A Randomised, Open Label, Interventional Study Evaluating the Efficacy & Safety of Dry Powder Ivy Extract (Syrup Prospan) Versus NAC Among COPD Patients (SyProNAC Trial)
Phase: NA
Conditions: Chronic Obstructive Pulmonary Disease
Sponsor: National University of Malaysia

1 
DEPARTMENT OF INTERNAL MEDICINE 
UNIVERSITI KEBANGSAAN MALAYSIA 
Official Title : A Randomised, Open Label, Interventional 
Study Evaluating the Efficacy & Safety of Dry Powder Ivy 
Extract (Syrup Prospan) versus NAC among COPD 
Patients 
(SyProNAC Trial) 
Research Identification Number : FF-2023-433
Date of Document : Version 1st February 2024
 ___________________________________________________ 
Candidate: 
Dr Muhamad Thaqif Sidek
(P126274)
Supervisor: 
Dr Mas Fazlin Mohamad Jailaini 
Respiratory Unit, Department of Medicine, HCTM 
Co-supervisor: 
Associate Professor Dr Mohamed Faisal Abdul Hamid 
Associate Professor Dr Andrea Ban Yu-Lin  
Dr Azat Azrai Dato Azmel 
Dr Ng Boon Hau 
Dr Nik Nuratiqah Nik Abeed 
Respiratory Unit, Department of Medicine, HCTM 

 
2 
CONTENTS 
 
 
 
 
 
 
 
PAGE 
 
Section 1: Introduction                                                              3
 
 
 
 
 
 
 
 
Section 2: Literature Review 
 
 
 
 
 
4    
 
Section 3: Hypothesis  
 
 
 
 
                  6 
 
Section 4: Research Objectives                                                 6
 
 
 
 
 
 
 
 
Section 5: Research design & methodology                            7 
5.1 Study Design 
5.2 Study Population 
5.3 Inclusion and Exclusion Criteria 
5.4 Study Protocol and Data Acquisitions 
5.5 Operational Terms Definition 
5.6 Sample Size and Power of Study 
 
Section 6: Statistical Analysis                                                  13
 
 
 
 
 
 
 
Section 7: Research Ethics  
                                            14
 
 
 
 
 
 
Section 8: Estimated Cost of Study                                          15 
 
Section 9: Research Information                                              16 
 
Section 10: Consent Form                                                        20 
 
Section 11: Data Collection Sheet                                            22
 
 
 
 
 
 
 
 
 
 
 
Section 12: Gantt chart 
                                                     24
 
 
 
 
 
 
 
Section 13: Appendices  
 
                                            25
 
 
 
 
 
 
Section 14: References  
                                                     30
 
 
 
 
 
 
 
 

 
3 
Section 1: Introduction 
 
 
 
As the third global leading cause of death, Chronic Obstructive 
Pulmonary Disease (COPD) affects more than 300 million 
people worldwide [1,2]. These patients suffer from 0.5–3.5 
exacerbations per year on average. Each exacerbations 
dampened their health status as well as quality of life, not to 
mention a great burden to our healthcare system [3,4]. Those 
partially treated or prolonged exacerbations would subsequently 
lead to unfavorable disease progression. Hence a holistic 
approach in managing each exacerbations is very crucial [5]. 
Mucus hypersecretion in COPD patients plays a pivotal role in 
acute exacerbations and associated with unfavorable outcomes 
[6]. These exacerbations comes with sputum increment as much 
as its purulence. Mucolytics are believed to to ease patient to 
expectorate and benefits them from tip into an exacerbations or 
even the consequent hospitalisation [7]. 
Mucolytics work by reducing sputum viscosity hence improved 
its expectoration. N-acetylcysteine (NAC) is a mucolytic with 
antioxidant and anti-inflammatory properties, commonly used in 
practice among COPD patients [8]. Meanwhile, Syrup Prospan 
is ivy leaf preparations, obtained as extracts from leaves of the 
plant Hedera helix L. It is widely used over-the-counter cough 
remedy containing saponins which are believed to have 
expectorant properties [9]. Studies show evidence of 
antispasmodic, bonchodilating, anti-inflammatory and 
antitussive properties and its usage is authorised by the 
European Medicines Agency [10]. 
 
 
 
 
 
 

 
4 
Section 2: Literature Review 
 
 
 
Mucolytics are defined as medications that decrease mucus 
viscosity and can be divided into classic and peptide mucolytics. 
Classic and peptide mucolytics depolymerize mucin 
glycoproteins and DNA with F-actin polymer networks, 
respectively [11]. 
 
NAC alters mucus viscosity by modifying the crosslinks and 
molecular interactions within mucin polymers. These changes 
enhancing mucociliary clearance and subsequent sputum 
expectoration. This effects are beneficial in mucus 
hypersecretory states such as COPD and cystic fibrosis. 
Several studies on NAC suggest apart from its mucolytic 
properties, it exerts anti-inflammatory effects by inhibiting 
chemotaxis, reducing lysozymes and lactoferrin concentration as 
well as neutrophils and macrophages in bronchoalveolar lavage 
fluid [12]. In addition, it inhibits bacterial adherence to the 
ciliated epithelium [13]. 
Latest 2023 GOLD Report stated that COPD patients not 
receiving ICS, regular treatment with mucolytics such as 
carbocysteine and N-acetylcysteine (NAC) may reduce 
exacerbations and modestly improve health status. 
 
A meta-analysis by Papadopoulou et al included 24 RCTs 
involving 2192 patients with COPD exacerbations demonstrated 
with moderate certainty that mucolytics appear to improve the 
treatment success rate and symptoms [14]. 
 
Another meta analysis conducted by Cazzola et al demonstrates 
that mucolytics are useful in preventing COPD exacerbations as 
maintenance add-on therapy to patients with frequent 
exacerbations. The effectiveness of mucolytics is independent of 

 
5 
the severity of airway obstruction and the use of inhaled 
corticosteroids [15]. 
Various trials proved the efficacy and safety of ivy leaves 
preparation for acute URTI and also chronic bronchitis. 
Schaefer et al proved consistent superiority of ivy leaves cough 
liquid in a randomized, placebo-controlled, double-blind trial 
[16]. A cohort study in Germany provided further evidence that 
the use of ivy leaves preparations contribute to inappropriate 
antibiotic usage for respiratory infections in adult patients with 
cough symptoms [17]. 
To date there are no studies comparing Ivy leaf preparations 
with other mucolytic agents. A meta analysis by Rogliani et al 
assessed the efficacy of erdosteine, carbocysteine, and NAC on 
acute exacerbation and concluded that overall efficacy and 
safety profile of erdosteine is superior to that of both 
carbocysteine and NAC [18]. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
6 
Section 3: Hypothesis 
 
1. Syrup Prospan is non inferior to NAC - no significant 
difference of cough symptoms and its impact on daily 
activities, health related quality of life, as well as lung 
function test at 30 days of treatment 
2. Patients received Syrup Prospan has higher satisfaction 
score compared to N-Acetylcysteine 
 
Section 4: Research Objectives 
 
Primary objective 
To demonstrate that Syrup Prospan is non inferior to N-
Acetylcysteine in assessment of  cough symptoms and its impact 
on daily activities using Cough and Sputum Assessment 
Questionnaire (CASA-Q) during 30 days of treatment. 
 
Secondary objective 
1. To evaluate the effectiveness of Syrup Prospan vs  
N.Acetylcysteine in terms of  
I. 
McGill COPD Quality of Life Questionnaire on Day 
1 and 30 days of treatment. 
II. 
Lung function test (including morning pre-dose 
FEV1) and FVC on Day 1 and 30 days of treatment.  
III. 
Incidence of adverse effects (in %) 
2. To assess satisfaction of treatment using the 5 point Likert 
Scale.  
 
 
 
 
 

 
7 
Section 5: Research Design & Methodology 
 
 
 
 
5.1 Study Design 
 
A randomised, open label, interventional study evaluating the 
efficacy and safety of dry powder Ivy Extract (Syrup Prospan) 
versus NAC among COPD patients. 
Randomization 1:1 to received either N.Acetylcysteine 600 mg 
BD or Syrup Prospan 7.5mls BD (Block randomization) 
 
 
5.1.1 Period of Study 
 
The study will be conducted from December 2023 to 
November 2026 after receiving approval by the research 
ethics committee. 
 
 
 
5.2 Sampling Population 
 
This study will include All patients are stable COPD patients 
under Respiratory Clinic HCTM follow-up, aged ≥ 40 year 
old and above and able to perform spirometry from 
September 2023 to February 2024. Demographic and clinical 
data will be collected. Patient will be followed-up at Day 15 
and Day 30 after intervention. 
 
 
 
 
 
 

 
8 
5.3 Inclusion and Exclusion Criteria 
 
Inclusion criteria 
1. Patients with documented post bronchodilator FEV1/FVC 
< 70 or <LLN  
2. Age 40 years and above 
3. Able to perform spirometry 
4. Patient with Stable COPD based on GOLD 2023 strategy 
Exclusion criteria 
1. Diagnosis of other chronic lung diseases: Asthma, 
Asthma-COPD Overlap, Interstitial Lung Disease, 
Bronchiectasis, Lung Cancer 
2. Patients with contraindication for spirometry: recent 
cardiac complications, major surgery, severe advanced 
respiratory disease, or those with cognitively or 
neurologically impairment 
3. Hypersensitivity to acetylcysteine or any component of the 
formulation 
4. Hypersensitivity to dry powder ivy extract 
5. Pregnant or nursing (lactating) women, where pregnancy 
is defined as the state of a female after conception and 
until the termination of gestation, confirmed by a positive 
hCG (human Chorionic Gonadotropin) laboratory test 
6. Patients on pre-existing regular mucolytics (at least 1 
month prior) 
7. Illiterate patients  
 
 
 
 
 
 
 
 

 
9 
5.4 Study Protocol and Data Acquisitions 
 
 
 
This is a prospective interventional study conducted on 
COPD patients under the Respiratory Unit, Department of 
Internal Medicine in HCTM, who qualified both the inclusion 
and exclusion criteria. Patients will be briefed about this 
study. 
 
Subsequently, consent will be obtained from those who are 
agree to participate from the patient him/herself. 
 
Patients’ will be assessed first with several modalities 
particularly spirometry, CAT score, McGill COPD Quality of 
Life and Cough and Sputum Assessment Questionnaire 
(CASA-Q) prior to the commencement of treatment. Patients 
will be seen on Day 15 to evaluate patients’ adherence, 
compliance as well as adverse effect. Then patients will be 
assessed again on Day 30 of treatment with the same set of 
evaluation tools as in the beginning of the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
10
5.4.1 Recruitment/Data Collection Pathway 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligible patients in HCTM are screened & consent obtained 
Number of 
patients excluded 
and reason for 
exclusion 
Number of patients recruited (n) 
DAY 1 
• 
Demographic data collected. 
• 
Baseline spirometry and CAT Score.  
• 
Cough and Sputum Assessment Questionnaire (CASA-Q) 
• 
McGill COPD Quality of Life Questionnaire 
DAY 15 
• 
Adherence and Compliance 
• 
Adverse Effects 
DATA ANALYSIS 
DAY 30 
• 
Repeat spirometry and CAT Score.  
• 
Cough and Sputum Assessment Questionnaire (CASA-Q) 
• 
McGill COPD Quality of Life Questionnaire 

 
11
 
5.5 Operational Term Definitions 
 
 
 
Stable COPD based on GOLD 2023 strategy 
All outpatient COPD patients, GOLD I, II, III, IV as per 
GOLD 2023 Guidelines seen in Respiratory Clinic HCTM 
and not in exacerbation upon recruitment 
 
Exacerbation (as per GOLD Executive Summary) 
An event in the natural course of the disease characterise 
by change in the patient’s baseline dyspnoea, cough and/or 
sputum beyond normal day-to-day variation that is acute 
onset and may warrant change in regular medications 
 
Adherence and compliance 
 
Using pill count method, the adherence rate is determined 
by the following formula 
 
% adherence = (Quantity dispensed) - (Quantity 
remaining) / (Prescribed no of tablets/day) x (No of days 
between dispensing date and interview) 
 
For Syrup Prospan we will quantify by determine the 
volume of syrup 
 
Adverse Effects 
 
Any desirable effects that experienced by patients after 
started on the aforementioned medication 
 
 
 
 

 
12
 
5.6 Sample Size and Power of Study 
 
 
In order to calculate the required sample size, we will employ 
the Cohen’s d formula for estimating the effect size (Cohen, 
1988) [19]. The formula is given as 
 
 
 
Where d is the Cohen’s effect size, M1 and M2 are the mean for 
the first and second group, and SD1 and SD2 are the standard 
deviation for the first and second group respectively.  
Based on a similar study by Kuzmenko et al. (2020) [20] which 
employs the CAT score to assess the efficacy of NAC in 
patients with COPD, the mean and standard deviation for before 
and after treatment are given as: 
 
Before treatment: 23.46 ± 3.66 
After treatment: 20.38 ± 5.78 
 
Hence, this give the values of M1 = 23.46 and M2 = 20.38, and 
SD1 =3.66 and SD2 = 5.78 that can use to estimate the effect size 
using the formula above.  
 
 
 
Therefore, it gives an estimated effect size of 0.637 which is 
considered to be a medium effect size. 
 
With a power of 80% and a level of significance of 5% for 
detecting an effect size of 0.637, we calculate the required 

 
13
sample size using an online sample size calculator (Dhand & 
Khatkar, 2014) [21] for comparing paired differences. It gives at 
a value of 23 participants for each group which mean the 
required number of participants is 46. 
 
Additional of 20% samples is recruited to avoid missing data 
due to withdrawal or drop out. Therefore, a total of minimum 55 
patients will be recruited for this study. However, we aim to 
recruit 100 patients for our study where the treatment is given to 
equal number of participants in each group. 
 
 
 
 
 
Section 6: Statistical Analysis 
 
 
 
Data were collected manually with a data collection sheet. 
Demographic data and patient characteristic will be analysed 
using descriptive analysis and Chi-square method. 
Continuous variables were presented as mean ± SD and 
categorical variables as percentages, unless stated otherwise. 
 
All statistical analysis for the study will be performed using 
statistic software SPSS version 24.0 (IBMSPSS Statistics 
2017). A p-value of <0.05 is considered statistically 
significant. 
 
 
 
 
 
 
 
 

 
14
Section 7: Research Ethics 
 
Approval from the Research and Ethics Committee of Hospital 
Canselor Tuanku Muhriz onbtained with research code FF-
2023-433. . All the collected information will be strictly 
confidential and only accessible by the research team members. 
All patients will be kept anonymous and coded into the data 
collection sheet.  
 
Participant will only be recruited in this study if informed 
consent was given, and will be allowed to withdraw from the 
study at any point. The research will be conducted according to 
standard of good clinical practice and the rights and safety of the 
participants are guaranteed throughout the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
15
Section 8: Estimated Cost of Study  
 
 
 
 
 
 
 
ACTIVITY / 
DEVICE 
AMOUNT 
COST 
PER 
ITEM 
ESTIMATED 
COST 
Syr Prospan 7.5ml 
BD 
(Sponsored by 
DELFI) 
450ml (4 and 
half bottle) x 
50 patients 
RM18.9 
per 
bottle 
RM4725 
Tab NAC 600mg 
BD 
(Sponsored by 
DELFI) 
60 tablets x 50 
patients 
RM3.29 
per 
tablet 
RM9870 
Printing: 
i) 
Research 
Information 
 
ii) 
Consent form 
 
iii) 
Data 
collection 
sheet 
 
iv) 
CAT Score 
Questionnaire 
 
v) 
McGill COPD 
QoL 
Questionnaire 
 
 
 
2 pages for 
each set x 100 
 
1 page for 
each set x 100 
 
2 pages for 
each set x 100 
 
1 page for 
each set x 100 
 
6 pages for 
each set x 100 
 
 
RM0.40 
 
 
 
RM0.20 
 
 
RM0.40 
 
 
 
RM0.20 
 
 
RM1.20 
 
RM48 
 
 
 
RM24 
 
 
RM48 
 
 
 
RM24 
 
 
RM144 
 
 
TOTAL ESTIMATED COST 
RM14883 
 

 
16
Section 9: Research Information Sheet  
 
 
 
 
 
 
Research Title: 
A Randomised, Open Label, Interventional Study Evaluating the Efficacy & Safety of 
Dry Powder Ivy Extract (Syrup Prospan) versus NAC among COPD Patients 
 
Researcher’s Name:  
Dr Mas Fazlin Mohamad Jailaini / Dr Muhamad Thaqif bin Sidek 
 
Place of Conduct:  
Respiratory Unit, Department of Internal Medicine, Hospital Canselor Tuanku Muhriz 
 
Introduction: 
COPD is a progressive airway disease and mucolytics help controlling symptoms as 
well as prevent future exacerbations.NAC is a common mucolytic agent and Syrup 
Prospan is ivy leaf preparations used to serve this purpose. 
 
Purpose of Study: 
This study aims to evaluating the efficacy and safety of Ivy Extract preparations 
against NAC as mucolytic in COPD patients. 
 
Type of Intervention:  
You will be randomised either in ‘Interventional group’ or ‘non-interventional group’. 
For the interventional group, we will change your mucolytic agent to Syrup Prospan. 
For the non-interventional group, we will continue your current NAC. We will first 
get a baseline spirometry, CAT score, McGill COPD QoL Questionnaire and CASA-
Q on D1. We will continue follow-up closely for both group and assess your 
adherence to medications and adverse effects on D15 and finally on D30 of treatment 
with repeat spirometry, CAT score, McGill COPD QoL Questionnaire and CASA-Q. 
 
Risk of joining in this study: 
• There are no surgical intervention / life threatening side effects involved with 
this study, therefore no major risk is associated upon enlistment. 
• The documented side effects for both medications are as follows; 
o NAC – anaphylaxis; skin rash, urticaria, bronchospasm, angioedema 
o Ivy Leaf Extract – nausea, vomiting, diarrhoea, allergic reaction 
 
*If you experiences any side effects other than mentioned above, kindly 
inform us for subsequent appropriate measures. 
 

 
17
Participation in this study is entirely voluntary. It is your choice to participate (or 
allow patient to participate). Regardless of your choice, the standard quality of care 
and treatment remain the same. All data obtained will be recorded and will be used for 
analysis. 
Confidentiality: 
Information collected during this study will be kept confidential. Access to the data is 
only by the researcher team and the Research Ethics Committee of HCTM. No 
specific reference to any individual will be reported in this study. Participants have 
the right to know the outcome of this study.  
 
Reimbursements: 
Participants do not have to pay for the spirometry, nor be paid for participating in this 
study. 
 
Right to Refuse or Withdraw: 
This study is of voluntary basis, patient or his/her next-of-kin have the right to 
withdraw from this study at any time of the study. The choice is yours and all your 
right will be respected. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
18
Section 10: Consent Form 
Research Title:  
A Randomised, Open Label, Interventional Study Evaluating the Efficacy & Safety of 
Dry Powder Ivy Extract (Syrup Prospan) versus NAC among COPD Patients 
Researcher’s Name:  
Dr Mas Fazlin Mohamad Jailaini / Dr Muhamad Thaqif bin Sidek 
 
I, …………………………………………………………………, 
IC No: ……………………………….............,    
• Have read all the information in the Patient Information Sheet and understand 
the aim and purpose of this study. 
• Have been given enough time to think about it and all of my question have 
been answered to my satisfaction. 
• Understand that I may freely choose to withdraw from this study at any time 
without reason and without repercussions. 
• Understand that anonymity will be ensured in the final write up. 
I understand all the above and voluntarily agree to take part in this research study, to 
follow the study procedures and to provide the necessary information as requested. 
 
……………………………………………            
Signature/Thumbprint 
DATE:                                       
 
 
……………………………………………             
Witness Name/IC no: 
DATE:                                              
 
 
……………………………………………. 
Researcher Name/IC no: Dr Muhamad Thaqif Sidek (900617-10-6037) 
DATE: 
 
 
 
 

 
19
Section 11: Data Collection Sheet 
 
 
                                                                                 Patient’s Sticker 
 
 
 
 
Contact Number: ………………………………………………………... 
 
Age: ………………………………………………………………………. 
 
Gender: …………………………………………………………………... 
 
Ethnicity: ………………………………………………………………… 
 
Background Medical Problem:  
• Diabetes Mellitus  
 
 
 
• Hypertension 
 
 
 
 
 
• Ischaemic heart Disease 
 
 
 
• Heart Failure 
 
• Previous stroke 
 
• Dyslipidaemia 
 
• Others: …………………………….  
 
Weight: ………………………. 
Height: ……………………….. 
BMI: …………………………. 
 
First diagnosis of COPD: ……………… 
MMRC: ………………………………… 
CAT Score:……………………………... 
 

 
20
Number of exacerbations in the past 1 
year: ……………………………………………………. 
 
Date of recent spirometry: …………………………….  
 
FEV1 (post-bronchodilator): ………………………….  
 
 
Types of inhalers:  
 
Inhaler technique:  
Correct 
 
 
 
 
Incorrect 
 
 
 
D1 
D30 
Spirometry 
 
 
CAT score 
 
 
McGill COPD QoL 
 
 
CASA-Q 
 
 
 
 
Adherence: ……………………………………………………………….
. 
 
 
Adverse 
effects: …………………………………………………………... 
 
 
 
 
 
 
 
 
 
 
 

 
21
 
 
Section 12: Gantt Chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Progression / Timeline  
 
 
Mac 
2023 - 
May 
2023 
 
Jun 
2023 - 
Oct 
2023 
 
Dec 
2023 
 
Jan 
2024 
- Dec 
2024 
 
Dec 
2024 
- Dec 
2025 
 
Jan 
2026 
- Oct 
2026 
 
Nov 
2026 
Literature review  
 
 
 
 
 
 
 
 
Proposal preparation, 
correction and 
presentation to Medical 
Department, UKMMC  
 
 
 
 
 
 
 
 
Approval of UKMMC 
Research and Ethics 
Committee  
 
 
 
 
 
 
 
 
Patient recruitment  
 
 
 
 
 
 
 
 
Data entry and analysis  
 
 
 
 
 
 
 
 
Final result and 
manuscript submission  
 
 
 
 
 
 
 
 
Thesis presentation  
 
 
 
 
 
 
 
 

 
22
 
 
Section 13: Appendices 
 
 
 
 

 
23
 
 
 
 

 
24
 
 

 
25
 
 
 
 

 
26
 
 
 
 
 
 
 

 
27
 
 
 
 
 
 
 

 
28
Section 14: References  
 
 
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mortality in COPD--a review of potential interventions. Int J Chron Obstruct Pulmon 
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12. Linden M, Wieslander E, Eklund A, et al. Effects of oral N-acetylcysteine on cell 
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. 
 
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20. Kuzmenko, N., Iaremenko, O., Dobrianskiy, D., Ilnytskyi, R., and Gumeniuk, G. 
(2020). The efficacy and safety of inhaled acetylcysteine in comparison with oral 
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