemic recordings during each time of sensor
placement (14days) in intervention group
FGMS timing Hypoglycemic recordings (Mean) Range
FGMS 1 48 0-143
FGMS 2 62 4-160
FGMS 2 63 0-196
No of hypoglycemic recordings during daytime (6am-6pm) and night time (6pm-
6am) was calculated and shown in table 10.
Table: 10. No of hypoglycemic recordings during daytime (6am-6pm) and
night time (6pm-6am) over 14 days
Patient
s.no
FGMS 1 FGMS 2 FGMS 3
Day
time
Night
time
Day
time
Night
time
Day
time
Night
time
1 4 31 4 30 29 90
2 6 12 7 6 8 9
3 0 15 1 3 0 0
4 57 72 * * 56 59
5 2 0 30 43 19 0
6 28 16 5 40 9 26
7 47 98 * * 36 158
8 0 4 4 30 0 0
9 12 6 71 88 34 25
10 16 53 38 109 7 68
62
*Patient missed 2nd FGMS sensor
Except for 1 patient during the 1st FGMS sensor all the other patients had more
number of hypoglycemic recordings in the night than day. During 2nd
and 3rd
FGMS sensor placement also hypoglycemic recordings were more during the night
than day time.
Day time and night time hypoglycemia
Total time spent in hypoglycemia was calculated. This total time spent in
hypoglycemia was divided into day time hypoglycemia (6am-6pm) and night time
hypoglycemia (6pm-6am). Individual duration of day time and night time
hypoglycemia over 14 days of sensor placement and average time of hypoglycemia
over 24 hours during day time and night time separately is shown in table 11.
Mean of average day time hypoglycemia was 18.36 minutes, 21.36minutes and
21.14 minutes during 1st, 2
nd and 3
rd FGMS respectively.
Mean average of night time hypoglycemia was 32.63minutes, 46.51minutes and
46.48 minutes during 1st, 2
nd and 3
rd FGMS respectively.
63
Table 11 Total day and night time (minutes) hypoglycemia over 14days and average day and night time
hypoglycemia in minutes/ 24 hours during 3 FGMS sensor placement (n=10)
Patient missed 2
nd FGMS sensor
FGMS 1 FGMS 2 FGMS 3
Patient
S.No
Day
time
Avg time in
min/24hours
Night
time
Avg time in
min/24hours
Day
time
Avg time in
min/24hours
Night
time
Avg time in
min/24hours
Day
time
Avg time in
min/24hours
Night
time
Avg time in
min/24hours
1 60 4.2 465 33.2 60 4.2 450 32.1 435 31 1350 96.4
2 90 6.4 180 12.8 105 7.5 90 5 120 8.5 135 9.6
3 0 0 225 16 15 1 45 3.2 0 0 0 0
4 855 61 1080 77.1 * * * * 840 60 885 63
5 30 2.1 0 0 450 32 645 46 285 20.3 0 0
6 420 30 240 17 75 5.3 600 42.8 135 9.6 390 27.8
7 705 50 1470 105 * * * * 540 38.5 2370 169.2
8 0 0 60 4.2 60 4.2 450 32.1 0 0 0 0
9 180 12.8 90 5 1065 76 1320 94.2 510 36 375 26
10 240 17.1 795 56 570 40.7 1635 116.7 105 7.5 1020 72.8
64
With In Group Analysis of Baseline and Follow Up Parameters
Baseline and follow up parameters in intervention group (FGMS + SMBG)
HbA1c and insulin intake (units/kg/day) at baseline,3 months and 6months was
compared in intervention group. Of the 10 participants in intervention group 4 had
shown a decrease in HbA1c from baseline to 6 months while remaining 6
participants had an increase in HbA1c. Values are shown in table 12.
Table: 12. HbA1c and Insulin requirement (units/kg/day) comparison in
intervention group (n=10)
Patient
S.No
HbA1c
Baseline
Insulin
Unit/kg/day
HbA1c
3 months
Insulin
Unit/kg/day
HbA1c
6 months
Insulin
Unit/kg/day
1 10.1 1.8 10.2 2.4 10.1 2.4
2 10.3 1.1 11.2 1.75 10.6 1.73
3 10.8 1.9 10.3 1.9 11 1.5
4 9.1 0.9 7.8 0.7 7 0.8
5 9.5 1.5 8.7 1.7 10.2 1.7
6 10.5 1.1 9 1.4 9 1.4
7 9.5 0.9 10.4 1 10.6 1
8 13.1 1.3 11.7 2.1 13.5 1.1
9 11.5 1.5 9.9 1.8 10.6 1.8
10 8.8 1.2 9.2 2.1 9.4 2.1
Median HbA1c 6 months prior to study was 10.55% (IQR; 10.1 -11.72) with range
8.1-13.8 in intervention group. Baseline median Hba1c was a10.2% (IQR; 9.5-
10.8) with range 8.8-13.1. Insulin intake at baseline was 1.32 ± 0.35 (Mean ± SD)
65
units/kg/day. In intervention group changes of outcome variables within a cohort at
different study points (Baseline, 3rd
and 6 months) were analyzed with pared t test
for normally distributed data and non parametric Wilcoxon- rank sum test was
used for rest of the data. Table 13&14
Table: 13. Baseline and 3 month follow up parameters in intervention group
(n=10)
S.No Parameter Baseline 3 months Change
1 HbA1c
Median(IQR)
Range
10.2%(9.5-10.8)
(8.8-13.1)
10.05%(9-10.4)
(7.8-11.7)
0.65%( - 0.4 -1.4)
(-0.9 – 1.6)
2 Insulin
(units/kg/day)
Mean± SD
1.32 ± 0.35 1.68 ± 0.52 -0.36 ± 0.36
Table: 14.Baseline and 6 month follow up parameters in intervention group
(n=10)
S.No Parameter Baseline 6 months Change
1 HbA1c
Median(IQR)
Range
10.2%(9.5-10.8)
(8.8-13.1)
10.6%(9.75-10.8)
(9-13.5)
- 0.25%(-0.5 - 0.45)
(-1.1 – 1.5)
2 Insulin
(units/kg/day)
Mean± SD
1.32 ± 0.35 1.55 ± 0.5 -0.23 ± 0.40
66
Baseline and follow up parameters in control group (SMBG alone)
Individual values of HbA1c and insulin requirement in control group at baseline
and change of the same at 3months and 6 months are shown in table 15.
Of 11 participants in control group 10participnats had shown a decrease in HbA1c
at the end of 6months from baseline.
Table: 15. HbA1c and Insulin requirement (unit/kg/day) comparison in
control group (n =11)
Patient
S.No
HbA1c
baseline
Insulin
Unit/kg/day
HbA1c
3 months
Insulin
Unit/kg/day
HbA1c
6 months
Insulin
Unit/kg/day
1 10.3 2.1 7.7 2.2 8.6 2.2
2 10.4 1.4 12.5 1.7 10.7 1.7
3 13.8 2.1 12.5 1.2 13.1 1.4
4 9.8 0.8 9.4 0.9 7.4 0.9
5 7.3 1.2 7.7 1.2 5.8 1.2
6 8.9 1.3 7.3 1.3 6.9 1.4
7 9.6 1 9.6 1.2 9 1
8 10.1 1.3 8 1.1 8 1.2
9 13.5 0.8 11.8 1.5 9.5 1.5
10 9 1.2 9.8 1.4 8.3 1.4
11 10.9 1 10.1 1.3 9.9 1.2
67
Median HbA1c 6 months prior to study was 9.7% (IQR; 9.4 – 10) with range 7.3-
12.8 and baseline median hba1c was 10.1% (IQR; 9.0- 10.9) with range 7.3-13.8 in
SMBG group. Baseline total insulin intake was 1.29 ± 0.45 units (Mean ± SD).
Change in HbA1c and insulin intake at the end of 3 months and 6 months is
depicted in table 16 & 17
Table: 16. Baseline and 3 month follow up parameters in control (SMBG) group
(n=11)
S.No Parameter Baseline 3 months Change
1 HbA1c
Median(IQR)
Range
10.1%(9.4-10.9)
(7.3-13.8)
9.6%(7.7-10.1)
(6.7-12.5)
0.8%(0.4 -1.7)
(-0.8 – 2.6)
2 Insulin
(units/kg/day)
Mean± SD
1.29 ± 0.45 1.35 ± 0.36 -0.05 ± 0.39
In control group changes of outcome variables within a cohort at different study
points (Baseline, 3rd
and 6 months) were analyzed with pared t test for normally
distributed data and non parametric Wilcoxon- rank sum test was used for rest of
the data.
68
Table: 17. Baseline and 6 month follow up parameters in control (SMBG) group
(n=11)
S.No Parameter Baseline 6 months Change
1 HbA1c
Median(IQR)
Range
10.1%(9.4-10.9)
(7.3-13.8)
8.6%(7.4-9.9)
(5.8-13.3)
1.5%( 0.7 -2.1)
(0.3 – 4)
2 Insulin
(units/kg/day)
Mean± SD
1.29 ± 0.45 1.37 ± 0.36 -0.08 ± 0.33
COMPARISON OF CHANGE IN OUTCOME PARAMETERS BETWEEN
TWO GROUPS
Table: 18. Comparison of change in outcome parameters at 3 months between
two groups
S.No Parameter FGMS +SMBG SMBG P value
1 HbA1c
Median(IQR)
Range
0.65%( -0.4 -1.4)
(-0.9 – 1.6)
0.8%(0.4 -1.7)
(-0.8 – 2.6)
0.2904
2 Insulin
(units/kg/day)
Mean± SD
1.68 ± 0.52 1.35 ± 0.36 0.1115
69
Change in HbA1c and insulin requirement from baseline to 3 months in both
intervention groups and control group is shown in table 18. P value for both the
parameters is not significant
Table: 19. Comparison of change in outcome parameters at 6 months between
two groups
S.No Parameter FGMS +SMBG SMBG P value
1 HbA1c
Median(IQR)
Range
-0.25%(-05-0.45)
(-1.1 – 1.5
1.5%( 0.7 -2.1)
(0.3 – 4)
0.0081
2 Insulin
(units/kg/day)
Mean± SD
-0.23 ± 0.40
-0.08 ± 0.33
0.4380
Change in HbA1c from baseline to 6 months showed a significant reduction in
control group but no such change observed in intervention group P value was
0.0081. Change in Insulin requirement in both groups was not statistically
significant. Table 19
70
Hypoglycemic recording by SMBG in both groups
Hypoglycemic recordings by SMBG in intervention group
In the intervention group participants had done SMBG once in 2 weeks. While
FGMS sensor was placed 3 times during the study period simultaneous SMBG was
continued. While all the participants during 1st and 2
nd FGMS sensor placement
and 9 of 10 participants during 3rd
FGMS sensor placement showed hypoglycemic
recordings, simultaneous glucose monitoring by SMBG showed hypoglycemic
recordings only in 3 participants. Refer to table 5 for individual SMBG recordings
during FGMS sensor placement.
Hypoglycemic recordings done by SMBG (for 3days) simultaneously during 14
days of FGMS sensor placement showed 1.2%, 3.2% and 3.2% of hypoglycemic
recordings.
Hypoglycemic recordings by SMBG in control group
SMBG values at baseline and 3 months and 6 months were recorded for 11
participants in control group. Hypoglycemic recordings were present in 4, 4 and 5
participants at baseline, 3months and 6 months respectively.
Average percentage of glucose recordings below the range (<70mg/dl) was 5%,
71
2.9% and 7% at baseline, 3 months and 6 months respectively.
FGMS and SMBG glucose values correlation
FGMS measures interstitial blood glucose and SMBG measures capillary blood
glucose. Participants in intervention group (FGMS + SMBG) performed SMBG for
3-4 consecutive days once in 2 weeks like control group. Glucose values of both
FGMS and SMBG were compared for the days on which both values were
available. Table20 describes the comparison of FGMS and SMBG values. The
difference between FGMS and SMBG values were calculated. The mean of
differences between FGMS and SMBG glucose values was 14± 3.5 mg/dl (Mean ±
SD) was within the variability described in previous studies.(54)
72
Table: 20. Simultaneous FGMS (interstitial glucose in mg/dl) and SMBG (capillary glucose in mg/dl) glucose
values and the difference between both during FGMS1 (VALUES for 1day)
FGMS SMBG Diff FGMS SMBG Diff FGMS SMBG Diff FGMS SMBG Diff FGMS SMBG Diff FGMS SMBG Diff
1 180 196 4 301 324 23 295 308 13 311 329 18 378 398 20 133 143 10
2 233 255 22 90 115 25 111 123 12 119 127 8 383 423 40 233 245 12
3 244 262 18 121 140 19 171 182 11 442 479 37 50 66 16 467 499 22
4 231 253 22 290 303 13 135 147 12 53 61 8 266 278 12 198 214 16
5 211 226 15 155 179 24 107 112 5 158 162 4 311 333 22 211 225 14
6 151 169 18 66 70 16 156 164 8 87 91 4 266 279 13 297 303 6
7 99 108 9 199 204 5 226 233 7 99 103 4 119 127 8 169 174 5
8 287 291 4 299 308 9 456 471 15 134 148 14 211 224 13 166 173 7
9 166 185 19 75 88 13 89 93 4 244 277 33 269 297 28 151 162 11
10 440 454 14 90 104 14 88 96 8 197 208 11 150 177 27 400 420 20
3.00 am6:00 AM 9.00am 12.00noon 6.00pm 9.00 pm
FGMS- Flash Glucose Monitoring System, SMBG- Self Monitoring of Blood Glucose, Diff- Difference between SMBG and FGMS
values
73
Adverse events and technical problems with FGMS sensor
Serious adverse events like infection, swelling at the site of sensor
placement were not noticed in any of the 10 patients analyzed.
For total of 10 patients included in intervention arm total of 30 sensors were
used.
8 patients completed 3 sensor placements during the study period
(24sensors). Of these for 1 participant FGMS sensor was repeated during 2nd
time because FGMS sensor read only 6 hours.
2 participants had sensor placement for 2 times only, of these for one
participant during 1st FGMS placement, sensor was damaged and it could
not be inserted properly and fell off from insertion site. For this patient a
new sensor was placed and secured with regular measures.
Accidental premature removal of sensor was noticed in one participant on
day 11 after sensor placement.
One participant had minimal bleeding at the time of insertion which was
controlled with manual pressure. The same participant had pain at insertion
site which was controlled with single dose of analgesic.
All the participants found sensor socially acceptable and not interfering with
privacy and daily activities.
74
Table: 21. Description of sensor count in intervention group
Description No of patients No of sensors
Completed 3 sensor
placements
8 24
Completed 2 senor
placements
2 4
Sensor repeated 1 1
Failed sensor insertion 1 1
Total 10 30
75
DISCUSSION
76
DISCUSSION
Design and setting of the study
In this prospective open label randomized controlled trial, a total of 30 patients
were intended to be enrolled however we could enroll only 23 patients. Of these 23
patients 12 participants received the intervention (FGMS) along with standard care
(SMBG). Other 11 patients received only standard care (SMBG). Study period
was from January 2017 till December 2107. Patients were enrolled from February
2017 to April 2017. Participants were enrolled from pediatric endocrinology clinic,
Christian medical college, Vellore.
Demographic details
A total of 23 patients were enrolled as against 30 as per protocol. Of 23 only 21
patients (10 in the intervention group and 11 in control group) were included in
final analysis. 2 were excluded from study. Of these 9 were male, 5 (45%) in
control group and 4 (40%) in intervention group. There were 12 female
participants of which 6 (55%) in control group and 6 (60%) in intervention group.
Justification for the study
Type 1 diabetes is a most common endocrine disorder of child hood. Strict
glycemic control was proven to improve the quality of life and prevent the long
term complications. Self monitoring of blood glucose (SMBG) by finger prick
77
method is commonly practiced to monitor blood sugars and glycemic control is
assessed by SMBG records and HbA1c done once in 3months. However self
monitoring of blood glucose can miss the glucose excursions that vary according to
activity and food intake. Continuous glucose monitoring (CGMS) helps in
achieving the better glycemic control and this has been established by systematic
reviews and metanalysis. However cost and need for finger pricks for machine
calibration is cumbersome. FGMS is a novel method of continuous glucose
monitoring which is cost effective and does not require finger pricks for
calibration. Till date many trials done in adults have proven effectiveness of FGMS
in glycemic control and identifying hypoglycemic events. Use of FGMS in
children with type 1 diabetes is sparse. To the best of our knowledge, till date only
few studies assessed the use of FGMS in children and none form India. The
current study was planned with the idea that FGMS in addition to SMBG in
children with type 1 diabetes will improve the glycemic control when compared to
self monitoring of blood glucose alone and will also help in identifying the hypo
and hyperglycemic changes which otherwise might go unnoticed with SMBG
alone. This open label randomized control study was done in type 1 diabetics with
the primary objective of assessing the effectiveness of FGMS in glycemic control
and in identifying hypoglycemia events. The secondary outcomes of our study
were to assess the correlation of FGMS interstitial glucose recordings with
78
glucometer capillary recordings and to assess the feasibility and acceptability of
FGMS.
FGMS – DESCRIPTION AND DATA ANALYSIS
Intervention group (FGMS + SMBG) had 12 participants. But only 10 participants
were included in final analysis. Of the 2 who were excluded from the final analysis
one patient withdrew consent and lost to follow up after 1st FGMS ,the other
patient missed 2nd
FGMS sensor and the 3rd
FGMS sensor recording was
inadequate( recorded only for 6hours) .
Total of 30 sensors were used during the study period. A total of 8 patients
completed 3 sensor placements. Of the 8 participants who completed 3 sensor
placements, for one patient 2nd
FGMS sensor had to be repeated as it recorded
glucose values only for 6 hours. 2 participants completed only 1st and 3
rd sensors,
but were included in final analysis to retain the strength of sample size.
All patients had tolerated FGMS sensors well with minimal side effects. With the
exception of FGMS data recorded for only 6 hours in 2 participants all the other
sensor recordings were enough for therapeutic decisions.
Limitations of FGMS
1) One of the limitations in FGMS data was non availability of real time data to
patient and absence of alarms unlike in CGMS (39,40). Patients had to visit
79
the hospital for the sensor to be read and avail the glucose readings. Device
to read the sensor recording is currently not available for patient use in India,
but is available to patients in some countries.
2) Another limitation of FGMS found in our study was the need for patient to
come to hospital to insert and to check the working condition of sensor. Julie
et al studied the effectiveness of FGMS as a replacement to SMBG in type 1
diabetic children. In their study patients had three hospital visits. After the
sensor placement patient had their second visit between 5-8days and a final
visit between 12-15 days (61). In resource poor countries like India calling
the patient multiple times to hospital for ensuring the working condition of
sensor is practically difficult. This was overcome by Al Algha et al in a
study done in type 1 diabetic children during Ramadan fasting, all the
participants were given a scanning devise to avail the glucose values(60).
3) FGMS gives retrospective data for 14days. We found that patients were not
able to recollect the nature of symptoms and activity at which time FGMS
showed hypoglycemic and hyperglycemic results.
During 3 times of sensor placement over 6 month duration, we found all the
children had episodes of hypoglycemia. 100% of children had night time
hypoglycemia. The interstitial glucose value measured by FGMS sensor is usually
10-15% lower than blood glucose was a well recognized physiology.
80
Although the data was analyzed retrospectively FGMS sensor gives data similar to
CGMS devise. The major difference to currently available CGMS is no need for
calibration for FGMS. Data over 14 days can be collected with minimal effort from
the caregiver or patient.
In our study FGMS data obtained helped to identify patterns of glycemic
excursions like pre and post meal hypoglycemia and hyperglycemia and nocturnal
hypo and hyperglycemia. We found identification of asymptomatic nocturnal
hypoglycemia was much beneficial which was not at all possible with standard
SMBG done 4 times a day (in our study population 4days / 2weeks). Identification
of nocturnal hypoglycemia detected in all the subjects in intervention group affirms
the presence of unrecognized nocturnal hypoglycemia in children with type 1
diabetes.
Unlike CGMS cost of FGMS is very economical and gives data for14 days as
compared to 3days data by CGMS. Each FGMS senor cost is Rs. 2000. As per
American diabetes association and International society for pediatric and
adolescent diabetes consensus guidelines (ISPAD) self monitoring of blood
glucose should be done a minimum of four times a day (24, 32) . If self monitoring
of blood glucose is done daily for four times with currently available glucose strips
the cost ranges from Rs 840-1960 ( for 14days) which is almost the same as FGMS
sensor. But the amount of data on glycemic fluctuations with meals and activity
81
and night time continuous monitoring by FGMS is cost effective. Because of this
reason in a motivated and affordable patient FGMS can replace self monitoring of
blood glucose by conventional finger prick method. Study by Julie et al compared
FGMS as an alternative method to capillary blood sugar values. They found FGMS
data was found to be accurate, safe and user acceptable. (61)
Outcome of study
In our study we analyzed the effectiveness of FGMS in addition to SMBG in
glycemic control assessed by reduction in HbA1c and identification of
hypoglycemic episodes when compared to SMBG alone. We also analyzed the
correlation of FGMS and SMBG glucose values and feasibility and acceptability of
FGMS.
Although this was a computer generated randomization, we noted that age of the
patient at diagnosis and age at inclusion into study were both significantly different
in both groups, with all other baseline demography well matched. Children in
intervention group were younger and diagnosed at a younger age with type 1
diabetes compared to control group.
Children and adolescents of 12-18 years of age with type 1 diabetes for more than
1 year period with HbA1c between 8-14% were included in the study. All the
82
subjects are on basal bolus or split mix regimen and doing self monitoring of blood
glucose for 4 days once in 2 weeks.
The reason to include the children and adolescents of 12-18 years of age was that
FGMS was not at all studied in younger children and was recently only licensed
for use in children. Other reason was adolescence is a challenging period with
more physical activity hence feasibility of the device is better studied in this group.
The reason to include children with diabetes over a year was to exclude
honeymoon period which is transient and could have fluctuating blood glucose
levels.
We planned to enroll 30 patients in our 6months study. However at the end of
enrollment period we could get only 21 patients.
Randomized controlled design was planned so as to exclude the selection bias.
However because the intervention is not blinded to participants, we planned for
open label study design. Hence in our study the primary investigator and
participants were blinded till the allocation which was concealed by use of opaque
envelopes. Randomization was done by using computer generated random number
list. The allotment was revealed to participants after the written consent was
obtained for the study.
83
The ideal outcome of this study would require daily self monitoring of blood
glucose and a follow up period of at least one year. Though the recommendation
for home monitoring is at least 4 recordings daily, in our institution and various
other health centers the clinical practice has been that home blood glucose
monitoring are done once in 2 weeks for 3-4 consecutive days because of the poor
economic status of the families and not being able to afford the cost of glucose test
strips.
Also a large sample size would have been ideal. Till now there are no published
data available from India comparing SMBG and FGMS in children with type 1
diabetes. Hence we conducted this pilot study. Performing HbA1c once in 3
months is a proven indicator for monitoring good glycemic control however it
gives no information regarding the glucose excursions that happen during the day.
FGMS gives data for every 15minutes for 14days.
Primary outcome
The change in HbA1c was not significant in intervention group compared to
control group. We expected that FGMS would result in significant reduction
HbA1c because of longer duration (14days) and frequent measurement (once in
15minutes) of glucose. The possible explanations as to why FGMS did not achieve
better glycemic control could be,
84
1) Baseline characters like age of the patient and age at the time of diagnosis
was unmatched (P values were 0.003 and 0.007 respectively).
2) Randomization was done using computer generated random numbers hence
resulted in statistically significant difference between control and
intervention groups and could have influenced the final outcome of study.
3) 5 patients in intervention group missed regular diabetes clinic visits but
continued to inform SMBG data over phone for insulin tailoring. This was
because all the patients in intervention group had to come twice to hospital
for insertion and removal of FGMS sensor apart from regular clinic visits.
At the time of insertion each individual had to wait for 2-3 hours to ensure
working condition of the sensor. Study done by Al Algha et al gave 3
separate pre educational sessions (20minutes each) to participants and
parents in their one month study period. We could not give a separate
educational session apart from explaining about the devise and adherence to
routine follow up at the beginning of the study and at the time of sensor
insertion. Responsibility shared among care takers and adolescents result in
a better glycemic control. (24) Multidisciplinary management in type 1
diabetes helps to achieve better glycemic control. However non compliance
to treatment protocols was also been observed as the patient has to consult
multiple health professionals.
85
4) FGMS data evaluation and insulin adjustment in our study was done by
different treating endocrinologists resulting in non uniformity of
interpretation of complex FGMS data.
We observed a significant change in HbA1c in control group. One possible reason
for this could be participation in study itself and participants knowing that they
were not given FGMS sensor (a special machine) which could have made this
group more compliant to multidisciplinary management.
In intervention group all the patients had hypoglycemia recordings documented by
FGMS during each time of sensor placement. While simultaneous glucose values
by SMBG had shown hypoglycemic recording only in 3 patients. Remaining 7
patients there was no documented hypoglycemia by SMBG.
In addition to identification of hypoglycemic values which were missed by SMBG
FGMS data also helped in identifying the time at which hypoglycemia happened
(day time or night time). There is no other way to identify a low sugar value except
to check glucose by finger prick. Use of CGMS to identify this asymptomatic
hypoglycemia and nocturnal hypoglycemia was proved in studies done by Golicki
et al, Gandhi et al and Chetty et al.
86
Superiority of FGMS in identification and reduction in time spent in hypoglycemia
was proved in clinical experience trial by Larry et al and open label randomized
control trial by Thomas et al in adult population.
In our study we found that hypoglycemic recordings identified by FGMS were
more than SMBG confirming the results of other similar studies.
Secondary outcome
FGMS (interstitial fluid glucose) and SMBG (capillary blood glucose) values were
compared in intervention group. The normal difference between capillary blood
glucose and interstitial fluid glucose is 10-15mg/dl. In our study we found the
difference between FGMS and SMBG values was 14 ± 3.5mg/dl.
All the participants found sensor socially acceptable and not interfering with
privacy and daily activities. None of the participants had major side effects. Of the
33 sensors used during study period 2 sensors fell from the site at the time of
insertion. And 2 sensors recorded data only for 6 hours.
Power of the study
Difference in HbA1c from baseline to 6 months in intervention and control groups
were -0.02 ± 0.84 and 1.49 ± 1.15 (mean± SD). Estimated power for a 2 sample
87
mean test by Satterthwaite’s test assuming unequal variances with (alpha error=
0.0500, N=23 and delta error of=3.5166) was 0.8.
88
CONCLUSION
89
CONCLUSION
1) Use of FGMS in improving glycemic control with reduction of Hba1c was
not noted in our study. Rather than reading the sensor at the end of 14days, a
change in the study design allowing the clinician to read FGMS at interval of
4-5days during each sensor placement for insulin modification needs to be
explored.
2) The primary benefit as seen in our study for the use of FGMS is in
identifying hypoglycemic events. FGMS is a good tool to identify
hypoglycemia compared to SMBG. We found all the participants in
intervention group (n=10) had hypoglycemic recordings by FGMS but such
episodes were identified in only 3 participants by SMBG.
3) FGMS helps in identifying asymptomatic glycemic variations which affects
the long term outcome of disease. Adjusting insulin depending on glycemic
excursion helps in better glycemic control by avoiding rebound
hyperglycemia after episodes of hypoglycemia.
4) FGMS values were comparable with SMBG values. The mean difference of
14 ± 3.5mg /dl was found in our study.
5) FGMS is feasible and acceptable for use in children and adolescents with
type 1 diabetes mellitus.
90
6) FGMS sensor for 14days almost cost the same as SMBG if done daily.
Hence it is in a way cost effective and gives much frequent and larger
number of glucose values than SMBG.
91
LIMITATIONS
92
LIMITATIONS
Our study has various limitations
1) Being an open label randomized study intervention was not blinded to
participants and the primary investigator after allocation.
2) Small sample size.
3) Randomization technique used was computer generated random sequence of
number. Hence baseline characteristics like age and duration of illness were
not matched between the study groups.
4) We could not meet the estimated sample size within the study period
because the study group is in school going age and not willing for multiple
visits.
5) As FGMS data obtained was retrospective, and there were no alarms
available for abnormal glucose recordings patients and clinicians were
unaware of real time data and no clinical intervention was possible close to
the event.
6) FGMS data interpretation and insulin adjustments were done by different
clinicians which could have bearing effect on the outcome of study.
7) FGMS had shown an improving HbA1c during FGMS 2 but this declined
during FGMS 3. This clearly demonstrated the need for regular clinic visits
93
in tandem with FGMS monitoring was necessary for complete diabetes
management.
Further randomized studies with larger sample size and long term follow up period
comparing the FGMS with daily SMBG monitoring can show the effect of FGMS
on reduction of HbA1c. In between visits while the patient is on FGMS sensor will
help in assessing the working condition of sensor.
94
BIBILIOGRAPHY
95
BIBILIOGRAPHY
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31. Association AD. 12. Children and Adolescents. Diabetes Care. 2017 Jan 1;40(Supplement 1):S105–13.
32. Rewers MJ, Pillay K, de Beaufort C, Craig ME, Hanas R, Acerini CL, et al. ISPAD Clinical Practice Consensus Guidelines 2014. Assessment and monitoring of glycemic control in children and adolescents with diabetes. Pediatr Diabetes. 2014 Sep;15 Suppl 20:102–14.
33. Larsen ML, Hørder M, Mogensen EF. Effect of Long-Term Monitoring of Glycosylated Hemoglobin Levels in Insulin-Dependent Diabetes Mellitus. N Engl J Med. 1990 Oct 11;323(15):1021–5.
34. Nathan DM, Singer DE, Hurxthal K, Goodson JD. The clinical information value of the glycosylated hemoglobin assay. N Engl J Med. 1984 Feb 9;310(6):341–6.
35. Molnar GD, Taylor WF, Ho MM. Day-to-day variation of continuously monitored glycaemia: A further measure of diabetic instability. Diabetologia. 1972 Nov 1;8(5):342–8.
36. Service FJ, Molnar GD, Rosevear JW, Ackerman E, Gatewood LC, Taylor WF. Mean amplitude of glycemic excursions, a measure of diabetic instability. Diabetes. 1970 Sep;19(9):644–55.
37. Maia FFR, Araújo LR. [Accuracy, utility and complications of continuous glucose monitoring system (CGMS) in pediatric patients with type 1 diabetes]. J Pediatr (Rio J). 2005 Aug;81(4):293–7.
38. V P, Rodrigues DP. NON INVASIVE GULCOSE ESTIMATION ALGORTHIMS IMPACT IN CGMS. Int Educ Res J [Internet]. 2017 May 26 [cited 2017 Aug 2];3(5). Available from: http://ierj.in/journal/index.php/ierj/article/view/952
39. Monsod TP, Flanagan DE, Rife F, Saenz R, Caprio S, Sherwin RS, et al. Do sensor glucose levels accurately predict plasma glucose concentrations during hypoglycemia and hyperinsulinemia? Diabetes Care. 2002 May;25(5):889–93.
40. Garg S, Zisser H, Schwartz S, Bailey T, Kaplan R, Ellis S, et al. Improvement in glycemic excursions with a transcutaneous, real-time continuous glucose sensor: a randomized controlled trial. Diabetes Care. 2006 Jan;29(1):44–50.
41. Golicki DT, Golicka D, Groele L, Pankowska E. Continuous Glucose Monitoring System in children with type 1 diabetes mellitus: a systematic review and meta-analysis. Diabetologia. 2008 Feb;51(2):233–40.
42. Gandhi GY, Kovalaske M, Kudva Y, Walsh K, Elamin MB, Beers M, et al. Efficacy of continuous glucose monitoring in improving glycemic control and reducing hypoglycemia: a systematic review and meta-analysis of randomized trials. J Diabetes Sci Technol. 2011;5(4):952–965.
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44. Poolsup N, Suksomboon N, Kyaw AM. Systematic review and meta-analysis of the effectiveness of continuous glucose monitoring (CGM) on glucose control in diabetes. Diabetol Metab Syndr. 2013 Jul 23;5:39.
45. Chetty VT, Almulla A, Odueyungbo A, Thabane L. The effect of continuous subcutaneous glucose monitoring (CGMS) versus intermittent whole blood finger-stick glucose monitoring (SBGM) on hemoglobin A1c (HBA1c) levels in Type I diabetic patients: a systematic review. Diabetes Res Clin Pract. 2008 Jul;81(1):79–87.
46. Langendam M, Luijf YM, Hooft L, Devries JH, Mudde AH, Scholten RJPM. Continuous glucose monitoring systems for type 1 diabetes mellitus. Cochrane Database Syst Rev. 2012 Jan 18;1:CD008101.
47. Heinemann L. Finger Pricking and Pain: A Never Ending Story. J Diabetes Sci Technol Online. 2008 Sep;2(5):919–21.
48. Pérez-Ayala M, Oliver P, Rodríguez Cantalejo F. Prevalence of bacterial contamination of glucose test strips in individual single-use packets versus multiple-use vials. J Diabetes Sci Technol. 2013 Jul 1;7(4):854–62.
49. FDA Approves Abbott’s FreeStyle Libre Pro System for Diabetes [Internet]. Medscape. [cited 2017 Aug 4]. Available from: http://www.medscape.com/viewarticle/869386
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51. Weinzimer SA, Beck RW, Chase HP, Fox LA, Buckingham BA, Tamborlane WV, et al. Accuracy of newer-generation home blood glucose meters in a Diabetes Research in Children Network (DirecNet) inpatient exercise study. Diabetes Technol Ther. 2005 Oct;7(5):675-680; discussion 681-683.
52. Rebrin K, Steil GM. Can interstitial glucose assessment replace blood glucose measurements? Diabetes Technol Ther. 2000;2(3):461–72.
53. Corradini S, Pilosio B, Dondi F, Linari G, Testa S, Brugnoli F, et al. Accuracy of a Flash Glucose Monitoring System in Diabetic Dogs. J Vet Intern Med. 2016 Jul;30(4):983–8.
54. Ólafsdóttir AF, Attvall S, Sandgren U, Dahlqvist S, Pivodic A, Skrtic S, et al. A Clinical Trial of the Accuracy and Treatment Experience of the Flash Glucose Monitor FreeStyle Libre in Adults with Type 1 Diabetes. Diabetes Technol Ther. 2017 Mar;19(3):164–72.
55. A Multicenter Evaluation of the Performance and Usability of a Novel Glucose Monitoring System in Chinese Adults With Diabetes. - PubMed - NCBI [Internet]. [cited 2017 Aug 4]. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27559031
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57. Distiller LA, Cranston I, Mazze R. First Clinical Experience with Retrospective Flash Glucose Monitoring (FGM) Analysis in South Africa: Characterizing Glycemic Control with Ambulatory Glucose Profile. J Diabetes Sci Technol. 2016 Nov;10(6):1294–302.
58. Ish-Shalom M, Wainstein J, Raz I, Mosenzon O. Improvement in Glucose Control in Difficult-to-Control Patients With Diabetes Using a Novel Flash Glucose Monitoring Device. J Diabetes Sci Technol. 2016 Nov;10(6):1412–3.
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60. Al-Agha A, Kafi S, Zain Aldeen A, Khadwardi R. Flash glucose monitoring system may benefit children and adolescents with type 1 diabetes during fasting at Ramadan. Saudi Med J. 2017 Apr 1;38(4):366–71.
61. Edge J, Acerini C, Campbell F, Hamilton-Shield J, Moudiotis C, Rahman S, et al. An alternative sensor-based method for glucose monitoring in children and young people with diabetes. Arch Dis Child. 2017 Jun;102(6):543–9.
100
ANNEXURES
101
ANNEXURE 1
STUDY PROFORMA
Name DATE -
Hospital id-
Unique ID
DOB- DD/MM/YYYY
Age YY/MM
SEX - Male 1 Female 2
Phone number-
Place-
Socio economic status
102
Weight kg Height cm BMI-
Age at the time of diagnosis - - year/months
Duration of illness- - year/months
Insulin Storage
1Fridge 2 Mud pot 3 Wraps in cloth 4 Open place
Previous episode of DKA Yes 1 No2
Hypoglycemic awareness 1Yes 2 No
Previous episodes of hypoglycemia 1yes 2 No
End organ involvement Kidney Yes 1 No 2
Eye Yes 1 No 2
CNS Yes 1 No 2
Other associated conditions
GAD
TSH
T3
TTG T4
Thy Ab
Any other conditions
Insulin intake at base line
Type of insulin NAME Units Timings
103
Ultra short
1.
2.
3.
Long acting 4.
Drugs other than Insulin for glycemic control
1 Yes 2 No
HbA1c
Date HbA1c 6-12 months prior
Base line 3 months
6 months
Insulin intake during study period
Type of insulin Baseline 2months 4months 6months
Short acting
Long acting
Hospitalization during study period-
104
SMBG sugar levels
WEEK
No of hypoglycemic episodes
105
ANNEXURE 2
PARENT INFORMATION SHEET
A randomized trial comparing (FGMS) Flash Glucose Monitoring System + SMBG Vs
(SMBG) self monitoring of blood glucose alone for glycemic control in adolescents of
12-18years age with Type 1 diabetes mellitus.
Dear Parent, your child is currently under treatment for Type 1 diabetes mellitus in the
endocrinology division under Child health Unit 1. Your child is on insulin for the control of
sugar levels.
Type 1 diabetes is a condition in which strict control of sugars prevents the damage to vital
organs of body (Kidney, Eyes, Nervous system). However a low sugar level which can occur
due to excess activity or high dose of insulin can be harmful.self monitoring of blood glucose
(SMBG) by finger pricks is the most commonly used method to monitor sugars at home. HbA1c
is the test which gives an average sugar control of past 3 months which we consider as the test of
choice.
What is Flash glucose monitoring system?
FLASH glucose monitoring system (FGMS) is a recent advance in which a small device will
collect continuous sugar levels from the fluid around the body cells (Interstitial fluid). FGMS has
a sensor with a needle. Sensor is 5mm height and 35mm wide with a needle. Needle is of 0.4mm
thickness placed 5millimeters under the skin surface.
Does FGMS has any side effects?
Usually you will not feel the discomfort of the filament under the skin. Your child may
experience minimal pain at the time of insertion of needle. Sensor can be worn while bathing,
swimming and exercise.
If you take part what will you have to do?
If you allow your child to participate in this study, your child’s sugars will be monitored either
by FGMS+ SMBG or SMBG alone. Irrespective of the group your child assigned to you will
have to do SMBG once in every 14days (4times/day) as you have been routinely doing as per
protocol in the unit.In addition to this if your child belong to (SMBG + FGMS group) along with
SMBG, FGMS Sensor is to be worn for total of 14days for 3 times in next 6 months. ( At
beginning ,2 months and at 4 months).
While on FGMS device, parent/care giver will have to keep record of all meals, exercise,
symptoms of low/high sugars and any other time which the patient/caregiver feel could affect the
sugar level. Neither you nor your doctor will have any choice in whether you will get
FGMS+SMBG or SMBG as this will be decided by a computer program; this is like tossing a
coin and you have an equal chance of getting either method.
106
You will be expected to come for a review to the hospital 2 months after starting the test and
again after 2 months and finally after a further 2 months.HbA1c will be done at the beginning of
the study and at 3rd
and 6months. At each visit you will be given a sheet to document the meals
taken, insulin requirement, any symptoms related to low/high sugars. Difficulties (In-
convenience / interference with daily activities) encountered during the time of FGMS is to be
recorded. No additional procedures or blood tests will be conducted routinely for this study.
If at any time you experience any problems, you will be expected to report this to the doctor.
You will also be contacted by telephone at least once in between the monthly visits by the
doctors in this study who will ask you about any side effects you are experiencing.
Purpose of this study
We assume that continuous sugar monitoring by FGMS can achieve better glycemic control and
there by helps in adjusting the insulin for reduction in HbA1c.
What will happen if you develop any study related injury?
We do not expect any injury to happen to you but if you do develop any side effects or problems due to the study, these will be treated at no cost to you. How will it help you?
This study may or may not help you. At the end of this study if use of FGMS has resulted in
reduction if HbA1c levels and helped in identifying low sugar levels which SMBG missed. Your
doctor may prescribe it for further use.
Will it benefit other people?
The results of the study may provide benefit to other children with Type 1 diabetes for better
management.
Do I have to allow my child/ myself to be part of the study?
No, you are free to refuse the inclusion of your child in the study.
Even if you choose for your child not to be included in the study your child will be treated as per
the protocol followed in endocrinology unit.
If you allow your child to be part of the study you can still withdraw your child from the study at
anytime.
Do i need to pay for the cost of FGMS?
There is no extra cost incurred to the patient. FGMS are provided free of cost to you.
Instructions to caregiver/ patient
1) You have to wear the sensor continuously for 14days
2) Document the details in the sheet provided to you
3) Test finger prick blood glucose 4 times a day once in every 2weeks using the blood
glucose monitoring device
4) Protect the sensor from accidental removal from insertion site
107
ANNEXURE 3
CONSENT TO TAKE PART IN A CLINICAL TRIAL
Study Title: A randomized trial comparing (FGMS) Flash Glucose Monitoring System+ SMBG Vs
(SMBG) self monitoring of blood glucose for glycemic control in adolescents of 12-18years age
with Type 1 diabetes mellitus.
Participant’s name:
Date of Birth / Age (in years):
I_____________________________________________________________
___________, son/daughter of ___________________________________
(Please tick boxes)
Declare that I have read the information sheet provide to me regarding this study and have
clarified any doubts that I had. [ ]
I also understand that my participation in this study is entirely voluntary and that I am free to
withdraw permission to continue to participate at any time without affecting my usual
treatment or my legal rights [ ]
I also understand that neither I, nor my doctors, will have any choice or knowledge of whether I
will get FGMS +SMBG or SMBG alone [ ]
I also understand that during study period, FGMS will be provided free, but after this, if FGMS is
needed, I may have to pay for it [ ]
I understand that I will receive free treatment for any study related injury or adverse event but I
will not receive and other financial compensation [ ]
I understand that the study staff and institutional ethics committee members will not need my
permission to look at my health records even if I withdraw from the trial. I agree to this access [
]
I understand that my identity will not be revealed in any information released to third parties or
published [ ]
108
I voluntarily agree to take part in this study [ ]
Signature (or Thumb impression) of the Subject/Legally Acceptable
Date: _____/_____/______
Signatory’s Name: _________________________________ Signature:
Or
Guardian's name & signature: ………………………………………..
Or
109
ANNEXURE 4 CHILD INFORMATION SHEET
A randomized trial comparing (FGMS) Flash Glucose Monitoring System + SMBG Vs
(SMBG) self monitoring of blood glucose alone for glycemic control in adolescents of
12-18years age with Type 1 diabetes mellitus.
Dear child, you are currently under treatment for Type 1 diabetes mellitus in the endocrinology
division under Child health Unit 1. Your are on insulin for the control of sugar levels.
Type 1 diabetes is a condition in which strict control of sugars prevents the damage to vital
organs of body (Kidney, Eyes, Nervous system). However a low sugar level which can occur
due to excess activity or high dose of insulin can be harmful.
Self monitoring of blood glucose (SMBG) by finger pricks is the most commonly used method
to monitor sugars at home. HbA1c is the test which gives an average sugar control of past 3
months which we consider as the test of choice.
What is Flash glucose monitoring system?
FLASH glucose monitoring system (FGMS) is a recent advance in which a small device will
collect continuous sugar levels from the fluid around the body cells (Interstitial fluid). FGMS has
a sensor with a needle. Sensor is 5mm height and 35mm wide with a needle. Needle is of 0.4mm
thickness placed 5millimeters under the skin surface.
Does FGMS has any side effects?
Usually you will not feel the discomfort of the filament under the skin. Your child may
experience minimal pain at the time of insertion of needle. Sensor can be worn while bathing,
swimming and exercise.
If you take part what will you have to do?
If you agree to participate in this study, your sugars will be monitored either by FGMS+ SMBG
or SMBG alone.
Irrespective of the group you assigned to you will have to do SMBG once in every 14days
(4times/day) as you have been routinely doing as per protocol in the unit.
In addition to this if you belong to (SMBG + FGMS group) along with SMBG, FGMS Sensor is
to be worn for total of 14days for 3 times in next 6 months. ( At beginning ,2 months and at 4
months).
While on FGMS device, you/care giver will have to keep record of all meals, exercise, symptoms
of low/high sugars and any other time which the patient/caregiver feel could affect the sugar
level. Neither you nor your doctor will have any choice in whether you will get FGMS+SMBG
or SMBG as this will be decided by a computer program; this is like tossing a coin and you have
an equal chance of getting either method.
You will be expected to come for a review to the hospital 2 months after starting the test and
again after 2 months and finally after a further 2 months.HbA1c will be done at the beginning of
110
the study and at 3rd
and 6months. At each visit you will be given a sheet to document the meals
taken, insulin requirement, any symptoms related to low/high sugars. Difficulties (In-
convenience / interference with daily activities) encountered during the time of FGMS is to be
recorded. No additional procedures or blood tests will be conducted routinely for this study.
If at any time you experience any problems, you will be expected to report this to the doctor.
You will also be contacted by telephone at least once in between the monthly visits by the
doctors in this study who will ask you about any side effects you are experiencing.
Purpose of this study
We assume that continuous sugar monitoring by FGMS can achieve better glycemic control and
there by helps in adjusting the insulin for reduction in HbA1c.
What will happen if you develop any study related injury?
We do not expect any injury to happen to you but if you do develop any side effects or
problems due to the study, these will be treated at no cost to you.
How will it help you?
This study may or may not help you. At the end of this study if use of FGMS has resulted in
reduction if HbA1c levels and helped in identifying low sugar levels which SMBG missed. Your
doctor may prescribe it for further use at which point you need to buy the devise at your own
expense.
Will it benefit other people?
The results of the study may provide benefit to other children with Type 1 diabetes for better
management.
Do I have to be part of the study?
No, you are free to refuse to be included in the study.
Even if you choose for your child not to be included in the study you will be treated as per the
protocol followed in endocrinology unit.If you are willing to be part of the study you can still
withdraw your child from the study at anytime.
Do i need to pay for the cost of FGMS?
There is no extra cost incurred to the patient. FGMS are provided free of cost to you.
Instructions to caregiver/ patient
1) You have to wear the sensor continuously for 14days
2) Document the details in the sheet provided to you
3) Test finger prick blood glucose 4 times a day once in every 2weeks using the blood
glucose monitoring device
4) Protect the sensor from accidental removal from insertion site.
111
ANNEXURE 5 CONSENT TO TAKE PART IN A CLINICAL TRIAL
Study Title: A randomized trial comparing (FGMS) Flash Glucose Monitoring System+ SMBG Vs
(SMBG) self monitoring of blood glucose for glycemic control in adolescents of 12-18years age
with Type 1 diabetes mellitus.
Participant’s name:
Date of Birth / Age (in years):
I_____________________________________________________________
___________, son/daughter of ___________________________________
(Please tick boxes)
Declare that I have read the information sheet provide to me regarding this study and have
clarified any doubts that I had. [ ]
I also understand that my participation in this study is entirely voluntary and that I am free to
withdraw permission to continue to participate at any time without affecting my usual
treatment or my legal rights [ ]
I also understand that neither I, nor my doctors, will have any choice or knowledge of whether I
will get FGMS +SMBG or SMBG alone [ ]
I also understand that during study period, FGMS will be provided free, but after this, if FGMS is
needed, I may have to pay for it [ ]
I understand that I will receive free treatment for any study related injury or adverse event but I
will not receive and other financial compensation [ ]
I understand that the study staff and institutional ethics committee members will not need my
permission to look at my health records even if I withdraw from the trial. I agree to this access [
]
I understand that my identity will not be revealed in any information released to third parties or
published [ ]
I voluntarily agree to take part in this study [ ]
112
Signature (or Thumb impression) of the Subject/Legally Acceptable
Date: _____/_____/______
Signatory’s Name: _________________________________ Signature:
Or
Guardian's name & signature: ………………………………………..
Or
113
ANNEXURE 6
114
115
116
117
118
ANNEXURE 7
119
ANNEXURE 8
FGMS DATA