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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

d 2

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 antidiabetic 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 Particulars Period – 24 months1 Literature collection 2month2 Study drug drug preparation 1 month3 Subject recruitment 12 months4 Data entry & processing 3 months5 Data analysis 2 months

6. Manuscript writing 4 months.

Budget:

Particulars 1st year 2nd yearEquipments 100000 -----Study drug purchase 1,20000 80000

Reagents and chemicals 100000 60000

Books& journals 20,000 10000Stationary & consumables 10000 10000

TA/DA 20,000 20,000contingency 20000 20000Total

3,90000 200000

Rupees Five lakhs ninety thousand only 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 Hos .ID NO : Sl.No

Name : ________________________________________________________________________________

3. Gender Male Female

4. Date of Birth : Age (in yrs.) :

5.Address.........................................................................................................................................................................

Contact Number …………………………………………….

CRITERIA OF SELECTION Yes (1 ) No (0)

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

NIS

Date: ____________ Signature of the Investigator: ______________________

. The Tamilnadu Dr. MGR. Medical University , Guindy,Chennai




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 Read and write Primary

Middle school High school College

6. Nature of work :

Sedentary Field work with physical labour

Field work with intellectual

Indicate nature of work……………………………………………………….

7. Complaints and Duration:

8. History of present illness:

9. History of Past illness:

10. Socio economic status:

2 3

5 6

1

1

4

Income group 1.lower 2.middle 3.higher

11. Treatment History:Had the patient been treated before with Allopathy drug? Yes No

1.Yes 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 1. Yes; duration ________ years; Quantity _____ ___ 2.NoB) Tobacco chewing 1. Yes; duration ________ years 2.No C) Betel chewing 1. Yes; duration ________ years 2.NoD) Alcoholism 1. Yes; duration ________ years; Quantity ______ml 2.No

14.Dietry style: A.)Pure vegetarian B.)Non-vegetarian C.) mixed diet

15. Menstrual & Obstetric history:

Date: ____________ Signature of the Investigator: ______________________





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? Yes No

1 2 3 4AdverseExperience

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 medicationUnrelated-1,Possible-2,Probable-3

Did the event require to stop the drug

Outcome of the event

Date and time of report

Signature of the investigator

SIDDHA ASPECTS:

Parameter 0 Day 15th Day 30th Day 45th DayNilam KurinjiMullaiMaruthamNeithalPalaiParuvakalam KarKoothirMunpaniPinpaniElavenilMuthuvenilUdalthanmaiVathamPithamKabamKalappuGunam SathuvamRasathamThamasamVatham PirananAbananViyananUthananSamananNagamKoormanKirugaran DevathatnPitham Anal pithamRanjaga pithamSadhaga pithamAlosaga pithamPirasaga pithamPoripulangal Mei-oooru Vai-suvaiKan-oliMooku-manamSevi-osaiKanmenthiriu -Kai-vasanam

kal-kamanam

vai-dhanam

Eruvai-visarkam

Parameter 0 Day 15th Day 30th Day 45th DayKaruvai-anantham.

PiraUruppukalin Nilai IruthayamPuppusam

Eraippai

Kalleral

Manneeral

Kudal

Siruneeragam

Siruneerpai

Moolai.

Kabam Avalambagam

Kiletham

Pothgam

Tharpagam

Sandhigam

Udal Thathukkal Saaram

Senner

Oon

Kozhuppu

Enbu

Moolai

Sukkilam/Suronitham

Signature of the investigator:

Envagai Thervugal

S.N

o

Siddha Parameters 0 Day 15th Day 30th Day 45th Day

1 NAA THERVU - TONGUE

Niram (colour)

Thanmai (Character)

Pulan (sense)

2 NIRAM THERVU –

Examination of colour

3 MOZHI THERVU-

EXAMINATION 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

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 15th day 30th day 45 day

LOCOMOTOR SYSTEM

CARDIOVASCULAR SYSTEM

RESPIRATORY SYSTEM

GASTROINTESTINAL SYSTEM

CENTRAL NERVOUS SYSTEM

UROGENITAL SYSTEM

ENDOCRINE SYSTEM

16. CLINICAL SYMPTOMS

S.NO CLINICAL SYMPTOMS 0th day 15th day 30th day 45 day

1. POLYURIA

2. NOCTURIA

3. POLYDIPSIA

4. POLYPHAGIA

5. BODY PAIN

6. WEIGHT GAIN / Loss

7. TIREDNESS

8. BURNING FEET

9. GENITAL PRURITUS

SIGNATURE OF THE INVESTIGATOR





LABORATORY PARAMETERS-CHART

1. OP/IP No: _____________ 2.S. No:

3. Name: _________________________ 4. Age: _______ years 5.Gender: M/F

BLOOD INVESTIGATION NORMAL VALUES

BEFORE TMT

Date:

AFTER TMTDate:

HB( gms%) M:13-18W:11-16

T.RBC(milli/cu.mm)M:4.5-6.5W:3.5-5.5

ESR (mm)

½ hr. -

1 hr. M:0-10W:0-20

T.WBC (/cu.mm) 4000-11000

DIFFERENTIAL COUNT (%)

Polymorphs 40-75

Lymphocytes 20-35

Monocytes 2-10

Esonophils 1-6

Basophils 0-1

Blood Investigation Normal Values

Before TMT Date:

After TMT Date:

Lipid profile (mg/dl)

Serum cholesterol 150-250

HDL 30-60

LDL Upto 130

VLDL 40

TGL Upto 160

RFT (mg/dl)

Blood urea 16-50Serum creatinine 0.6-1.2

Serum Uric acid M:3-9W: 2.5-7.5

LFT (mg/dl)

Total bilirubin 0.3-1Direct bilirubin 0.1-0.3Indirect bilirubin 0.2-0.8Serum total protein 6-8Serum Albumin 3.5-5.5Serum globulin 2-3.5Serum calcium 9-11Serum phosphorous 2-5SGOT (IU/L) 6-18SGPT (IU/L) 3-26Alkaline phosphatase (IU/L) 80-290

SPECIFIC INVESTIGATION:

HBA1c Before Tmt After Tmt

SIGNATURE OF THE INVESTIGATOR

URINE INVESTIGATION 0,15, 30 ,45,60 ---90

Albumin

Fasting sugar

PP sugar

Deposits

creatinine

BLOOD GLUCOSE LEVEL 0 day 15th day 30th day

Fasting Blood Glucose

2 Hours Postprandial

MEDICINE DAILY INTAKE CHART

1. Subject name : 2. Patient ID No : Starting Date:

Day Dose Day Dose

1 Morning 12 Morning

Evening Evening


Evening Evening


Evening Evening


Evening Evening

5 Morning

Evening

6 Morning

Evening

7 Morning

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 – 47AYOTHIDASA PANDITHAR HOSPITAL


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 1 st 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 – 47AYOTHIDASA PANDITHAR HOSPITAL


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 Signature

Patient

Investigator

Witness

åŠ¹î™ ð®õ‹

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