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SAR-PM 3 March 2011

STUDY PROTOCOL

A Unicenteric, Observational Trial To Assess The Efficacy Of


Ayurvedic Therapy In Progressive Myopia, Ayurveda In
Curing/ Maintaining/ Preventing Further Complication Of
Progressive Myopia.

STUDY NUMBER: 311

STUDY CODE: SAR- PM

VERSION DATE: 3 March2011

CLINICAL STUDY DIRECTOR:

Any and all information presented in this document shall be treated as confidential and shall remain the exclusive
property of sreedhareeyam ayurvedic eye hospital. The use of such confidential information must be restricted to the
recipient for the agreed purpose and must not be disclosed, published or otherwise communicated to any unauthorized
persons, for any reason, in any form whatsoever without the prior
written consent of sreedhareeyam ayurvedic eye hospital .

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SAR-PM 3 March 2011

Name and Address

Investigator Dr.N.P.P.Namboothri
President, Sreedhareeyam Ayurvedic Eye Hospital and
Research Institute,
Nelliakkattu Mana, Kizhakombu,
Koothattukulam,Ernakulam,
Kerala- 686662

Co-Investigator Dr.Sreekant .P. Namboothri,


Director of Clinical Research Dept,
Sreedhareeyam Ayurvedic Eye Hospital and Research
Institute,
Nelliakkattu Mana, Kizhakombu,
Koothattukulam,Ernakulam,
Kerala-686662

Sponsor Ayush

Other Emergency
Telephone Numbers

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SAR-PM 3 March 2011

CLINICAL TRIAL SUMMARY


Title A Unicenter, Observational Trial To Assess The Efficacy Of Ayurvedic
Therapy In Progressive Myopia , Ayurveda In
Curing/Maintaining/Preventing Further Complication Of Progressive Myopia.
Trial location Sreedhareeyam Ayurvedic Medicines, NelliakkattuMana, Kizhakombu,
Koothattukulam,Ernakulam,Kerala-686662
Study Objective -The primary objective is to demonstrate the efficacy of ayurveda
in treating progressive myopia.
-The secondary objective is to see whether Ayurveda is more effective as
- Curing the condition.
- Maintaining the progressive myopia
- Preventing from further complications.
Study Design - Observational trial where in the patients will receive ayurvedic
medication as per the complaints.
- 1 year trial with 2 inpatient visit; 2 follow up (telephonically); end of
treatment visit (OPD)
- Written consent of the patient will be obtained from all the patients
participating before study enrollment.
- 60 patients will be randomized to get 50 completers; the number of patients
can be increased as per need.
- Enrollment period is 90 days followed by treatment and follow up visit

Study Duration 1 year from baseline visit of the patient (per patient)

Study Population 50 patients; the number of patients can be increased as per need.

Assessment Schedule - Patient assessed at baseline visit will be enrolled for the trial if found eligible,
- There will be 2 inpatient treatment visits and telephonic follow ups will be
done every 3 months..
- Patients who discontinued study will be assessed for follow up in
every 3 months, at least up to their planned end of treatment period.
-End treatment will be 1 year from baseline visit +/-1months.
Statistical consideration The statistical analysis will be done with SPSS 15.0,ANOVA
Inclusion criteria ▪ Male and female; age- between 3-25yrs irrespective of sex, race, religion,
socio-economic status
▪ Patients clinically diagnosed as progressive myopia.
▪ Women of child bearing potential are required to have a documented
negative serum or urine pregnancy test before the start of therapy.
Exclusion criteria ▪ Patients with any eye associated complications.
▪ Advanced degenerative changes on opthalmoscopy.
▪ Any previous eyes operation.
▪ Any major disease associated

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1. STUDY FLOWCHART: VISITS AND STUDY PROCEDURES

Baseline Follow up V2 Follow End of


visit -V1 3rd month th
6 month up 9th study -
Evaluation (IPD) (Telephonic) (IPD) month 12th month
(Telephonic) (OPD)
General medical status
×
Inclusion/Exclusion
criteria and Informed ×
Consent
AE/SAE reporting
× × × ×
Clinical evaluation
including: ×
Medical history, Lab;
BP; height,
body weight
QoL Questionnaire
× × ×
Symptom Score
× × × × ×
Refraction /Visual
Acuity
× × ×

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2. TABLE OF CONTENTS
1 FLOW CHARTS (VISITS AND STUDY PROCEDURES)....................................................................4

2 TABLE OF CONTENTS ...........................................................................................................................5

3 INTRODUCTION ………………..............................................................................................................6

4 STUDY OBJECTIVES ..............................................................................................................................8


4.1 PRIMARY..................................................................................................................................................8
4.2 SECONDARY ...........................................................................................................................................8

5 STUDY DESIGN ........................................................................................................................................8


5.1 DESCRIPTION OF THE PROTOCOL.....................................................................................................8
5.2 DURATION OF STUDY PARTICIPATION ..........................................................................................8

6.DATA MONITORTING COMMITTEE.........................................................................................................9

7SELECTION OF PATIENTS.....................................................................................................................9
7.1 NUMBER OF PATIENTS PLANNED.....................................................................................................9
7.2 INCLUSION CRITERIA...........................................................................................................................9
7.3 EXCLUSION CRITERIA .........................................................................................................................9
7.4 ASSESSMENT PARAMETERS………………………………………………………………………...9

8TREATMENTS…......................................................................................................................................10

9PATIENT SAFETY....................................................................................................................................11
9.1 ADVERSE EVENTS MONITORING.....................................................................................................11
9.2 DEFINITIONS OF ADVERSE EVENT(AE)………………………………………………………..…11

10. PROCEDURE FOR WITHDRAWAL OF PATIENTS FROM STUDY FOLLOW-UP


SCHEDULE..........................................................................................................................................11
10.1 CONSEQUENCE...................................................................................................................................11

11 STUDY PROCEDURES ........................................................................................................................11


11.1 VISIT SCHEDULE................................................................................................................................11

12 DEFINITION OF SOURCE DATA.......................................................................................................12

13 STATISTICAL CONSIDERATIONS.................................................................................................12

14 ETHICAL AND REGULATORY STANDARDS................................................................................12


14.1 ETHICAL PRINCIPLES........................................................................................................................12
14.2 LAWS AND REGULATIONS..............................................................................................................12
14.3 INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC)……...12.

15 STUDY MONITORING.........................................................................................................................13
15.1SOURCE DOCUMENT REQUIREMENTS..........................................................................................13
15.2USE AND COMPLETION OF CASE REPORT FORMS AND ADDITIONAL REQUEST. ............13

16 RECORD RETENTION IN STUDY SITES (S) ..................................................................................13

17 CONFIDENTIALITY.............................................................................................................................14

18 DATA PROTECTION............................................................................................................................14

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3. INTRODUCTION:

Progressive /Degenerative/Pathological Myopia, as name indicates is a rapidly


progressive error resulting in high myopia during early adult life which is usually
associated with degenerative changes in the eyes.
Progressive myopia is reported to be the seventh ranking cause of legal
blindness in United States & fourth ranking cause in Hong Kong affecting 27 to 33% of
all myopic eyes & corresponding to a prevalence of 1.7 to 2.1 % in the general population
of the United States. It is more common in Asia & Middle East affecting 6.9 % in India.
To summarize the course of this condition: It presents for the majority of
people as an inherited genetic condition. An affected individual will show accelerated
growth of size of the eye during the normal growth-periods of childhood & adolescence,
so that, by the late teens, or early twenties, the eye is much longer than normal. The eye is
said to have high axial myopia. Much of the sight loss in high axial myopia is throught to
be due to the damaging effects of the stretching & thinning of the inner part of the eyes.
The sclera,the choroids, the retina and the interface between the retina and the vitreous
gel are all affected by deformation. In the central retina, damage to the functioning of the
macula results in vision loss. This process of macular scarring is termed myopic macular
degeneration.High myopic eyes are also liable to loss vision from cataract and glaucoma,
increased vulnerability to the damage effects from eye trauma.

The etiological hypothesis for progressive myopia can be summarized as below:


Genetic factors General growth process
(Plays major role) (Plays minor role)

More growth of retina

Stretching of sclera

Increased axial length

Degeneration of choroids Features of progressive myopia

Degeneration of retina

Degeneration of vitreous

The refractive changes appears in early childhood, usually between 5-10 yrs & increases
steadily upto 25 yrs or beyond resulting in a high degree of myopia, accompanied by
degenerative changes in choroids & other parts of eyes.

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The key findings associated with progressive myopia can be seen on ophthalmoscopic
examination of the posterior pole: myopic crescent; posterior staphyloma; flat, obliquely
inserted discs; patchy choroidal atrophy. Extensive vitreous syneresis and posterior
vitreous detachment are typical. Additional findings include lacquer cracks’ sub retinal
neovascular membrane, fuch’s spot, retinal breaks and retinal detachment.
According to Ayurveda the visible areas of eye include five mandalas,six
sandhis and six patalas.By our ancient Aacharyas 76 eye disease are mentioned in
texts.Out of them few are refractive errors which are common in today’s life. Although
these refractive errors are very common but they affects one’s life significantly.
Progressive myopia in modern science has no definite terminology in classical Ayurveda.
But some drishtigataroga lakshnas have symptomatic similarity with Progressive myopia.
A deeper study and classification of pratham & dwitiya patalgata Timira in dristigata
rogas can be done on the basis of several stages of samprapthi in dristipatalas.
There has not been proposed any specific line of treatment in modern
management, other than spectacular correction or laser management, so it is worth to
discuss the Ayurvedic perspective in the therapeutics of Progressive myopia.
Vitiated kapha dosha progresses towards 2nd ( Mamsa dhatu) patala of eye
this is a milestone in pathogenesis of the disease ,when doshas get localized (sthana
samshrayam) in 2nd patala ( mamsa ashritapatala) and srotorodhana reaches at its peak.As
a result vata dosha also gets affected & degenerative process comes in picture. Due to
these changes vision gets more blurrd , patient sees non-existing thingse.g. haiors,spider
webs ect and sees distant things near and near things far away. If doshas are accumulated
in the upper part of the patala then perception of distant objects will be difficult.This
stage is more prone to vata dosha drusthi, more potent vata shaman & shodana drugs
should be given for a longer duration.

SYMPTOMS:

• Defective Vision.
• Floating black opacities in front of the eyes, occur due to degenerated liquefied
vitreous.
• Night Blindness (by very high myopes having marked degenerative changes)
• Headaches
• Sensitivity to light

SIGNS:

• The eyes are often prominent, appearing elongated & even simulating an
exophthalmos especially in unilateral cases mainly affecting the posterior pole &
surrounding area.
• Cornea is large& Pupils are slightly large, reacts sluggishly to light.

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FUNDUS EXAMINATION:

• Optic disc appear large & pale.


• Degenerative changes in retina & choroids characterized by white atrophic
patches at the macula with little heaping up of pigment around them.
• Estasia of sclera posteriorly (posterior staphyloma)
• Posterior vitreous detachment & vitreous liquefaction
• Visual fields show contraction and in some cases ring scotoma may be seen
• ERG reveals subnormal electroretinogram due to chorioretinal atrophy

4. STUDY OBJECTIVE:

4.1. Primary Objective

• To demonstrate the efficacy of Ayurvedic treatment in progressive myopia

4.2. Secondary Objective


Whether Ayurveda is more effective in-
• Curing the condition.
• Maintaining the present state of progressive myopia
• Preventing from further complications.

5. STUDY DESIGN:
5.1 DESCRIPTION OF THE PROTOCOL

SAR-PM is an observational trial. Patients who meet inclusion criteria, and who do not
meet exclusion criteria will be randomized in this trial.

The individual treatment duration will be variable, depending on the total duration of the
study. The minimum inpatient treatment duration for each patient will be 21 days. There
will be two inpatient visit each consisting of 21 days during the protocol period. All
patients will visit the clinic once every six months for clinical assessment and for
assessment of treatment compliance. In addition, telephonic follow-ups will be done in
every 3 months after randomization of the patient.

Subject’s refraction will be checked in every 6 month at the time of visit to


Sreedhareeyam hospital.

During the course of the trial, an Independent Data Monitoring Committee (DMC) will
Periodically review safety.

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5.2 DURATION OF STUDY PARTICIPATION

The study end-date will be 12 months following randomization of the last patient. All
patients must be followed up to the planned end of treatment period

6. DATA MONITORING COMMITTEE:


During the study, the Data Monitoring Committee will regularly review the data for
safety and assessment of any AEs.

7. SELECTION OF PATIENTS

7.1 NUMBER OF PATIENTS PLANNED

Approximately 60 patients will be randomized to complete 50 patients accounting for


dropouts.

7.2 INCLUSION CRITERIA

▪ Male and female; age- between 3-25yrs irrespective of sex, race, religion,
socio-economic status
▪ Patients clinically diagnosed as progressive myopia.
▪ Women of child bearing potential were required to have a documented negative serum
or urine pregnancy test before the start of therapy.

7.3 EXCLUSION CRITERIA

▪ Patients with any eye associated complications.


▪ Advanced degenerative changes on opthalmoscopy.
▪ Any previous eyes operation.
▪ Any major disease associated

7.4 ASSESSMENT PARAMETERS:

I. Efficacy:
1. Auto refraction is used for the assessment of refractive status of each eye.
2. Eye examination by ophthalmologist / doctors.
3. Visual acuity as assessed by Snellen’s chart at every visit of the patient for 1 year
before and after the treatment
4. National eye institute refractive error quality of life instrument-42(NEI RQL-42)- to
improve the knowledge about vision correction and how it affects the personal life of
a person.

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II. Symptoms assessed will be:

- Defective Vision
- Headaches
- Watering of eyes
- Sensitivity to light
- Floating black opacities in front of the eyes
- Night Blindness
III. Signs assessed will be:

- Fuch’s spot in the macular area.


- Tilting or malinsertion of the optic disc
- Prominent eyes
- Cornea is large& Pupils are slightly large, reacts sluggishly to light

The symptoms will be assessed by means of a linear scale from 0-3 where:
0 = symptoms absent.
1 = mildly affected by the symptoms.
2 = moderately affected by the symptoms
3 = severely affected by the symptoms
The minim score will be 0 and maximum will be 30

8. TREATMENTS
After the patient is randomized and is the inpatient following treatment will be done
according to the patients complaints:-

 Nasayam : - Anutailam
- Ksheerabala 21 Av

 Sekam : - Kashyapasekam

 Aschotanam : - Ananthagritham

 Sirodhara : - Sasankathailam
- Balaswagandha thailam
- B P thailam

 Anjanam : - Chandanadi anjanam


- Mukulanjanam

 Eye massage : - Ksheerabala 21 Av

 Pichu : - Sasankathailam
- Balaswagandha thailam
- B P thailam

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 Tarpanam : - Triphala ghritham


- Anantha ghritham
- Jataveda ghritham

Internal medication may vary according to the physician and will be noted.

9. SAFETY INSTRUCTIONS
9.1 ADVERSE EVENTS MONITORING
All events will be managed and reported in compliance with all applicable regulations,
and included in the final clinical study report.

9.2DEFINITIONS OF ADVERSE EVENT (AE)


An Adverse Event is any untoward medical occurrence in a patient or clinical
investigation patient administered a pharmaceutical product and which does not
necessarily have to have a causal relationship with this treatment.

10. PROCEDURE FOR WITHDRAWAL OF PATIENTS FROM


STUDY FOLLOW-UP SCHEDULE
The patients may withdraw from the study follow-up schedule, before study completion
if they decide to do so, at any time and irrespective of the reason.
All study withdrawals should be recorded by the Investigator in the appropriate CRF
pages and in the patient’s medical records when considered as confirmed

10.1 CONSEQUENCE
Patients who have withdrawn from the study cannot be re-included in the study. Their
inclusion and treatment number must not be reused.

11. STUDY PROCEDURES


11.1VISIT SCHEDULE

I At Baseline: The screening and baseline visit will be on the same day with the
refraction test done on same day or +1 day.
Quality of life questionnaire will be assessed by self-reporting

II 21 days inpatient treatment


Assessments before and after each main therapy such as sirodhara, nasyam and
tarpanam

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III Assessments at Follow–Up 1 (3 months from baseline): Done telephonically


where symptom score will be assessed and AEs will be noted if any

IV Assessments at Visit 2(6 months from the baseline visit +/- 1 month): Auto
refraction, eye examination, visual acuity, Quality of life questionnaire will be
assessed.

V Assessments at Follow-Up 2 (9 months from baseline): Done telephonically


where symptom score will be assessed and AEs will be noted if any

VI Assessments at The End Of Treatment Visit: 12 months from baseline visit


+/- 1 month: Auto refraction, eye examination, visual acuity, Quality of life
questionnaire will be assessed.

12. DEFINITION OF SOURCE DATA


In this study, source data will comprise the medical records, the visual acuity and results
of laboratory (if any).

13. STATISTICAL CONSIDERATIONS.

The statistical analysis will be done with SPSS 15.0 & ANOVA.The changes in
refraction and visual acuity will be assessed from baseline to end of study, paired t-test.
ANOVA provides a statistical test of whether or not the means of several groups are all
equal.

14. ETHICAL AND REGULATORY STANDARDS

14.1 ETHICAL PRINCIPLES


This Clinical Trial will be conducted in accordance with the principles laid down by the
18thWorld Medical Assembly (Helsinki, 1964) and all applicable amendments laid down
by the World Medical Assemblies and the ICH guidelines for Good Clinical Practice
(GCP).

14.2 LAWS AND REGULATIONS


This Clinical Trial will be conducted in compliance with all international laws and
regulations, and national laws and regulations of the country(ies) in which the Clinical
Trial is performed, as well as any applicable guidelines.

14.3 INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE


(IRB/IEC)
As required by local regulation, the Investigator or the Sponsor must submit this Clinical
Trial Protocol to the appropriate Ethics Committee (IRB/IEC), and is required to forward

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to the respective other party a copy of the written and dated approval/favorable opinion
signed by the Chairman with Ethics Committee (IRB/IEC) composition.
During the Clinical Trial, any amendment or modification to the Clinical Trial Protocol
should be submitted to the Ethics Committee (IRB/IEC) before implementation, unless
the change is necessary to eliminate an immediate hazard to the patients, in which case
the IRB/IEC should be informed as soon as possible. It should also be informed of any
event likely to affect the safety of patients or the continued conduct of the Clinical Trial,
in particular any change in safety.
A progress report is sent to the Ethics Committee (IRB/IEC) at least annually and a
summary of the Clinical Trial’s outcome at the end of the Clinical Trial.

15. STUDY MONITORING


15.1SOURCE DOCUMENT REQUIREMENTS
According to the ICH guidelines for Good Clinical Practice, the Monitoring Team must
check the Case Report Form entries against the source documents, except for the pre-
identified source data directly recorded in the Case Report Form.

15.2 USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL
REQUEST
It is the responsibility of the Investigator to maintain adequate and accurate CRFs
designed by the Sponsor to record all observations and other data pertinent to the clinical
investigation. All CRFs should be completed in their entirety in a neat, legible manner to
ensure accurate interpretation of data.
Should a correction be made, the information to be modified must not be overwritten.
The corrected information will be transcribed by the authorized person next to the
previous value, initialed and dated.

16. RECORD RETENTION IN STUDY SITES


The Investigator must maintain confidential all study documentation, and take measures
to prevent accidental or premature destruction of these documents.
It is recommended that the Investigator retain the study documents at least fifteen (15)
years after the completion or discontinuation of the Clinical Trial.
However, applicable regulatory requirements should be taken into account in the event
that a longer period is required.
The Investigator must notify the Sponsor prior to destroying any study essential
documents following the Clinical Trial completion or discontinuation.
If the Investigator's personal situation is such that archiving can no longer be ensured by
him/her, the Investigator shall inform the Sponsor and the relevant records shall be
transferred to a mutually agreed upon designee.

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17. CONFIDENTIALITY
Protocol, the CRFs, and the results obtained during the course of the Clinical Trial, is
confidential.
However, the submission of this Clinical Trial Protocol and other necessary
documentation to the Ethics Committee (IRB/IEC) is expressly permitted, the IRB/IEC
members having the same obligation of confidentiality.

18. DATA PROTECTION


The patient's personal data and Investigator's personal data which may be included in the
Sponsor database shall be treated in compliance with all applicable laws and regulations.
When archiving or processing personal data pertaining to the Investigator and/or to the
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access
to this data by any unauthorized third party.

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