Comparative study on the changes in HBA1c levels in pre

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Comparative study on the changes in HBA1c levels in pre-diabetic
and diabetic individuals treated with Siddha formulation – A non
randomized open clinical study
Investigators:
PI
Dr. K. RAJALAKSHMI M.D.(s) P.G.Dip in drug standardisation
Assistant professor ,
Department of Siddha,
The Tamilnadu DR. MGR. Medical University, Chennai
Co PI -1 Dr. Shunmuga priya , M.D.(s)
Lecturer,
Department of Toxicology ( Nanjunool)
National Institute of Siddha ,Chennai
Co PI -2 Dr. Christian , M.D.(s)
Associate professor
Department of Pathology,( NoI Nadal)
National Institute of Siddha ,Chennai
Protocol submitted to
The Institutional Ethical Committee at NIS, Chennai.
Comparative study on the changes in HBA1c levels in pre-diabetic and
diabetic individuals treated with Siddha formulation – A non randomized
open clinical study
Background and justification:
Diabetes mellitus (DM) is a chronic progressive metabolic disorder characterized by
hyperglycemia mainly due to absolute (Type 1 DM) or relative (Type 2 DM) deficiency of
insulin hormone. (1) Eventhough the Conventional modern therapy provides a number of
treatment modalities for type 2 diabetes like a lifelong commitment to blood sugar monitoring
healthy eating regular exercise, possible diabetes medication or insulin therapy, the burden of the
disease is steadily progressing. The World Health Organization (WHO) has projected that the
prevalence of diabetes is increasing in epidemic proportions especially in developing countries.
India has the highest number of people with Diabetes in the World . Every 8 seconds a person
dies of diabetes at the same 8 seconds two persons become diabetics (2).
As per the 2011 ICMR studies showed that there are 62.4 million people live with diabetes in
India, and 77.2 million people are on the threshold, with pre-diabetes. Indian Council of Medical
Research – India Diabetes (ICMR-INDIAB) Study have provided data from three States and one
Union Territory, representing nearly 18.1 per cent of the nation's population was diabetic.(3)
Diebetes is a comparable condition with Madhumegam or neerizhivu In Siddha literatures. A
number of siddha formulations and single drugs are widely used to treat diabetes . Mostly they
are all not well documented and also scientific data is lacking. With this current scenario this
study is planned to evaluate the efficacy of a Siddha formulation Avirai Kudineer with herbal
ingredients mentioned in the olden literature Theran Kudineer -100 and also in Gunapadam
mooligai vaguppu. Even though this combination is popularly used in the clinical practice, we
are not able to find out any scientific evaluation and published data about this formulation. The
HbA1c has become the most commonly used measure of chronic glycaemia in epidemiological
studies,clinical trials and the management of diabetes since its introduction more than 25 years
ago (4)
Through this study it planned to evaluate the efficacy of Avirai Kudineer a in pre diabetic and
diabetic individuals with respect to the changes in glycosilated haemoglobin. And also to
compare the efficacy of the drug in pre- diabetic and diabetic groups.
Objectives :
Primary Objectives:
Changes from baseline in glycosylated hemoglobin
Secondary objectives







Estimate the Blood glucose levels .
Change from baseline in other Clinical Laboratory Tests
Change from baseline in Body Weight
Percentage of treatment responders defined as a patient with 0.6% decrease in HbA1c
from baseline visit to final visit or accomplishment of a HbA1c value at or below 6.5 (4)
Changes in symptom scores
Adherence to drug treatment
Adverse event if any.
Methods:
Study design:
Non-randomized open clinical study.
Sampling Method:
Purposive sampling
Sample size calculation:
Proportion of efficacy is assumed as 50% and the difference is assumed as 30%. With this
assumption the sample size is calculated.
P1Q1 + p 2 q2
___________________
( Z& + Z B )2
d2
With the 20% extra subjects for dropouts, the desired sample size for this study is 50 subjects in
each group will be included for this study.
Study area and Study population
Patients who are attending the OPD of National Institute of Siddha, Chennai -47 are included.
Study Period:
Two years from getting the ethical clearance.
Operational definition:
Diabetes:
It is defined as the subjects with the HbA1c 6.5% or higher estimation.
Prediabetes:
It is defined as the study subjects with the HbA1c 5.7%-6.4%.(7)
As per the ADA recommendation the above are followed. If ADA set new levels that will be
followed.
Inclusion criteria




Age> 20 years
both gender
diagnosed with or without clinical symptoms
HbA1c : 5.7% - 6.4% in group 1 without exposure to anti-diabetic treatment


HbA1c: 6.5% or higher in group 2 with or without prior anti- diabetic treatment
Post prandial blood sugar <300 mgs/dl
Exclusion criteria








Existing renal failure and elevated serum creatinine levels
Pregnant and lactating women
Age<20 years
known hepatic and cardiac diseases
Subjects those who are not willing to give informed consent
Women those who are planning for pregnancy
HbA1c less than 5.7%
PP blood sugar >300 mgs/dl
Ethical clearance:
Ethical clearance will be obtained from IEC of National Institute of Siddha, Chennai.
Informed consent:
Informed consent will be obtained from all the participants before the subject recruitment.
Description of Intervention:
Dosage/ Dosage regimen/Route of administration/Frequency of administration.
Avirai Kudineer decoction 60 ml per oral twice daily for three months( 5,6)
Follow up procedure:
On the day of admission to the study:



FBS, OGTT, HbA1c, lipid profile, Renal function test, Urine- routine, albumin creatinine
ratio
Baseline clinical parameters assessment.
Medicines will be issued for 15 days reviewed once in 15 days for three months.
At the end of the study:


Above mentioned laboratory investigations will be repeated
Clinical parameters assessment will be done in each visit.
Expected Outcomes:
Primary:
HbA1C decrease with 0.6% from baseline visit to final visit
Secondary:
Reduction in blood glucose levels from base line to end of the study period
Changes in other laboratory parameters.
Changes in symptoms score.
Change from baseline in Body Weight
Data collection procedures and data analysis:
Data will be collected with the semi-structured questionnaire and from the investigation reports.
Data will be entered in Excel and imported to SPSS. It will be coded and cleaned. Statistical
analysis will be done by using SPSS.
Time line:
Sl.no
1
2
3
4
5
Particulars
Literature collection
Study drug drug preparation
Subject recruitment
Data entry & processing
Data analysis
Period – 24 months
2month
1 month
12 months
3 months
2 months
6.
Manuscript writing
4 months.
Budget:
Particulars
Equipments
Study drug purchase
1st year
100000
1,20000
2nd year
----80000
Reagents and chemicals
100000
60000
Books& journals
Stationary & consumables
20,000
10000
10000
10000
TA/DA
contingency
Total
20,000
20000
20,000
20000
3,90000
Rupees Five lakhs ninety thousand only
200000
5,90,000
References:
1.Role of self-care in management of diabetes mellitus Saurabh et.al Journal of Diabetes &
Metabolic Disorders 2013, 12:14
2. www.idf.org/webdata/docs/.../Parliamentary-template.do... - United States
3. V. Mohan icmr indiab-study-provides-new-figures-for-diabetes/article2497931.ece
Sep 29, 2011
4.Nathan, D.M., Turgeon, H., Regan, S., Diabetologia 2007, 50, 2239- 2244.
5.Observational Study to Assess Glycosylated Hemoglobin Changes After 6 Months of
Treatment With Pioglitazone. ClinicalTrials.gov Identifier: NCT00449553 2007.
6. Theran kudineer -100 (74th stanza), 2nd edition, Central council for Research in Ayurveda and Siddha,
New Delhi-110058.
7.Vaithiya rathinam, K.S.Murugesa mudaliar, Gunapaadam mooligai vaguppu, Indian Medicine and
Homeopathy; 4th edition at 1988; page no- 65.
8. http://www.nlm.nih.gov/medlineplus/medlineplus.html
The Tamilnadu Dr. MGR. Medical University , Guindy,Chennai
&
NATIONAL INSTITUTE OF SIDDHA, CHENNAI
AYOTHIDASA PANDITHAR HOSPITAL
Comparative study on the changes in HBA1c levels in pre-diabetic and diabetic
individuals treated with Siddha formulation – A non randomized open clinical study.
FORM I – SCREENING BEFORE TREATMENT
1. Centre
Name :
NIS
Hos .ID NO :
Sl.No
________________________________________________________________________________
3. Gender
Male
4. Date of Birth :
Female
Age (in yrs.) :
5.Address.........................................................................................................................................................................
Contact Number …………………………………………….
CRITERIA OF SELECTION







Age> 20 years
Diagnosed with or without clinical symptoms .
HbA1c : 5.7% to 6.4% in group 1
HbA1c: 6.5% or higher in group 2
IFG
IGT
PPBS < 300
CRITERIA FOR EXCLUSION
 Existing renal failure,
 Pregnant and lactating women,
 Age<20 years,
 known hepatic and cardiac diseases
 Subjects those who are not willing to give informed consent,
 Women those who are planning for pregnancy .
 HbA1c <5.6
 IDDM

PPBS > 300
Yes (1 )
No (0)
Date: ____________
Signature of the Investigator:
______________________
. The Tamilnadu Dr. MGR. Medical University , Guindy,Chennai
&
NATIONAL INSTITUTE OF SIDDHA, CHENNAI
AYOTHIDASA PANDITHAR HOSPITAL
Comparative study on the changes in HBA1c levels in pre-diabetic and diabetic individuals
treated with Siddha formulation – A non randomized open clinical study.
CASE REPORT FORM II – HISTORY
1.Centre
Hospital ID Number
Sl. No.
2 Subject Name : ....................................................................................................................
3 Gender
Male (1)
Female (2)
4. Date of Birth :
Age (in yrs.):
5. Educational status:
Illiterate
1
Read and write 2
Middle school
4
High school
Primary
College
5
6. Nature of work :
Sedentary
1T
Field work with physical labour
4
4
a
Field work with intellectual
1
4
m
Indicate nature of work………………………………………………………. 4
i
7. Complaints and Duration: l
n
a
8. History of present illness: d
u
D
9. History of Past illness: r
.
M
10. Socio economic status: G
R
.
M
e
F
i
e
l
d
w
o
r
k
w
i
t
h
i
3
6
Income group 1.lower
2.middle
3.higher
11. Treatment History:
Had the patient been treated before with Allopathy drug? Yes
1.Yes
No
2.No
Insulin injection
Oral antidiabetic drugs
Duration of Treatment ………………………………….
12. Family history:
Whether diabetes mellitus runs in family?
1) Yes
2) No
If yes, mention the relationship of affected person(s)
1. ______________
2. ______________
3. ______________
13. Habit of
A) Smoking
B) Tobacco chewing
C) Betel chewing
D) Alcoholism
1. Yes; duration ________ years; Quantity _____ ___
1. Yes; duration ________ years
1. Yes; duration ________ years
1. Yes; duration ________ years; Quantity ______ml
14.Dietry style: A.)Pure vegetarian
B.)Non-vegetarian
2.No
2.No
2.No
2.No
C.) mixed diet
15. Menstrual & Obstetric history:
Date: ____________
Signature of the Investigator:
______________________
The Tamilnadu Dr. MGR. Medical University , Guindy,Chennai
&
NATIONAL INSTITUTE OF SIDDHA, CHENNAI
AYOTHIDASA PANDITHAR HOSPITAL
Comparative study on the changes in HBA1c levels in pre-diabetic and diabetic individuals
treated with Siddha formulation – A non randomized open clinical study.
CASE REPORT FORM III A - ADVERSE EVENTS RECORD
1. Centre :
ID Number
Sl. No
3. Subject Name : ....................................................................................................................
7. Date of Assessment :
ADVERSE EVENTS
1. Does the patient have any symptoms with medication in trial group?
1
Adverse
Experience
Event Date& Time
Date of 1St Dose
Date of Last dose
Pattern
Isolated1,Intermittent2Continuous-3
Severity
Mild-1,Moderate-2,Severe-3
Serious*
Yes-1 , No-2
Relationship to study medication
Unrelated-1,Possible-2,Probable-3
Did the event require to stop the drug
Outcome of the event
2
Yes
3
No
4
Date and time of report
Signature of the investigator
SIDDHA ASPECTS:
Parameter
Nilam
Kurinji
Mullai
Marutham
Neithal
Palai
Paruvakalam Kar
Koothir
Munpani
Pinpani
Elavenil
Muthuvenil
UdalthanmaiVatham
Pitham
Kabam
Kalappu
Gunam
Sathuvam
Rasatham
Thamasam
Vatham Piranan
Abanan
Viyanan
Uthanan
Samanan
Nagam
Koorman
Kirugaran
Devathatn
Pitham Anal pitham
Ranjaga pitham
Sadhaga pitham
Alosaga pitham
Pirasaga pitham
Poripulangal Mei-oooru
Vai-suvai
Kan-oli
Mooku-manam
Sevi-osai
0 Day
15th Day
30th Day
45th Day
Kanmenthiriu -Kai-vasanam
kal-kamanam
vai-dhanam
Eruvai-visarkam
Parameter
Karuvai-anantham.
PiraUruppukalin Nilai
Iruthayam
Puppusam
Eraippai
Kalleral
Manneeral
Kudal
Siruneeragam
Siruneerpai
Moolai.
Kabam Avalambagam
Kiletham
Pothgam
Tharpagam
Sandhigam
Udal Thathukkal Saaram
Senner
Oon
Kozhuppu
Enbu
Moolai
Sukkilam/Suronitham
0 Day
15th Day
30th Day
45th Day
Signature of the investigator:
Envagai Thervugal
S.No Siddha Parameters
1
NAA THERVU - TONGUE
Niram (colour)
Thanmai (Character)
Pulan (sense)
2
NIRAM THERVU –
Examination of colour
3
MOZHI THERVUEXAMINATION OF SPEECH
4
VIZHI THERVU – EYE
Niram (colour)
Thanmai (Character)
Pulan (sense)
5
MALAM THERVU-MOTION
Niram (colour)
Nurai (Froth )
Elaga/ Erugal (constancy)
6
MOOTHIRAMTHERVUURINE
a) Neerkuri:
Niram (colour)
Adarthi (specific graviy)
Manam (Odour)
Nurai (froth)
Enjal ( deposits)
(b) Neikuri
7
PARISAM THERVU
By TOUCH
8
NAADI THERVU – PULSE
0 Day
15th Day
30th Day
45th Day
Thanmai (Pattern)
Nadi (throb )
Signature of the investigator:
14. GENERAL EXAMINATION:
0th day
15th day
30th day
45 day
Height (cms)
Weight (kg)
Temperature(°F)
Pulse rate (per min)
Heart rate (per min)
Respiratoryrate(per min)
Blood pressure(mm/Hg)
Pallor
Jaundice
Cyanosis
Lymphadenopathy
Pedal edema
Clubbing
Jugular venous pulsation
15. SYSTEMIC EXAMINATION:
0th day
LOCOMOTOR
SYSTEM
CARDIO
VASCULAR
SYSTEM
15th day
30th day
45 day
RESPIRATORY
SYSTEM
GASTRO
INTESTINAL
SYSTEM
CENTRAL
NERVOUS
SYSTEM
UROGENITAL
SYSTEM
ENDOCRINE
SYSTEM
16. CLINICAL SYMPTOMS
S.NO
CLINICAL SYMPTOMS
1.
POLYURIA
2.
NOCTURIA
3.
POLYDIPSIA
4.
POLYPHAGIA
5.
BODY PAIN
6.
WEIGHT GAIN / Loss
7.
TIREDNESS
8.
BURNING FEET
9.
GENITAL PRURITUS
0th day
SIGNATURE OF THE INVESTIGATOR
15th day
30th day
45 day
The Tamilnadu Dr. MGR. Medical University , Guindy,Chennai
&
NATIONAL INSTITUTE OF SIDDHA, CHENNAI
AYOTHIDASA PANDITHAR HOSPITAL
Comparative study on the changes in HBA1c levels in pre-diabetic and diabetic individuals
treated with Siddha formulation – A non randomized open clinical study.
LABORATORY PARAMETERS-CHART
1. OP/IP No: _____________
2.S. No:
3. Name: _________________________
BLOOD INVESTIGATION
M:4.5-6.5
W:3.5-5.5
T.RBC(milli/cu.mm)
½ hr.
1 hr.
T.WBC (/cu.mm)
DIFFERENTIAL
COUNT (%)
NORMAL
VALUES
M:13-18
W:11-16
HB( gms%)
ESR (mm)
4. Age: _______ years
M:0-10
W:0-20
4000-11000
Polymorphs
40-75
Lymphocytes
20-35
Monocytes
2-10
Esonophils
1-6
Basophils
0-1
BEFORE
TMT
Date:
5.Gender: M/F
AFTER TMT
Date:
Blood Investigation
Serum cholesterol
Lipid
profile
(mg/dl)
30-60
LDL
Upto 130
TGL
Blood urea
Serum creatinine
Serum Uric acid
Total bilirubin
LFT
(mg/dl)
Direct bilirubin
Indirect bilirubin
Serum total protein
Serum Albumin
Serum globulin
Serum calcium
Serum phosphorous
SGOT (IU/L)
SGPT (IU/L)
Alkaline
phosphatase (IU/L)
URINE
INVESTIGATION 0,15,
30 ,45,60 ---90
Albumin
Fasting sugar
PP sugar
150-250
HDL
VLDL
RFT
(mg/dl)
Normal
Values
40
Upto 160
16-50
0.6-1.2
M:3-9
W: 2.5-7.5
0.3-1
0.1-0.3
0.2-0.8
6-8
3.5-5.5
2-3.5
9-11
2-5
6-18
3-26
80-290
Before TMT
Date:
After TMT
Date:
Deposits
creatinine
SPECIFIC INVESTIGATION:
BLOOD GLUCOSE LEVEL
0 day
15th day
30th day
Fasting Blood Glucose
2 Hours Postprandial
HBA1c
Before Tmt
SIGNATURE OF THE INVESTIGATOR
After Tmt
MEDICINE DAILY INTAKE CHART
1. Subject name
Day
1
Dose
Morning
2. Patient ID No:
:
Day
12
Evening
2
Morning
Morning
13
Morning
Evening
5
Morning
Evening
6
Morning
Evening
7
Morning
Morning
Evening
14
Evening
4
Morning
Evening
Evening
3
Dose
Morning
Evening
15
Morning
Evening
Starting Date:
Evening
8
Morning
Evening
9
Morning
Evening
10
Morning
Evening
11
Morning
Evening
Informed consent form,
The Tamilnadu Dr. MGR. Medical University , Chennai &
NATIONAL INSTITUTE OF SIDDHA, CHENNAI – 47
AYOTHIDASA PANDITHAR HOSPITAL
Comparative study on the changes in HBA1c levels in pre-diabetic and diabetic individuals
treated with Siddha formulation – A non randomized open clinical study.
Information to patient .
You are asked to take part in “ Comparative study on the changes in HBA1c levels in pre-diabetic
and diabetic individuals treated with Siddha formulation – A non randomized open clinical study.”
. It is important to know about the study, how the study is being done and how your information will be
used and the possible benefits, risks and discomforts. Hence please read the following information.
What is the background and the purpose of the study?
The stones that are formed in the urinary passage and the kidney are called urolithiasis. Food habits,
drinking water and personal activities are the major reasons for this problem. Recent data shows 5-15%
of people are affected by this problem world-wide and there is 50% chance of relapse of stone disease is
also possible. The occurrence is increasing day by day especially in tropical countries like India.
The kidney stones are mainly treated by surgical removal. Medical treatment part is not that much
satisfactory in treating the stone disease. In Siddha literatures many herbal and herbo-mineral
preparations are available for not only to treat the stones but also to prevent from relapse with oral
medication.
The purpose of the study is to provide an effective medical cure through Siddha
formulations.
What are the clinical symptoms?
Acute colicky flank pain that may radiate to lower abdomen or groin often associated with nausea
and vomiting. Urinary symptoms like burning urination, frequency and urgency or sometimes urinary
obstruction and passing of small sand like material or a small stone along with urine.
What are the complications that may occur if untreated ?
If untreated the stone size will increase day by day and sometimes when it descends it will obstruct
the urinary passage and may require immediate surgery. Renal failure may occur in certain cases.
What are the study drugs?
Sindhuvallathy mezhugu capsule -500 mg twice daily and Kalladaippu kudineer -130 ml two times a
day for 45 days. These Siddha medicines that will be used are herbal and herbo-mineral preparation that
are in use for centuries. Most of them are already proved for its effect on kidney stones. They are found
naturally and devoid of major side effects. You will be given the option to tae part in this interventional
study after your consent if you don’t want to participate, you can stop the treatment at any point of
time.
Likewise, the doctor conducting the study may decide that continuing with study medication is no
longer in your best interest and in that case you will be advised to stop
Form –E (page 2 of 3)
taking the study medicines. Even if your study medications is stopped your health progress will be
followed for the remaining study period.
What will happen to me if I take part?
You will be interrogated via structural questionnaires to collect information on you personal data,
health information, physical activity level, nutritional data and psychological pattern, Your constitutional
assessment and your naadi, neerkuri tests will be done on first day and also in every follow up.
A series of blood tests urinary tests, X-ray KUB and ultrasound will be done. You will be asked to
collect 24 hours urine during the follow-up visits. X-ray and/or ultrasound will be done on 1st and 45th
days or as of when required. The results of the tests will then be explained to you.
What are the possible benefits of taking part?
It
is hoped that the treatment you receive will help to reduce the size of the stone, expel it easily and
prevent from further formations. This helps to avoid serious renal problems. However this cannot be
guaranteed. The information we get from this study may help us in the future to improve the treatment
of subjects with kidney stones, promote the use of Siddha medicine as a cost effective substitute to the
more expenditure surgical treatment.
This is a chance to know about the health of the renal system with these tests whether you have risk
factors like diabetes and any other underlying disease. You have the benefit of dietary advice, water
intake etc. You will get the reports of the investigation done on you. You have a chance of getting all the
above facilities and the Siddha drugs for 45 days at free of cost.
What will be the expenses to take part?
You need not pay any money for the study up to the study period. The cost of medicines and
investigations will be bourne by the investigator / funding agency.
Any remuneration will be given to participate in this study?
You will not be paid any amount to take part in this study. In case of any emergency you will be
referred to the urology department of nearby government hospital for further treatment or to assess
the problem.
How will my personal data be used?
By signing this form you give your consent to collect and use your personal data for the study. The study
data which does not have a specific expiration date but the confidentiality of the data will be
maintained. The study data will be identified by an Id number and the personal identity will not be
disclosed or shared it with others.
Form –E (page 3 of 3)
Your data will be used to find out the efficacy of Siddha formulation on kidney stones. This information
may be highly useful in deciding the therapy for the population at large.
You have the right to request information about your study. If you withdraw your consent the
investigator will no longer use your study data or share it with others.
The Tamilnadu Dr. MGR. Medical University , Chennai &
NATIONAL INSTITUTE OF SIDDHA, CHENNAI – 47
AYOTHIDASA PANDITHAR HOSPITAL
Comparative study on the changes in HBA1c levels in pre-diabetic and diabetic individuals
treated with Siddha formulation – A non randomized open clinical study.
Informed consent
I________________________________s/o or D/o ________________________Study ID number
__________________ have accepted to participate in this study. Your data will be used to find out the
efficacy of Siddha formulation on diabetes. This information may be highly useful in deciding the therapy
for the population at large.
You have the right to request information about your study. If you withdraw your consent the
investigator will no longer use your study data or share it with others.
Contact person
whenever you have question about the study or your study medication, you will be given a contact
number of the doctor so that you can call for help.
Dr. K. Rajalakshmi / Dr. Shunmuga priya/ Dr.Christian
Phone- 98409 61455.
Consent
I received verbal information on the above study and have read/ understood the attached written
information. I have been given the chance to discuss the study and ask questions. I consent to take part in
the study and I am aware my participation is entirely voluntary. I understand that I may withdraw any
time without this affecting my future care. I understand that I will have to take the treatment as specified
by the study and I will ensure that the medicines are taken as recommended. By signing this information
and consent form I agree that my personal data may be used as described in this consent form.
Name
Patient
Investigator
Witness
Signature
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