Final Presentation on Research Proposal

Title :

A Phase II clinical study of the effectiveness of

Andrographis paniculata (Burn.f.) Nees in the

y
treatment of erectile dysfunction

Presentor : Kutcharin Phunikhom

F
Faculty
lt off M
Medicine
di i
Kh
KhonKaen
K
U
University,
i
it Thailand
Th il d
2010

International Short Course Training in Research

Methodology and Biostatics 2010
Final Proposal

Title
A Phase II clinical study of the effectiveness of Andrographis paniculata
(Burn.f.) Nees in the treatment of erectile dysfunction

Presenter
Kutcharin Phunikhom, MD
Faculty of Medicine, Khonkaen University
Thailand 2010

Advisor
Assoc.Prof. Sumitr Sutra, MD
Assoc.Prof.Bandit Thinkhamrop, Ph.D.
1

Contents

Page

Background and rationale

Literature review
Justification to do the study
Research question
Objective of the study
Hypothesis
Conceptual framework
Key works and operational definitions
Research Methodology
Outcome variables
Measurement of the outcome (data collection)
Statistic component
Data collection form
Variable to be measured
Data presentation and plan of data analysis
Ethical consideration
Time schedule
Budget
Case report form
Data layout
References
Appendix 1 IIEF

3
4
9
10
10
10
11
12
13
14
14
16
19
20
21
27
30
31
33
38
39
41

Appendix 2 Modified SHIM IIEF-5

51

Appendix 3 SF-36

54
2

Background and rationale

Magnitude of the problem
Erectile dysfunction (ED) was defined as the persistent inability to achieve and
maintain erection sufficient for normal sexual satisfaction. ED should be distinguished from
problem with ejaculation, libido and orgasm. ED is a common physiological disorder (degree
of the dysfunction are chronic, occasional and situational). The incidence and prevalence is
high worldwide, affects about 52% of men age 40-70 years old, about 26 new case annually
per 1,000 men, affecting an estimated 150 million men worldwide (Morales,2009). Age,
smoking and obesity are the main risk factors. In about 20% of case, psychological problems
are the causes and other are organic causes, some of the organic causes are shown in figure 1.
Organic erectile dysfunction and cardiovascular disease share the same risk factors, including
diabetes, hypertension, dyslipidemia, obesity and smoking. These conditions also share the
same pathophysiology with endothelial dysfunction, inflammatory and endothelialprothrombotic activity and oxidative stress being their common denominators. Among the
three main line treatments for ED consist of oral therapy, self-injection therapy (papaverine,
prostaglandine E1 and phentolamine) and penile prosthesis implantation. Although many
treatments for ED are available, patients seem to prefer oral medication. Oral therapy is
always the first option. Sildenafil (Viagra) is the first available effective oral agent for ED.
Impact on health care
Although erectile dysfunction is a benign disorder. It is frequently associated with loss
of self esteem and can impact significantly on the quality of life of sufferers, partners and
family. It is important also to consider the physical and psychological health of the suffer.
3

Sildenafil (Viagra) is the first effective oral agent for ED since March 1998 by Pfizer, but this
drug is very expensive and increase adverse event in some patient. Patients also may prefer
herbal medicines for many reasons, including relatively low cost, ready availability and safety.
Further development of phytochemical studies of widely know herbal plants are desired.
Furthermore, there seems to be a large population that prefers to use phytotherapies rather
than pharmaceutical drugs for this health problem.
Figure 1 Some organic cause of erectile dysfunction show in pie graph.
organic cause of erectile dysfunction
DM 40%
vascular disease 30%
Radical surgery 13%
Spinal cord injury 8%
Endrocrinal disease 6%
Multiple sclerosis 3%

Literature review
Andrographis

paniculata(Family Acanthaceae) (figure 2) commonly known

worldwide as King of Bitters and Fah Talai Jone in Thailand (Li et al.,2007) is a
traditional medicine used extensively in Southeast Asia, India, Scandinavia and China. It has
been known to possess widerspread traditional application in the treatment of cold, fever,
laryngitis and infection. In Thailand, the aerial part of the plant (leaves and stems) are
normally used for extraction of the active phytochemicals to treat gastrointestinal tract and
upper respiratory infection, fever, herpes, sore throat and a variety of other chronic and
4

infectious disease(Standard of Thai Herbal Medicine,1999). The fresh and dry leaves as well
as the juice of the whole plant are widely used. The major of bioactive component of
Andrographis paniculata is andrographolide, its structure is shown in figure 3.

Figure 2 Andrographis paniculata(Burn.f.)Nees.

Figure 3 Biochemical structure of

andrographolide (Ruengsitagoon, 2005)

Pharmacological properties of andrographolide has been reported in both animal and

human, such as anti-platelet aggregation (Amroyan et.al.,1999; Thisoda e.al.t,2006), antiinflammatory (Suebsasana,2009; Shen et.al.,2002), anti-allergic(Xia.et.al,2004; Chandrase
karan et.al.,2010), antiviral:HIV(Reddy et.al.,2005; Wiart et.al.,2005), hepatoprotective
(Singha et.al.,2007), anti-diabetes (Reyes-Balanguer et.al., 2005; Yu et.al.,2008), stimulate
insulin secretion (Wibudi et.al.,2008), antithrombotic activity(Thisoda et.al.,2006), antidiabetic nephropathy (Lee et.al.,2010), treatment of common cold and respiratory
inflammation (Thamlikitkul et.al.,1991). Recently study in animal model showed that
andrographolide have effects on reproductive system, enhancing of sexual potency increasing
percentage of active form of spermatozoids and increasing of testosterone hormone level
(Sattayasai et.al.,2010) show in table 1.
Dosage and pharmacology of Andrographis paniculata in report of systematic review,
andrographolide 48-360 mg/day for treatment of upper respiratory infection. Rheumatoid
5

arthritis used 90 mg/day. Androgapholide was quickly and completely absorption, plasma
protein binding was 55 %, peak plasma 1.5-2 hrs, haft-life 6 hrs. and duration 10 hrs.
Metabolism by liver by conjugation and excretion by urine and faeces. Adverse drug reaction
were mild, infrequency and self-limiting (allergy, fatique, headache, nausea, diarrhea, metallic
taste, lymph node pain).

Mechanism of action of andrographolide

Sattayasai et.al(2010) study described mechanism of andrographolide action for
erection are two periods, in acute period are increased mounting frequency in three hours after
oral administration by antagonized alpha- one receptor due to relaxation of vascular smooth
muscle. In chronic period are increased testosterone level in four weeks but unknown
mechanism.

Table 1 Pharmacological property of andrographolide(AP1) on reproductive system.

Author/yrs./title
Allan JJ et.al.(2009)
Reproductive and fertility
effects of an extract of AP in
male Wistar rats
Panossian A et.al.(1999)
Effect of AP extract on
progesterone in blood
plasma of pregnant rats
Akbarsha MA et.al.(2000)
Aspects of the male
reproductive toxicity/male
antifertility property of AP1
in Albino rats: effect on the
testis and the cauda
epididymidal spermatozoa
Sattayasai J et.al.(2010)
Effects of AP1 on sexual
functions, vascular reactivity
and serum testosterone level
in rodents
Mkrtchyan A et.al.(2005)
A phase I clinical study of
AP fixed combination Kan
Jang versus ginseng and
valerian on the semen
quality of healthy male
subjects

participants
Male Wistar rats

Dose/duration
outcome
Per oral APE 20, 200, -no effect on fertility
1000 MKD for 65
-no effect on total sperm count & motility
day

Pregnant rats

Per oral APE 200,

600, 1000 MKD
For 19 day

Dose not exhibit any effect on the

elevated level of progesterone in the
plasma of rats

Albino rats

Per oral AP1 25, 50

MKD for 48 day

-Decreased sperm count

-not motile spermatozoa
-abnormality of sperm

Male ICR mice

Per oral AP1 50

-180 min: increase mounting frequency
MKD daily for 8 wks -4 wks: increased testosterone
-8 wks: no significant effect on sperm
morphology & motility

Healthy male

Per oral AP1 60, 120, -The results of the study revealed no
180 mg per day for
significant negative effect of Kan Jang on
13 day
male semen quality and fertility, but
rather a positive trend with respect to the
number of spermatozoids in the whole
ejaculate, the percentage of active
(normokinetic) forms of spermatozoids,
and fertility indexes, together with a
decrease in the percentage of inactive
(diskinetic) forms of spermatozoids and
others reported a subjective feeling of
enhanced sexual potency during the trial.

Table 2 clinical trial of andrographolide in other disease

Author/yrs/title

participants Dose/duration outcome

Amaryan G et.al(2003) Double-blind,

placebo controlled, randomized pilot
clinical trial of Immuno-Guard -a
standardized fixed combination of
Andrographis paniculata Nees, with
Eleutherococcus senticosus Maxime,
Schizandra chinensis Bail. And
Glycyrrhiza glabra L. extracts in patients
with Familial Mediterranean Fever.
Saxena RC et.al(2010) A randomized
double blind placebo controlled clinical
evaluation of extract of Andrographis
paniculata (KalmColdTM) in patients with
uncomplicated upper respiratory tract
infection.
Burgos RA et.al.(2009) Efficacy of an
Andrographis paniculata composition for
the relief of rheumatoid arthritis
symptoms: a prospective randomized
placebo-controlled trial.

Familial
ImmunoGuard
Mediterranean
370 mg
Fever (FMF) 25 (andrographolide
person
4 mg)
4 tab three time /day
(AP1 48 mg/day)
1 mouth

Coon JT et.al.(2004) Andrographis

paniculata in the treatment of upper
respiratory tract infections: a systematic
review of safety and efficacy.

Poolsup N et.al. (2004) Andrographis

paniculata in the symptomatic treatment
of uncomplicated upper respiratory tract

223 URI patients

Significant less episodes

FMF attacks in comparison
with these on placebo

KalmColdTM
Reducing symptoms of URI
200 mg/day
ADR: vomiting, epitaxis,
(APE 30 mg: AP1 urticaria, diarrhea, nausea,
31.30 %w/w)
lethargy

RA patients 30/arm AP1 30 mg three A significantly reduction

time/day, 14 day
for tender joint, number of
swollen joints, total grade
of tender joints
ARD: headache, diarrhea,
nausea,
stomach
discomfort,
fatigue,
common cold, pruritus/rash,
cramp
Seven control trial AP1 48-360 mg /day Andrographis paniculata is
Treatment 896
(1-10 MKD)
superior to placebo in
Placebo 1,235
alleviating
subjective
symptoms of URTI
ARD: mild, infrequent and
reversible
3 trial
APE (85-500 mg)
Andrographis paniculata
433 patients
4 tab three time /day more effective than placebo
and may be an appropriate
For 3-7 days
8

infection: systematic review

randomized controlled trial.

of

alternative treatment of
uncomplicated
upper
respiratory tract infection
Cui L et.al.(2005) Isolation and 8
healthy AP1( 50 mg/tab)
Seven conjugate metabolite
identification of seven glucoronide volunteers
3 tab three time /day in urine, determine by
conjugates of andrographolide in human
for 2 day
HPLC
urine.
(450 mg/day)

Justification to do the study

Why do you have to do research?
There are mainly 3 reasons to do this study, as the followings
Firstly: Erectile dysfunction is a common problem of men in Thailand, same
worldwide. The study of Levitra study no.10657-VENS in 2001 and 2004 found erectile
dysfunction affect 43% of men age 40-70 years old, affect about 4 million Thais men (in
2000).
Secondly: Drugs treatment (three phosphodiesterase-5 inhibitor: vardenafil (Levitra
2.5-20 mg), sidenafil(Viagra 25-100 mg) and tadatafil(Cials 5-20 mg) of erectile dysfunction
are very expensive, few people can affect it.
Lastly: Andrographis paniculata or Fah Talai Jone is a healthy food, extensively
used in Thailand in the treatment of many illness. That it demonstrate the positive effect on
ED in men, it may be the benefit for Thai people and worldwide.

What should be the benefit from doing that?

Fah Talai Jone is traditional Thai herb plant, used for treated of cold and antipyretic.
If it can improve erection in men, it will be benefit for root grass people regarding widely
available, low cost and low adverse event.

Research question
Primary question: Can per oral daily dose 60 and 120 mg of andrographolide from
Andrographis paniculata Nees for 4 weeks increase 20%(IIEF-5 score) erection in erectile
dysfunctions men?
Secondary question: How andrographolide effect testosterone hormone and
cholesterol?

Objectives of the study

1. To examine the treatment effectiveness of Andrographis paniculata (Burn. f.) Nees
in the patient with erectile dysfunction.
2. The secondary goals were to determine if there are any changes in both
testosterone hormone level and lipid profiles of the treated patient.

Hypothesis
Ho : Andrographolide have same effect to placebo in erectile dysfunction.
HA : Andrographolide have superior effect to placebo in erectile dysfunction .

10

Conceptual framework

11

Key words and operational definitions

Erectile dysfunction, Impotence, Andrographis paniculata, Angrographolide
Operational definition :
ED : erectile dysfunction, assessment by self-report on the IIEF-5. IIEF-5
(International Index of Erectile Function Questionnaire) is a questionnaire for assessment
erectile function. These questions ask about the effects patients erection problems have had
on sex life, over the past 4 weeks. IIEF-5 compost of 5 questions about sexual activity, 6
score per one question (0-5) and interpret erectile function depend on score:
Table 3 Interpreted of IIEF-5
IIEF-5 score
22-25
17-21
12-16
8-11
<7

Erectile function
normal erectile function
mild erectile dysfunction
mild to moderate erectile dysfunction
moderate erectile dysfunction
severe erectile dysfunction

Andrographolide : The main active compound of Andographis paniculata , extract from the
aerial part of the plant.

12

Table 4 Description of the IIEF questionnaire

Dimensions
Erectile function(EF)

Orgasmic function(OF)
Sexual desire(SD)
Intercourse satisfaction(IS)
Overall satisfaction

Number Cluster of
of items items
6
1,2,3,4,5,15

2
2
3
2

9-10
11-12
6,7,8
13,14

Directions of dimensions
1-10 severe erectile dysfunction
11-16 moderate dysfunction
17-21 mild to moderate dysfunction
22-25 mild dysfunction
26-30 no dysfunction
High score = Less dysfunction

Research Methodology
Study design: Experimental study, prospective, phase II clinical trial
Setting: Srinagarind hospital, faculty of medicine, KhonKaen university, Thailand
Target population: Patients with ED visiting at out-patient department of study site.
Sampling technique : Consecutive impotence patients who attend OPD andrology
during study period.
Eligible criteria
Inclusion criteria
1. Men age 40-70 years old in the andrology clinic at Srinagarind hospital with mild to
mild-moderated erectile dysfunction (as judged by IIEF-5 score 12-21)
2. A stable sexual partnership during the previous 6 month.

13

Exclusion criteria
1. Patients who included history of radical prostatectomy, spinal cord injury,
neurological impairment, Peyronies disease, drug abuse and specific previous
treatment.
2. Patients who included history of severe psychological problem.
3. Impaired renal and hepatic function.
4. Current ischemic heart disease (6 months ago).
Randomization : Computer generated random sequences using block randomization
and will be placed in the opaque sealed envelopes.
Intervention and assessor masking : Andrographolide and placebo will be prepare by
same color of capseal and will be dispensed in identical blister, labeled with code numbers
only.

Outcome variables
Primary outcome: improvement of erection measured by IIEF.
Secondary outcome: measure testosterone level and lipid profile before and after
treatment, quality of life assessment by SF-36

Measurement of the outcome (data collection)

How do you measure the outcome?
1. IIEF score for assess improvement of erection.
2. SF-36 score for assess quality of life.
3. Measurement of testosterone level by RIA

14

Study flow:

When do you collect the data?

1. Self report on the IIEF pre-treatment and 1, 2, 3 and 4 weeks post treatment
2. Self-report on SF-36 at 4 weeks post treatment.

Intervention performers
Clinician:
-Diagnostic ED
-enrollment
-evaluate outcome and assessment of adverse reaction.
-Provided signed informed consent after enrollment.
15

Registered nurse in OPD:

-Performed baseline and eligibility assessments
-open box set and sealed envelope to assigned patient to treatment group
Pharmacist:
-Prepare andrographolide and placebo by capseal them, identically and were dispensed
in identical blister, labeled with code number only.

Which tool will be used

IIEF and SF-36 questionnaire

Statistic component
Sample size calculation
This study is a phase II of clinical trial, the number of participant in phase II about 20300.The primary outcome is the improvement of erectile function that measurement by IIEF-5
score, compare between treatment and placebo group, because of this study is combination
phase IIA (assess dosing requirement) and phase IIB (study efficacy). We used the following
assumption to estimate the necessary sample size. The required sample size for difference
between three mean for multiple comparison was estimate. A 5 score(minimum detectable
different) of IIEF-5 was considered the smallest average difference change between
andrographolide treated (at least one dosing effective [therapeutic dose (60 mg) or double dose
(120 mg)] and placebo treatments to detect a clinical effect in a IIEF-5 score of 25 (equivalent
to 20% improve in the treatment group). The power of 80% was used to detect a true
difference in outcome between the placebo and the intervention group. The level of
significance was set at 5% (reject Ho if p>0.05). The common standard deviation used in the
sample size was 5 score of IIEF-5. The required sample size for each arm of AP1 60 mg, 120
mg or placebo was a minimum of 51 participant or a total 153 for the whole study. As drop
outs are common in clinical trial of a self-limiting condition, around 20% more participants
16

were added in each group, estimating 62 participants per group(total 186). The sample size is
calculated by PASS 2008 software.

Data analysis
Baseline characteristics of the participants and operative data in this study are
-Age (years)
-BMI (kg.m-2)
-Smoking (smoker /no smoker)
-Alcohol drinking (no/ yes)
-Underlying disease (DM/ HT/ CHD)
-Time period with ED (years)
-Exercise (no/yes, frequency)
And baseline laboratory analysis compost of
-CBC
-Blood chemistry (BS, HbA1C, BUN, Cr, Liver enzyme, Lipid profile)
-Testosterone level
-Urinalysis
-EKG

17

All data relevant to the study will carefully entered onto the CRF maintained
for each participant who had received trial medication. Data will managed using a
Microsoft Excel 2007 based database.
For continuous data such as age, BMI, time period of ED and laboratory test
will be presented using mean and standard deviation and categorical data such as
smoking, alcohol drinking and underlying disease will be presented as number and
percentage for each group. If these data are significant difference in both groups
(treatment and placebo), subgroup analyze will be done.
Erection is the main outcomes, will be measure by IIEF questionnaire at pretreatment and 1, 2, 3 and 4 weeks (post-treatment), data will be recorded as
continuous data and presented as mean of IIEF score+ SD. The effect of each
treatment will calculated as the increasing in the IIEF score from baseline to final
assessment. The mean difference in effect between AP1 60 mg, 120 mg and placebo
will be estimate. In the pooling of mean difference as well as the estimation of 95%
confidence interval and p-value. Comparison total and individual IIEF score
recorded at different time (pre/week1,2,3,4 post treatment) between groups will
analyzed using repeated measure ANOVA.
Statistical comparisons of quality of life between group by SF-36
questionnaire (post treatment) will be conducted using Kruskal-Wallis rank test.
H0 : u1=u2=u3
HA : u1#u2#u3

18

Data collection form

Subject Number

--

Subject Initial

ID

1. Age.yrs

AGE

2. Weight..kg
3. Heightcm.
4. BMI ..kg.m-2

WT

HT
BMI
5. Smoking Habit 0 Non-smoker 1 Ex-smoker 3 Smoke..number/day
SMK
6.Alcohol Drinking 0 Never 1Occasionally 2 Often glass/week
ALC
7. Exercise 0 No 1Occasionally(1-3 day/wk) 2 Often (4-7day/week)
EXC
8. Underlying disease 0 No
1 Yes, specific 2 DM3HT4CHD
UD
9. Time period with ED year
19

ED

Variable to be measured are

Baseline data
Variables

Type of data

scale

Age (years)

continuous

Ratio

BMI (kg.m-2)

continuous

Ratio

Smoking Habit

categorical

Nominal

Alcohol Drinking

categorical

Nominal

Exercise

categorical

Nominal

Underlying disease

categorical

Nominal

Time period with ED(year)

continuous

Ratio

Primary outcome
Variables

Type of data

scale

IIEF scale

continuous

ratio

20

Secondary outcome
Variables

Type of data

scale

Testosterone level

continuous

ratio

Lipid profile (cholesterol,

continuous

ratio

continuous

ratio

triglyceride, HLD, LDL)

SF-36 scale

Data presentation and plan of data analysis

Dummy Tables
Table 1 Baseline characteristics of the participant (data are present as mean +SD or
number of participant)
variables

placebo

AP1 60 mg

aP1 120 mg

Age (years)

Mean +SD

Mean +SD

Mean +SD

BMI (kg.m2)

Mean +SD

Mean +SD

Mean +SD

Exercise

N,%

N,%

N,%

21

Smoking

N,%

N,%

N,%

Alcohol

N,%

N,%

N,%

Underlying

N,%

N,%

N,%

Mean +SD

Mean +SD

Time for ED(years) Mean +SD

Table 2 Comparison of pre- and post-treatment IIEF score of the participant (data are
present as mean + SD, calculate magnitude of effect pre &post treatment with 95%CI, p-value
and comparison IIEF score post-treatment between three group by using ANOVA)
variables
Pre-Tx( IIEF wk0)
Post-Tx (IIEF wk4)
Mean different
95% CI
P-value
AP1=andrographolide

placebo
Mean +SD
Mean +SD
x1
Y1,z1
0.0xxx

AP1 60 mg
Mean +SD
Mean +SD
x2
Y2,z2
0.0xxx

AP1 120 mg
Mean +SD
Mean +SD
x3
Y3,z3
0.0xxx

Table 3 Comparison of IIEF score, pre(week 0) and post treatment(week 4) of the

participant
variables
IIEF score-pre

placebo
Mean +SD
22

AP1 60 mg
Mean +SD*

AP1 120 mg
Mean +SD**

post
Mean +SD
Mean +SD
Mean +SD
Erectile Function -pre
Mean +SD
Mean +SD
Mean +SD
-post
Mean +SD*** Mean +SD***
Mean +SD***
Orgasmic Function-pre
Mean +SD
Mean +SD
Mean +SD
-post
Mean +SD
Mean +SD
Mean +SD
Sexual Desire -pre
Mean +SD
Mean +SD
Mean +SD
-post
Mean +SD
Mean +SD
Mean +SD
Intercourse Satisfaction-pre
Mean +SD
Mean +SD
Mean +SD
-post
Mean +SD
Mean +SD
Mean +SD
Overall Satisfaction-pre
Mean +SD
Mean +SD
Mean +SD
-post
Mean +SD
Mean +SD
Mean +SD
*Symbol were found to be significantly different (one way ANOVA) from placebo
**Symbol were found to be significantly different (one way ANOVA) from AP1 60
mg
Table 4 Quality of life by SF-36 will be conducted using Kruskal-Wallis rank test
group

Mean +SD

p-value

Placebo

xx

Mean +SD

0.0xx

AP1 60 mg

xx

Mean +SD

0.0xx

AP1 120 mg

xx

Mean +SD

0.0xx

23

Table 5 Comparison laboratory value, testosterone and lipid profile data are present as
mean + SD and comparison three group by using ANOVA)
Outcome

placebo

AP1 60 mg

Testosterone, Mean(+SD)
Pre-treatment
Post-treatment
Cholesterol, mean(+SD)
Pre-treatment
Post-treatment
Triglyceride, mean(+SD)
Pre-treatment
Post-treatment
HDL-C, mean(+SD)
Pre-treatment
Post-treatment
LDL-C, mean(+SD)
Pre-treatment
Post-treatment

24

AP1 120 mg

p-value

Data presentation
Table 1 demographic data
variables

placebo

AP1 60 mg

AP1 120 mg

Age (years)

Mean +SD

Mean +SD

Mean +SD

BMI (kg.m2)

Mean +SD

Mean +SD

Mean +SD

Exercise (yes)

N,%

N,%

N,%

Smoking (yes)

N,%

N,%

N,%

Alcohol (yes)

N,%

N,%

N,%

Underlying (yes)

N,%

N,%

N,%

Time for ED(years)

Mean +SD

Mean +SD

Mean +SD

N,%

N,%

N,%

-mild-moderate(17-21) N,%

N,%

N,%

Severity of ED
-mild (12-16)

25

Table 2 magnitude of IIEF score, pre- and post-treatment of the participant

variables
placebo
AP1 60 mg
Pre-Tx (IIEF wk0) Mean +SD
Mean +SD
Post-Tx (IIEF wk4) Mean +SD
Mean +SD
Mean different
X1
x2
95% CI
Y1,z1
Y2,z2
P-value
0.0xxx
0.0xxx
*Symbol were found to be significantly different

AP1 120 mg
Mean +SD
Mean +SD
x3
Y3,z3
0.0xxx

Table 3 Comparison of IIEF score, pre and post treatment of the participant
IIEF

treatment

Week0

Week1

Week2

Week3

Week4

Mean

p-value

Mean score

Mean score

Mean score

Mean score

Mean score

difference
(wk4-wk1)

IIEF

IIEF-5

OF

SD

IS

Placebo

Mean +SD

Mean +SD

Mean +SD

AP60

Mean +SD

Mean +SD Mean +SD Mean +SD Mean +SD Mean

AP120

Mean +SD

Mean +SD

Mean +SD

Mean +SD

Mean +SD

Mean +SD

Placebo

Mean +SD

Mean +SD

Mean +SD

Mean +SD

Mean +SD

Mean +SD

AP60

Mean +SD

Mean +SD Mean +SD Mean +SD Mean +SD Mean

AP120

Mean +SD

Mean +SD

Mean +SD

Mean +SD

Mean +SD

Mean +SD

Placebo

Mean +SD

Mean +SD

Mean +SD

Mean +SD

Mean +SD

Mean +SD

AP60

Mean +SD

Mean +SD Mean +SD Mean +SD Mean +SD Mean

AP120

Mean +SD

Mean +SD

Mean +SD

Mean +SD

Mean +SD

Mean +SD

Placebo

Mean +SD

Mean +SD

Mean +SD

Mean +SD

Mean +SD

Mean +SD

AP60

Mean +SD

Mean +SD Mean +SD Mean +SD Mean +SD Mean

AP120

Mean +SD

Mean +SD

Mean +SD

Mean +SD

Mean +SD

Mean +SD

Placebo

Mean +SD

Mean +SD

Mean +SD

Mean +SD

Mean +SD

Mean +SD

26

Mean +SD

Mean +SD

Mean +SD
+SD

+SD

+SD

+SD

OS

AP60

Mean +SD

Mean +SD Mean +SD Mean +SD Mean +SD Mean

AP120

Mean +SD

Mean +SD

Mean +SD

Mean +SD

Mean +SD

Mean +SD

Placebo

Mean +SD

Mean +SD

Mean +SD

Mean +SD

Mean +SD

Mean +SD

AP60

Mean +SD

Mean +SD Mean +SD Mean +SD Mean +SD Mean

AP120

Mean +SD

Mean +SD

Mean +SD

Mean +SD

Mean +SD

+SD

+SD

Mean +SD

*Symbol were found to be significantly different (repeated measure ANOVA)

Table 4 Quality of life by SF-36 (Kruskal-Wallis rank test)

group

Mean +SD

p-value

Placebo

xx

Mean +SD

0.0xx

AP1 60 mg

yy

Mean +SD

0.0xx

AP1 120 mg

zz

Mean +SD

0.0xx

Ethical consideration
This study protocol compost of the study information and consent form must be
accepted by the ethic committee of medicine faculty, Khon Kaen University before starting
the recruitment of all participants into the study. All participants will receive adequate verbal
and written information regarding the study and information about the purpose, process,
27

advantages and adverse reaction of andrographolide before they decide to participate in the
study. The investigator must be responsible for obtaining the appropriate consent form from
the participants before recruiting them into the study.
All participants that meet the eligible criteria will be enrolled in this study and
randomized for each intervention. The refusal of a patient to participate in a study must never
interfere with the patient-physician relationship.
Limitation of this study
1. Srinagarind hospital is a tertiary care hospital, the participants with erectile
dysfunction are likely to have more severe disease than would be expected in the
generation population.
2. Erectile dysfunction is special problem but no life threatening, many patient no
need specific treatment, may be have compliance problem.
3. Information bias may occur in some patient because of IIEF is a self-questionnaire
measurement.
Possible benefits
As shown in justification, ED is common problem in worldwide and specific treatment
are very expensive. If andrographolide prove to be effective treatment for ED, many patient
may have low cost treatment for ED.
28

Possible harm
Possible harms from this treatment are expected to be low because of this plant used
commonly known worldwide as King of Bitters and Fah Talai Jone in Thailand(Li et
al.,2007). Andrographis paniculata is a traditional medicine used extensively in Southeast
Asia, India, Scandinavia and China. It has been known to possess widerspread traditional
application in the treatment of cold, fever, laryngitis and infection. Report of adverse even are
mild, low incidence and self limited.
Patient protection and management
Written informed consent will be done by every patient and/or authorized
representative on a voluntary basis. The details of the study will be provided transparently.
The participants can refuse to join the study at any time without conditions and not affect on
those patients care and management.
For safety of the participants, the patients with history of Andrographis paniculata
shall be excluded.
Compensation
There is no compensation for the participants of the study.
Responsible person
29

Kutcharin Phunikhom, MD.

Department of pharmacology, faculty of medicine, Khon kaen University
043-348397, 081-7178751

Time schedule
The study will be conducted between November 2010 and June 2011
Activity

Nov.-Dec 2010

protocol

Jan-Feb 2011

Mar-Aug 2011

Sep-Oct 2011

development
Ethics

application
Recruitment of

data collection
Analysis
Report

writng

and publication

30

Budget
Detail

Cost X unit(S)

Baht

Lab testing (in table below)

2550 X 186

474,300

Drug preparation

120 X 186

22,320

Patient travel

500 X 186

93,000

Data collection form preparation

3500

Office supplies

3000

Patient tracing (telephone call)

3000

Report preparation

3000

miscellaneous

2000

Total funding project

604,120

Lab testing
Lab test

Pre-treatment (baht)

Post-treatment (baht)

BS

40

40

HbA1C

150

150

BUN

50

50

31

Creatinine

50

50

Cholesterol

60

60

Triglyceride

60

60

HDL

100

100

LDL

150

150

CBC

90

90

Liver enzyme(ALT,AST,AP)

150

150

Testosterone

250

250

UA

50

EKG

200

total

1,400

1,150

32

Case report form

I will separate CRF in 2 part, pre-treatment and post treatment
Demographic and other information: pre-treatment
1. Number..initial..
2. Age.yrs
3. BW.kg, HT.cm.
4. BP..mmHg, HR../min, PR./min
5. Smoking 01.2
6. Alcohol0..1.2
7. Underlying0.1234
8. Exercise0.1..2
9. Time period with ED..yrs
10. CBC , Hb.mg%, Hctvol%, Plt..cell/dL
11. BS..mg/dL, HbA1C..mg%
12. BUNmg/dLCr..mg/dL
13. ALTU/L, AST..U/L, AP..U/L
14. Urinalysis.0..1
15. EKG0.1
33

Code

16. Cholesterol.mg/dL, Triglyceridemg/dL

HDL..mg/dL, LDLmg/dL
17. Testosterone level..mIU/dL
18. IIEF scoretotal
IIEF-5..
EF
OF..
SD..
IS..
OS

Demographic and other information: post-treatment

1. Number..initial..
2. BW.kg, HT.cm.
3. BP..mmHg, HR../min, PR./min
4. CBC , Hb.mg%, Hctvol%, Plt..cell/dL
5. BS..mg/dL, HbA1C..mg%
6. BUNmg/dLCr..mg/dL

34

Code

7. ALTU/L, AST..U/L, AP..U/L

8. Urinalysis.0..1
9. Cholesterol.mg/dL, Triglyceridemg/dL
HDL..mg/dL, LDLmg/dL
10. Testosterone level.mIU/dL
11. IIEF scoretotal
IIEF-5..
EF
OF..
SD..
IS..
OS
12. SF-36 score..

Data dictionary
Questionnaires

Details

Code

id

Identification number

001 to 064

age

Age

Age in years based on birthday

35

wt

Body weight

Body weight in kilogram

ht

Body high

Body high in centimeter

BMI

Body mass index

BMI in kg.m-2

=BW(kg)/Ht(m)2
SMK

Smoking status

0=no smoking
1=experience of smoking
(stop>6 mouth)
2=current smoking

ALC

Alcohol drinking

0=no drinking
1=occasional drinking (<3 day/week)
2=often drinking(>3 day/week)

EXC

Exercise

0=no exercise
1=occasional exercise (<3 day/week)
2=often exercise (>3 day/week)

UD

Underlying disease

0=no underlying
1=have underlying
2=DM, 3=HT, 4=CHD

ED

Time period with ED

Time in years

36

IIEF

IIEF score

Score 5 to 75

EF

Erectile function

Score 1 to 30

OF

Orgasmic Function

Score 0 to 10

SD

Sexual Desire

Score 2 to 10

IS

Intercourse Satisfaction

Score 0 to 15

OS

Overall Satisfaction

Score 2 to 10

SF-36

Short form quality of life Score 35 to 149

assessment score

CHO

Cholesterol level

Cholesterol level in mg/dl

TG

Triglyceride

Triglyceride in mg/dL

HDL

HLD

HLD in mg/dL

LDL

LDL-C

LDL-C in mg/dL

TES

Testosterone level

Testosterone level in mIU/dL

UA

Urinalysis

0 = normal or no clinical significant

1= abnormal

EKG

Electrocardiography

0 = normal or no clinical significant

1= abnormal

37

Data layout
id

age bmi smk alc exc ud ed IIEF EF OF SD IS OS SF cho tes

001
002
003

38

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antifertility property of andrographolide in Albino rats: effect on the testis and the
cauda epididymidal spermatozoa. Phytother Res 2000; 14: 432-5.
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standardized fixed combination of Andographis paniculata Nees. with
Eleutherococcus senticosus Maxim, Schizandra chinensis Bail. And Glycyrrhiza
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8. Cui L, Qui F, Yao X. Isolation and identification of seven glucoronide conjugates of
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39

9. Lee MJ, Rao YK, Chen K, Lee YC, Chung YS, Tzeng YM. Andographolide and 14deoxy-11-12-didehydroandographolide from Andographis paniculata attenuate high
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17. Reyes-Balanguer J, Solaz-Moreno E, Morata-Aldea C, Elorza-Montesinos P.

Spontaneous diabetic myonecrosis. Diabetes Care 2005;28: 980-1.
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Vijayabalaji V, Goudar KS, Venkateshwarlu K, Amit A. A randomized double blind
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25. Wiart C, Kumar K, Yusof MY, Hamimah H, Fauzi ZM, Sulaiman M. Antiviral
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42

Appendix 1

ID.Initial .............................................................
Visit ....................... 1.......... 2........... 3......... 4

( 4 )

/

(
)

43



1. ( 4)

............................................
............................................
( ) ............................................
( ).....................................
( )...........................................
...............................................
2. (4)

............................................
............................................
( ) ............................................
( ).....................................
( )...........................................
...............................................

44

3. (4)
( )
............................................
............................................
( ) ............................................
( ).....................................
( )...........................................
...............................................
4. ( 4)
( )

............................................
............................................
( ) ............................................
( ).....................................
( )...........................................
...............................................
5. ( 4)

45

 ............................................
............................................
( ) ............................................
( ).....................................
( )...........................................
...............................................
6. (4)
.....................................
1-2 ........................................................
3-4 .......................................................
5-6 .......................................................
7-10 .....................................................
11 ...............................................
7. ( 4)

........................................
............................................
( ) ............................................
( ).....................................
46

 ( )...........................................
...............................................
8. (4)
........................................................
...................................................
...........................................................
................................................
................................................
........................................................
9. (4)

...................
............................................
( ) ............................................
( ).....................................
( )...........................................
...............................................
10. (4)
( )
47

 .....................
............................................
( ) ............................................
( ).....................................
( )...........................................
...............................................
11. (4)
............................................
( ) ............................................
( ).....................................
( )...........................................
...............................................
12. (4)
.......................................................................
.............................................................................
..................... ............................................
..............................................................................
...................................................

48

13. ( 4)

.............................................................
....................................................
.............................
...............................................
.........................................................
14. ( 4)

.............................................................
....................................................
.............................
...............................................
.........................................................
15. ( 4)

.......................................................................
.............................................................................
..................... ............................................
49

..............................................................................
...................................................

50

Appendix 2
(Modified SHIM-IIEF5)
ID.Initial .............................................................

4

/

(
)

51

1.
.......................................
( )..........................................................
( )................................................
............................................................................
.......................................................................
.............................................................
2.
..................................................................................
.........................................................................................
.............................................................................
.........................................................................................
...................................................................................
3.

.....................................................
( )..........................................................
( )................................................
............................................................................
.......................................................................
52

.....................................................................
4.

.....................................................
( )..........................................................
( )................................................
............................................................................
................................................
.............................................................
5.

...............................................................................
...........................................................................
........................................................................
.................................................................................
................................................................................
.............................................................

53

Appendix 3
(SF-36)
IDinitial.................................................

1. 1

2. 1

54

3.


.
...............................................................
.
..............................................................................................................
. .......................................................................
. .................................................................................
. 1 .......................................................................................
. .........................................................................
. 1 ................................................................
. ..........................................................................
. 30
.............................................................................
. ........................................................................................
4.



. ................................
. ..............................................................
. ....................................
.
.......................................................
55

5. ( )


. ......................................
. ..............................................................
.
......................................................................
6. 1

7. 1

8. 1

56

9. 1

. ..................................................................................
. ................................................................................................
.
...............................................................................................
. .........................................................................................
. ..................................................................................................
. ..........................................................................................
. ......................................................................................
. ...........................................................................................
. ...........................................................................................
10. 1

57

11.

. ...............................................................
.
..........................................................................................
.
.............................................................................................
. .........................................................................

58