PROTOCOL 2004 To determine clinical research methods best suited for validating Ayurvedic medicines

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PROTOCOL (2004)To determine clinical research
methods best suited for validating Ayurvedic
medicines

• Dr Arvind Chopra, MD (Rheumatologist)
• Dr Sanjeev Sarmukaddam, PhD (Bio-Statistician)
• Dr Girish Tillu, MD (Ayurvedic Physician)
• Center for Rheumatic Diseases, Pune
• www.rheumatologyindia.org

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REFERENCES

• A clinical study of a herbal (Ayurvedic)
  formulation in rheumatoid arthritis. Arthritis
  Rheum 1996 39(9) S283
• A clinical study of an Ayurvedic (Asian Indian)
  medicine in OA knees. Arthritis Rheum 1998
  41(9) S198
• Ayurvedic medicine and arthritis. Rheum Dis
  Clinics N America 2000 26 133-144
• Randomized double blind trial of an Ayurvedic
  plant derived formulation for treatment of
  rheumatoid arthritis. J Rheumatology 2000 27
  1365-1372
• Exploring Ancient Ayurveda for Rheumatology
  Traditional Therapy, Modern Relevance and
  Challenges. APLAR J Rheumatology 2001 4 190-199
• Ayurvedic Medicine Core Concept, Therapeutic
  Principles, and Current Relevance.
  
  Med Clinics N America 2002 86 75-89
• Web site Physicians Information and Education
  Resource (PIER), American College of Physicians
  (ACP)- domain on Ayurvedic Medicine
• A 32 Week Randomized, Placebo-Controlled
  clinical evaluation of RA-11, an Ayurvedic drug
  on Osteoarthritis of the knees. J Clinical
  Rheumatology 2004 10236-245
• IRA-01, An Ayurvedic (Asian Indian) Drug for
  Rheumatoid Arthritis (RA) Evaluation for
  Efficacy and Safety, and a probable Lipid
  Modifying Effect (Abstract). Annals of the
  Rheumatic Diseases, 2004 63 275
• Rheumatology Made in India (Camps, COPCORD, HLA,
  Ayurveda, HAQ, WOMAC and Drug Trials).J Indian
  Rheum Assoc 20041243-53
• A controlled drug trial to evaluate Ayurvedic
  derived Shunthi-Guduchi based standard
  formulations in the treatment of Osteoarthritis
  (OA) Knees A Government of India NMITLI
  ARTHRITIS PROJECT (Abstract). Annals of the
  Rheumatic Diseases, 2006 65 226-227

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An Ayurvedic drug per se has therapeutic potential
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Kulkarni RR, Patwardhan B et al Efficacy of an
Ayurvedic formulation in rheumatoid arthritis A
double blind, placebo controlled, cross-over
study. Indian J Pharmacol 2498,1992
A 12 week clinical trial study using a
randomized, placebo- controlled, crossover design
reported efficacy of a multiple plant based
formulation ( W.somnifera, B. serrata, C. longa,
and zinc ash) in 20 patients with RA in
comparison with the placebo group, significant
improvement was reported in several efficacy
measures in the active group, and seroconversion
of rheumatoid factor from positive to negative
was reported in several patients.
5
182 patients were enrolled in this two arm RDBPC
parallel efficacy trial of 16 weeks duration
paracetamol rescue low dose daily Pred (lt7.5
mg) permitted NO NSAID/ DMARD RA-1 was a
standardized formulation of plant extracts from
Withania somnifera (ashwagandha), Boswellia
serrata (guggul),Zingiber officinale (ginger),
Circuma longa (turmeric)RESULTSAn
intent-to-treat analysis did not show
statistically significant difference between RA 1
and placebo for primary efficacy variables RA 1
showed excellent safety The RA-1 group differed
significantly (plt0.05) from placebo with
reference to (i) patients showing 50 reduction
in swelling (ii) overall decrease in RF titer
(nephlometry) (iii) increased hemoglobin
Arvind Chopra, Phil Lavin, Bhushan Patwardhan,
Deepa Chitre. Randomized double blind trial of an
Ayurvedic plant derived formulation (RA-1) for
treatment of rheumatoid arthritis. J Rheumatol
2000 27 1365-72
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RA 1- ONE YEAR FOLLOW UP
(N57)
Only minor episodic gut disturbances reported
by less than 2 patients
Arvind Chopra, Phil Lavin, Bhushan Patwardhan,
Deepa Chitre. Randomized double blind trial of an
Ayurvedic plant derived formulation (RA-1) for
treatment of rheumatoid arthritis. J Rheumatol
2000 27 1365-72 Presented at
the annual ACR meeting 1996
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Chopra A, Patil J, Saluja M, Anuradha V. IRA-01,
AN AYURVEDIC (ASIAN INDIAN) DRUG FOR RHEUMATOID
ARTHRITIS (RA) EVALUATION FOR EFFICACY AND
SAFETY, AND A PROBABLE LIPID MODIFYING EFFECT
Presented in EULAR 2004, Berlin published in
Ann Rheum Dis 200463 130 patients were enrolled
into a RDBPC parallel efficacy multi-centric drug
trial of 12 weeks duration. NO NSAID/ DMARD
/STEROID Paracetamol rescue allowed. In one
center, 58/84 completed a total period of one
year treatment

• Boswellia serrata (Salai Guggul) Curcuma longa
  (Turmeric) Piper nigrum (Black pepper) Tribulus
  terrestris (Gokshur) Trigonella foenum-graecum
  (Fenugreek) Linum usitatissimum (Flaxseed)
  Camellia sinensis (Green tea)
• 
  
• 
  

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OPEN LABEL PHASE MEAN CHANGE IN EFFICACY
MEASURES FROM RANDOMISATION BASELINE (N58)
HDLLDL RATIO Over Time
?inflammation atherogenesis link
Mean Change in Randomized phase IRA 01 -6.1
PLACEBO 2.9 (Plt0.05)
Plt0.05
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Is it disease specific?

• Experience with RA-11
• RA
• OA

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Chopra A, Lavin P, Patwardhan B, Chitre D. A 32
WEEK RANDOMISED, PLACEBO CONTROLLED CLINICAL
EVALUATION OF RA-11, AN AYURVEDIC DRUG, ON OA
KNEES. J Clin Rheumatol10236-245
plt0.05
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THE MEAN CHANGE IN MODIFIED WOMAC AND
PAIN VAS AT EFFICACY WEEK ENDPOINTS
BY TREATMENT GROUPS

Chopra A, Lavin P, Patwardhan B, Chitre D. A 32
week randomised, placebo controlled clinical
evaluation of RA-11, an ayurvedic drug, on OA
knees. J Clin Rheumatol10236-245
plt0.05Ra-11 contains extracts of Withania
somnifera (ashwagandha), Boswellia serrata
(guggul),Zingiber officinale (ginger), Circuma
longa (turmeric).
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NMITLI ARTHRITIS PROJECT 2002-2007 (New
millennium Indian Technology Leadership
Initiative, A Project of CSIR , GOI )

• DR ARVIND CHOPRA, MD
• PRINCIPAL INVESTIGATOR CO-ORDINATOR
• Director Chief Rheumatologist,
• CENTER FOR RHEUMATIC DISEASES (CRD), PUNE
• Website www.rheumatologyindia.org

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PARTICIPATING CENTERS

• UNIVERSITY OF PUNE Prof Bhushan Patwardhan
• IIIM (RRL), JAMMU
• Prof GN Qazi
• NBRI,LUCKNOW
• Prof Pushpagandhan
• ARI, PUNE
• Dr Mujumdar
• IRSHA, PUNE
• Prof U Wagh, Dr V Sumantran

• KEM-SPARC, MUMBAI
• Prof Lata Bichile
• Dr Ashwin Raut
• NIMS, HYDERABAD
• Prof G Narsimulu
• AIIMS, DELHI
• Prof Rohini Handa
• CRD, PUNEDr Arvind Chopra
• Several Research Fellows/ Associates

ACR 2008
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DISCLOSURE

• The project was totally sponsored and funded by
  the Council of Scientific and Industrial
  Research (CSIR), Government of India
• All investigators were either Govt salary
  employees or paid consultancy through the CSIR
  NMITLI research grant fund

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NMITLI ARTHRITIS PROJECTCLINICAL STRATEGY- AN
OVERVIEW

• Select Classification Criteria Define
  Targets For Medicines
• Short List Potential Medicinal Plant Candidates
• Choose Formulations/ Drugs With Fewer Components
• To Begin With, Choose 1-2 Potential Drugs With
  Best Efficacy Safety Using Several Exploratory
  Drug Trials
• Choose Popular Ayurvedic Proprietary/ Traditional
  Drugs for comparison
• Finally, Run A Statistically designed, adequate
  Power Drug Trial For 1-2 Best Potential Drugs

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HEAD TO HEAD COMPARISON BETWEEN AN
AYURVEDIC DRUG AND A STANDARD OF CARE MODERN
MEDICINE
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CLINICAL DRUG TRIALS IN OA KNEES
2002
OA EXPLORATORY (N245) RDB, P CC, 7 arm, 16
week
OA DOSING (N96) RSB, 4 arm, 6 weeks
OA FINAL(N440) RDB_CC, 4 arm, 24 weeks
EXTENTION PHASE(N100) RDB, 3 arm, 24 WEEKS
2007
N NUMBER OF PATIENTS RDB-RANDOMISED DOUBLE
BLIND RSBRANDOMISED SINGLE BLIND P
PLACEBO CC POSITIVE COMPARATOR CONTROL
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OA EXPLORATORY- CHANGE IN MEAN ACTIVE PAINVAS
OVER TIME
WA S H O U T
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OA EXPLORATORYMEAN PARACETAMOL TABLET (500 mg
each) CONSUMPTION IN the FOURTH MONTH
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OA EXPLORATORY NUMBER OF SUBJECTS WITH ADR IN
EACH ARM-
All Ayurvedic Vs GLU Z2.33 (x25.45), p0.02
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Potentiation Dosage

• Efficacy
• safety

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OA-DOSING Early Efficacy

• Randomised, Single Blind Study of 6 weeks
  duration (CRD, Pune NIMS, Hyderabad)
• Inclusion active painVAS gt 4
• 92 patients randomized into 4 treatment arms
• Treatment arms-
• ?B 2 capsules thrice a day
• ? B 2 capsules four times a day
• ? C 2 capsules each, thrice a day
• ? D Guggul formulation (Gg) 2 capsules each,
  twice a day
• NO RESCUE MEDICATION

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OA-DOSING Mean change (Percent) over 6 weeks
(N86)-PAINVAS (mm) using ANCOVA
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OA DOSING ADVERSE EVENTS(AE)- NUMBER (percent)
(N92)
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FINAL NMITLI OA SGPF DRUG TRIAL

• ? SUPERIORITY OR
• EQUIVALENCE

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A 24 week RDB multicentric trial to demonstrate
equivalence between individual drugs for
symptomatic treatment of OA knees Ayurvedic
(Indian Asian), Glucosamine and Celecoxib A NEW
MILLENIUM INDIAN TECHNOLOGY LEADERSHIP
INITIATIVE (NMITLI)

• PRESENTATION ON BEHALF OF THE NMITLI ARTHRITIS
  GROUP
• ARVIND CHOPRA, MD
• PRINCIPLE INVESTIGATOR CLINICAL
  CO-ORDINATORDIRECTOR CHIEF RHEUMATOLOGIST,
  CENTER FOR RHEUMATIC DISEASES (CRD), PUNE
  (www.rheumtologyindia.org )
• CO-ORDINATED BY
• COUNCIL OF SCIENTIFIC INDUSTRIAL RESEARCH
  (CSIR),
• GOVERNMENT OF INDIA
• Presented in the Annual Meeting of the American
  College of Rheumatology 2008

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NMITLI OA STAGE III/1TOTAL TARGET 440 (ITT
analysis420)
TOTAL TARGET - 440
CRD300 (Pune)
NIMS80(Hyderabad)
AIIMS60(Delhi)
243 COMPLETORS 57 WITHDRAWALS
26 COMPLETORS 34 WITHDRAWALS
47 COMPLETORS 33 WITHDRAWALS
ITT-286
ITT-75
ITT-59
NMITLI OA STAGE III/2 (n87)
ITT Intent to treat after adjusting for
patients lost to follow up after randomization
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NMITLI OA STAGE III/1OA-01 Vs CELECOXIB
DIFFERENCE IN THE MEAN CHANGE (BASELINE TO
COMPLETION-PER PROTOCOL ANALYSIS ) TRIAL OF
EQUIVALENCE
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NMITLI OA STAGE III/1NUMBER OF PATIENTS WITH
ADVERSE EVENTS (AE)- NUMBER (Percent) (N418)
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NMITLI OA STAGE III/1 Mean SGPT (IU/ml) over
time by treatment arm
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NMITLI OA STAGE III/1URINARY CTX II MEAN
CHANGE (95 CONFIDENCE INTERVAL) FROM BASELINE TO
COMPLETION (N233)
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NMITLI RA STAGE I/1

• 126 Patients with Active Rheumatoid Arthritis
  (RA)
• 3 ARM STUDY B (SGPF) (a NMITLI formulation)
  -AyP 2 (traditional proprietary)
  - HYDROXYCHLOROQUIN (HCQS)
• RANDOMISED, SINGLE BLIND, 24 WEEKS DURATION
• CONDUCTED AT CRD, NIMS, AIIMS KEM-SPARCHCQS
  is a DMARD (Disease Modifying Anti-Rheumatic
  Drug )

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NMITLI RA STAGE I/1 MEAN CHANGE (95 CI) OF
EFFICACY VARIABLES AT 24 WEEKS
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NMITLI RA STAGE I/1 ADVERSE EVENTS(AE)-
NUMBER (percent) (N96)
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CONCEPT TO PRODUCT
System Theory Application of Ayurvedic knowledge
base
OVERLAP
Most Potential Botanical Materials
PLANT PASSPORT DATAIN VITRO PHARMACOLOGY
ANIMALTOXICITYPRODUCT STABILITY
EXTRACTS-CMC
Preclinical
Finalize Dosage Form for clinical trial
MECHANISM OF ACTION- CELL CULTURE
CONTROLLED DRUG TRIALSRandomized , Blind,
Controlled, Parallel Efficacy Multi-Centric
Exploratory (POTENTIAL CANDIDATE)
Exploratory dosing ( LEAD Formulations)
PROOF OF EFFICACY( FINAL Formulation)
THE PRODUCT
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NMITLI OSTEOARTHRITIS PROJECT
Best Medicinal Plants Short listed Procured
2 0 0 2 TO 2 0 0 7
NBRI Botanical, Morphological Other tests
ISHS Preparation of Test materials
IIIM (RRL) Chemistry Profile, fingerprinting
PRE-CLINICAL -CHEMISTRY, MANUFACTURING, CONTROLS
PHARMACOLOGY IRSHA/ARI/ ISHS
Optimization studies, Final formulation,
Stability, Doses, Labeling Clinical Trial
Material
Overlap of Activities, Concurrent development,
EVALUATION COLLATION
Clinical Studies-Exploratory, Dosing Final
CRD, KEM, SPARC, AIIMS, NIMS
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NMITLI ARTHRITIS PROJECT Deviations (if any)
from Classic Ayurvedic Process An Overview
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Did we hit one or multiple target?

• Pain
• Swelling
• Disease modification/control
• General Health
• Oxidative stress
• Co-morbidity
• Safety

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Pragmatic Versus ExplanatorySingle drug Vs
black box careDisease centric Vs
holisticDisease specific drug Vs designer
drug

• General Guidelines for Methodologies on Research
  and Evaluation of Traditional
  Medicine. WHO,
  Geneva. WHO/EDM/TRM/2000.
• MacPherson. Pragmatic Clinical Trials. Comp Ther
  Med 2004 12 136-140
• Gagnier JJ et al. Reporting Randomized Controlled
  Trials of Herbal Interventions An
  Elaborated CONSORT Statement. Ann Intern Med
  2006 144 364-367

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RANDOMIZED TRIAL OF A WHOLE SYSTEM AYURVEDIC
PROTOCOL FOR TYPE 2 DIABETES I/V

• Elder C, Aickin M, Bauer V et al.
• ALTERNATIVE THERAPIES HEALTH MEDICINE, SEPT/OCT
  2006, VOL.12, NO.5 24-30

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WHOLE SYSTEM AYUR PROTOCOL FOR DIABETES
II/VOBJECTIVES

• The aims of this study were to determine the
  feasibility clinical impact of whole system,
  Ayurvedic intervention for newly diagnosed people
  with type 2 diabetes. DESIGN
• Phase II study with 60 patients randomly
  assigned to either an experimental or control
  arm, each with 30 patients.
• Technicians in central lab blinded. Pulse, BP
  and weight assessed by clinic personnel not
  blinded.
• MEASURES
• Clinical outcomes assessed at 3 6 months and
  included HbA1c, fasting glucose,lipids, blood
  pressure and weights

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WHOLE SYSTEM AYUR PROTOCOL FOR DIABETES
III/VSETTING

• Group model health maintenance organization
  (USA).
• Participants 60 adult patients with baseline
  glycosylated hemoglobin (HbA1c) values between
  6.0 and 8.0.
• INTERVENTION
• Experimental group
• included yoga stretches exercise,
  an Ayurvedic diet, meditation instruction and an
  Ayurvedic herb supplement (MA 471).
• Control group
• attended standard diabetes education classes
  with primary care clinician follow-up.

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WHOLE SYSTEM AYUR PROTOCOL FOR DIABETES
IV/VRESULTS

• No significant differences for clinical
  outcomes at 6 months between on study patient
  groups, though trends favored the Ayurvedic group.

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WHOLE SYSTEM AYUR PROTOCOL FOR DIABETES
V/VAdjusted Treatment Effects
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• SELECTION OF SUITABLE METHODOLOGY FOR
  EVALUATION OF INDIGENOUS TREATMENTS / MEDICINAL
  DRUGS

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• SHORT PRESENTATION BY
• Sanjeev Sarmukaddam Biostatistics Consultant,
  MIMH, B.J. Medical College Sassoon Hospital
  Campus, Pune

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• As pointed out often on evaluating complementary
  treatments, clinical trials are the best way of
  assessing the efficacy of treatments but not in
  their present form. The need is felt because
  many indigenous drugs even if found clinically
  useful, not proved to be significantly so in
  clinical trials.

48

• Few possible techniques for this purpose are
  identified (2004). These are just suggestions on
  the basis of difficulties realized in the field.
  They include

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•  Equivalence trial against an usual
  superiority/comparative trial
•        Use of evidence based randomization in
  adaptive allocation while applying play the
  winner rule
•      Zelens type A new design for randomized
  clinical trials, New Engl. Jr. Med. Vol, 300
  1242-1245 (1979) modification to reduce placebo
  effect

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• Clinical trials can be designed to be either
  pragmatic or explanatory. Pragmatic trials are
  designed to find out about how effective a
  treatment actually is in routine, everyday
  practice. Explanatory trials are designed to find
  out whether a treatment has any efficacy.

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Pragmatic clinical trials Hugh
MacPhersona, Complementary Therapies in Medicine
(2004) 12, 136140 A case is made for the
relevance of pragmatic trials in the evaluation
of alternative and complementary
medicine. Pragmatic trials are useful in
answering questions about how effective a therapy
is when compared to some standard or accepted
treatment.
52
They also overcome some specific difficulties
that can be encountered with explanatory trials
of complementary therapies, for example when
evaluating complex packages of care.
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Explanatory trials Vs Pragmatic trials
1.Evaluate efficacy, Compare effectiveness 2.Pla
cebo controlled, Not placebo controlled 3.Patients
blinded to minimise bias, Patients unblinded
to maximise synergy
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• SAFETY is of paramount importance which is
  inherently an accepted strength of Ayurved

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• Weighing SAFETY is very important. We should find
  out ways to do that.

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• To find role of SAFETY in one of the CRD
  trials, we analyzed data of paracetomol
  consumption by RIDIT analysis. Following diagram
  shows this as an example.

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OA-EXPLORATORY-KNEE STATUS CHANGE ON COMPLETION
A RIDIT (relative to identified distribution)
ANALYSIS
Interpretation (for mean Ridit gt0.5)More than
half of the time a randomly selected subject from
C group will have more extreme value
(improvement) than a randomly selected subject
from the reference group (Placebo and Glucosamine)
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 Other points to be considered are

• - Can we use Ayurved medicines to maintain
  remission or consolidate therapy results after
  the more aggressive modern medicines have dealt
  with the initial severe stage? Some sort of
  INTERFACE.
• -Platform formulation and Augmenters (Anupan
  i.e. vehicle/medium is also important in Ayurved)

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• -Interaction studies and sub-group identification
• -Specific differential diagnosis / sometimes it
  becomes essential to distinguish between
  treatment sensitive insensitive patients to
  help tailor the treatment better

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Disease subsets and drug response

• Drug activity could be better understood with
  proper statistical study of Ayurvedic disease
  subsets concepts.

Ayurvedic diagnostics
Statistical inputs
Santarpana
Drug response
Disease Subsets
Regression
Apatarpana

• Person with analytical vision can differentiate
  disease conditions with multiple aspects.

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How do we build in Safety performance into the
Efficacy Success Equation?

• Other important issues
• Quality of life
• Tolerance
• Compliance
• Satisfaction

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Predicting Responsiveness Improves the Overall
Outcome of Treatment
Patients with same Diagnosis
63
Predicting Adverse Events Improves the Outcome
Even More
Responder
64
Drug response and Ayurvedic covariates
In-depth consideration of patient specific
factors and drug properties lead to effective
treatment.
Individualization
Generalization
Ayurvedic drug utilization for global use
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CAN AYURVEDA BE DELIVERED IN A CAPSULE ?

• None of the Ayurvedic drug trials mentioned
  have tried to evaluate the relavance, if any, of
  the fundamental Dosha other crirtical Ayurvedic
  measures and attributes to the therapeutic
  outcome.
• Customized Ayurvedic holistic approach is
  difficult to validate. This approach has a
  tremendous commonsense appeal.

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DEFINING VALIDATING NEWER INTERDISCIPLINARY
INTEGRATIVE THERAPEUTIC APPROACHES

• Possibility of integrating some of the Ayurveda
  components into modern medicine. In the latter
  scenario, Ayurvedic therapy could occur
  concurrently or sequentially , depending on the
  stage and intensity of the illness.

Narahari SR et al. Evidence Based Approaches for
the Ayurvedic Traditional Herbal Formulations
Toward an Ayurvedic CONSORT Model This paper
describes an approach to evaluate multimodal
integrative medicine in the treatment of complex
pathologic conditions. It proposes a methodology
to evaluate clinical trials of multimodal patient
specific interventions.
67
Need of the hourPresentation of Ayurveda as
Evidence Based Medicine

• Scientifically validated studies with appropriate
  study designs
• Research on Research methodology
• Appropriate designs and tools for Ayurveda based
  studies

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Need to determine best suited research methods
for Ayurveda

• We have to address several challenges , e.g.
• Is conventional model of randomized, placebo
  controlled, superiority trials suitable for
  Ayurvedic studies?
• What modification we require in conventional
  clinical trial designs to validate holistic
  management , Ayurvedic medical care and total
  integrated approach?
• What should be statistical designs / theories
  appropriate for Ayurveda?

69
PROTOCOL (2006)To determine clinical research
methods best suited for validating Ayurvedic
medicines A study based on an analysis of
Ayurvedic drug trials (1996-2007) database
carried out in CRD, Pune.This is essentially a
study of methodology
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Objectives goals

• To clinically review earlier Ayurvedic drug
  trials For evaluating homogeneity in diagnosis
  and clinical approach to measure therapeutic
  response (Ayurvedic Allopathic)
• Apply better suited statistical methods For
  identifying subsets of patients with best outcome
  (efficacy and safety) response (Ayurvedic and
  Allopathic )
• Deduce clinical statistical research designs /
  methods best suited to validate Ayurvedic
  medicines

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Evidence Based MedicineA Hierarchy of Evidence
Systematic Reviews
Where do we position ?historical use, ancient
classics, Experiential data base?
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Why do we need to generate modern science
evidence based Ayurveda?

• Prescription drug use
• Newer drugs
• Newer intermedicinal system medical care
  management strategies
• To Position vis-à-vis other systems
• Global use
• who needs it?

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THANK YOU

• DR ARVIND CHOPRA, MD
• DIRECTOR CHIEF RHEUMATOLOGIST
• ARTHRITIS RESEARCH CARE FOUNDATION (ARCF)-
• CENTER FOR RHEUMATIC DISEASES (CRD), PUNE
• Please visit our Website www.rheumatologyindia.o
  rg