Clinical trial NCT01869491
Conditions: Gastroesophageal Reflux Disease Dyspepsia
Keywords: Gastroesophageal Reflux Disease GERD Dyspepsia Indigestion Heartburn Acid reflux Compound Sodium Alginate Double Action Chewable Tablets Gaviscon Double Action Tablets
Sponsor: Reckitt Benckiser Healthcare (UK) Limited
Start date: 2013-06-05; Completion date: 2014-05-01
Enrollment: 1107 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is being conducted to provide evidence that Compound Sodium Alginate Double Action Chewable Tablets are effective in managing the symptoms of heartburn, acid regurgitation and dyspepsia in patients with Gastroesophageal Reflux Disease (GERD).

Detailed description:

Arms: arm 1: Compound Sodium Alginate Double Action Chewable Tablets, 2 tablets four times daily arm 2: Matching placebo tablets, 2 tablets four times daily
Interventions: intervention 1: Compound Sodium Alginate Double Action Chewable Tablets intervention 2: Matching placebo tablets
Intervention descriptions: intervention 1: 2 tablets four times daily intervention 2: 2 tablets four times daily

Protocol documents:
Prot_000.pdf: 
 
Study Title: A Multi-centre, Randomised, Double-blind, Two Arm, Parallel Group, 
Placebo-controlled Study to Assess the Effect of Compound Sodium Alginate Double Action 
Chewable Tablets in Patients with Gastro-esophageal Reflux Disease 
ClinicalTrials.gov ID: NCT01869491 
Final Protocol, dated 28-Feb-2013  


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 1 of 76 
  
Reckitt Benckiser 
 
1 
STUDY PROTOCOL TITLE PAGE 
CTA (China) 
Number: 
2010L02452 
Study Number: 
GA1210  
Project Name: 
Shanghai 
Study Phase: 
III 
Study Country: 
China 
Indication: 
Gastro-esophageal reflux disease (GERD) 
Test Product(s): 
Compound Sodium Alginate Double Action Chewable Tablet. 
Reference 
Product(s): 
Placebo Matching Compound Sodium Alginate Double Action Chewable Tablet. 
Study Title: 
A multi-centre, randomised, double-blind, two arm, parallel group, placebo-
controlled study to assess the effect of Compound Sodium Alginate Double 
Action Chewable Tablets in patients with gastro-esophageal reflux disease. 
Short Study Title:
Compound Sodium Alginate Double Action Chewable Tablet Symptomatic Relief 
Study. 
Protocol Date: 
28 Feb 2013 
Protocol Version: 
Final v 2.0 
Confidentiality 
Statement: 
The information contained in this document is privileged and confidential. 
Do not copy, circulate or otherwise distribute without written authority 
from the Reckitt Benckiser Clinical Project Manager function. 
 
 
 
 
 
 
 
 
 
 


Investigational Study Protocol Template 
Study No: GA1210 
f Reckitt 
SOP 00365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
2 
PROTOCOL APPROVAL 
Reviewed and Agreed by: 
Protocol Author: 
Statistician: 
 
Date 
Senior Statistician 
Clinical Project Manager 
Reckitt Benckiser Healthcare 
(UK) Limited 
Reviewed and Approved by: 
R&D Manager- Clinical (Healthcare): 
Reviewed and Accepted by: 
Co-ordinating Principal Investigator: 
 
China 
Reckitt Benckiser Healthcare 
(UK) Limited 
Global Medical Director: 
Date 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HUB 70S; Telephone No: +44 (0) 1482 326151 ; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013 
Page 2 of 76 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 3 of 76 
3 
PROTOCOL SYNOPSIS 
3.1 
Rationale 
This study is being conducted to provide evidence for inclusion in applications to regulatory 
authorities that the Compound Sodium Alginate Double Action Chewable Tablets are 
effective in managing the symptoms of heartburn, acid regurgitation and dyspepsia in 
patients with GERD. 
 
3.2 
Objective(s) 
The primary objective of this study is to assess the efficacy of Compound Sodium Alginate 
Double Action Chewable Tablets (mint-flavoured) compared with a matched placebo in 
reduction of the symptoms of GERD in patients with GERD as assessed using the Reflux 
Disease Questionnaire (RDQ). 
The key secondary endpoint will compare between the two cohorts (Compound Sodium 
Alginate Double Action Chewable Tablets and matching placebo) for a 7-day treatment 
period for the following parameter: 
• 
Change from baseline in RDQ scores for dyspepsia dimension 
Other secondary endpoints will compare between the two cohorts (Compound Sodium 
Alginate Double Action Chewable Tablets and matching placebo) for a 7-day treatment 
period for the following parameters: 
• 
OTE as a measure for patient’s responsiveness/satisfaction 
• 
Change from baseline in RDQ scores for heartburn dimension. 
• 
Change from baseline in RDQ scores for regurgitation dimension. 
Safety will be assessed in terms of the overall proportion of patients with adverse events 
(AEs). 
 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 4 of 76 
3.3 
Primary Endpoint 
The primary study endpoint is to compare the change from baseline in RDQ symptom scores 
for the GERD dimension (heartburn and regurgitation) after a 7-day treatment period of a 
regimen of two Compound Sodium Alginate Double Action Chewable Tablets taken four 
times daily compared with a matched placebo. 
 
3.4 
Secondary Endpoints 
The key secondary endpoint will compare between the two cohorts (Compound Sodium 
Alginate Double Action Chewable Tablets and matching placebo) for a 7-day treatment 
period for the following parameter: 
• 
Change from baseline in RDQ scores for dyspepsia dimension 
Other secondary endpoints will compare between the two cohorts (Compound Sodium 
Alginate Double Action Chewable Tablets and matching placebo) for a 7-day treatment 
period for the following parameters: 
• 
OTE as a measure for patient’s responsiveness/satisfaction 
• 
Change from baseline in RDQ scores for heartburn dimension. 
• 
Change from baseline in RDQ scores for regurgitation dimension. 
Safety will be assessed in terms of the overall proportion of patients with adverse events 
(AEs). 
 
3.5 
Design Summary 
This is a multi-centre, randomised, double blind, two arm, placebo-controlled, parallel group, 
study. After signing a written informed consent, patients will undergo a screening period of 
up to 7 days.  Patients who satisfy the study entry requirements within 7 days of consent, will 
be randomised to receive either Compound Sodium Alginate Double Action Chewable 
Tablets (2 tablets four times daily) or matching placebo tablets (2 tablets four times daily), for 
a 7-day treatment period. At the beginning and end of the treatment period, patients will be 
required to complete the RDQ. 
In addition, at the end of the 7-day treatment period, patients will be required to complete the 
overall treatment evaluation (OTE). 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 5 of 76 
 
3.6 
Sample Size 
The sample size calculation, based on the UK pilot study date [10] and a previous pivotal 
China study, shows that 1054 evaluable patients need to complete the study (with the aim of 
having approximately 527 patients in each treatment group). An evaluable patient is defined 
as a randomised patient who completes the study treatment period and attends the end of 
treatment visit. In order to achieve this, it is estimated that approximately 1222 patients will 
have to be screened and approximately 1100 patients will have to be randomised.  
Patients will receive a screening number on signing the informed consent.  Patients will 
receive a separate randomisation number on being randomised to the study. 
It is anticipated that between 25 and 50 sites will take part in the study. Each site will be 
asked to recruit between 10 and 200 patients. 
 
3.7 
Anticipated Study Timings 
It is estimated that it will take 9 months to recruit the required number of patients. 
The duration of each patient’s participation in the study will be a maximum of 17 days (from 
screening visit to end of treatment visit) and involve 3 visits. 
Patients can enter the study, if eligible, as soon as all screening results are available 
following informed consent at Visit 1. A maximum of 7 days will be allowed to screen a 
patient at Visit 1. If eligible, the patient will be randomised and will commence the 7-day 
treatment period at Visit 2 (Day 0). 
The patients will be randomised to receive either Compound Sodium Alginate Double Action 
Chewable Tablets or matching placebo tablets for 7 days. Visit 3, the End of study visit, will 
occur on Day 8 (between Day 7 and Day 10). 
The anticipated overall duration of study conduct is expected to be approximately one year. 
 
3.8 
Inclusion Criteria 
Only patients to whom all of the following conditions apply will be included: 
1. Informed consent has been obtained. 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 6 of 76 
2. Age: ≥ 18 to ≤ 65 years 
3. Sex: male or female. 
4. Primary diagnosis: Current evidence of symptomatic GERD in accord with the 
Montreal definition [1,14]. This evidence can be based solely on symptom 
characteristics. Patients should have a GERD history of frequent episodes of GERD-
related symptoms during the last 3 months and also during 5 of the last 7 days prior to 
study screening. 
5. GERD Status: Patients will be patients at the clinic or members of the public who 
respond to an advertisement or via their doctor.  Patients must have had troublesome 
heartburn and/or regurgitation (with or without dyspepsia symptoms) of at least mild or 
moderate intensity* on at least five days during the week before the start of screening. 
If the patient also has other symptoms, the heartburn, regurgitation or dyspepsia 
should be the predominant symptoms.  
*Symptom intensity should be assessed using the following scale; 
• 
Mild: awareness of symptom but easily tolerated  
• 
Moderate: discomforting symptom sufficient to cause interference with normal 
activities including sleep 
• 
Severe: incapacitating symptom with inability to perform normal activities, 
including sleep 
6. Patients who have not taken any antacids within 24 hours before randomisation (Visit 
2) and be instructed not to take antacids throughout the remainder of the study. 
7. Patients taking mucous membrane protection drugs or prokinetics may enter the 
study provided that these are discontinued for at least 5 days before screening and 
throughout the remainder of the study. 
8. Systemic glucocorticosteroids or non-steroidal anti-inflammatory drugs (NSAIDs, 
except for low dose aspirin which can be given for cardioprotection) can only be taken 
for up to 3 consecutive days in the 28 days prior to screening 
9. Absence of relevant abnormalities in the physical examination, endoscopy, ECG and 
laboratory safety results. 
10. Patients must be sufficiently literate to be able to complete the RDQ unaided. 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 7 of 76 
 
3.9 
Exclusion Criteria 
Patients to whom any of the following conditions apply must be excluded: 
1. Patients who have a history of drug, solvent or alcohol abuse (weekly alcohol intake ≥ 
140g). 
2. Patients who have suffered cardiac chest pain within the last year. 
3. Patients who have suffered a recent, significant unexplained weight loss of more than 
6 Kg in the last 6 months. 
4. Female patients of childbearing potential who, for the duration of the study, are either 
unwilling or unable to take adequate contraceptive precautions (as defined in 
Section 10.3) or are unwilling to be sexually abstinent (as defined in Section 10.3).  
5. Pregnancy or lactating mother.  
6. Patients with a history and/or symptom profile and/or discovered on endoscopy 
suggestive of the following:  any other gastrointestinal (GI) disease, erosive GERD 
(Los Angeles [LA] classification grades C-D), Barrett’s esophagus, acute peptic ulcer 
and/or ulcer complications, Zollinger-Ellison syndrome, gastric carcinoma, pyloric 
stenosis, oesophageal or gastric surgery, intestinal obstruction, current pernicious 
anaemia, indication for H-pylori eradication therapy, known gastro-intestinal bleeding 
(hematochezia or hematemesis) within the last 3 months, and severe diseases of 
other major body systems. 
7. Patients who were observed on endoscopy to have a hiatus hernia with a diameter 
which exceeds 3cm. 
8. Patients who have taken anti-cholinesterase drugs, traditional Chinese medicines for 
treating gastrointestinal disease, ulcerlmin or misoprostol preparations within 7 days 
prior to screening or throughout the study. 
9. Patients who have taken PPIs during the 10 days prior to screening, prokinetics or H2 
antagonists during the 5 days prior to screening or systemic glucocorticosteroids, non-
steroidal anti-inflammatory drugs (NSAIDs, except for low dose aspirin which can be 
given for cardioprotection) on more than 3 consecutive days or PPI-based triple or 
quadruple therapy for eradication of H-pylori during the last 28 days. 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 8 of 76 
10. Patients taking or requiring to take macrolide antibiotics, such as erythromycin, 
azithromycin, from the day before screening. 
11. Patients with difficulty in swallowing. 
12. Patients with known hypophosphataemia, phenylketonuria or hypercalcaemia. 
13. Patients with severe constipation, or history of intestinal obstruction. 
14. In the opinion of the Investigator, patients with damaged heart or kidney diseases and 
patients who require a low sodium diet. 
15. Patients either with any co-existing condition which, in the opinion of the Investigator, 
would be likely to compromise patient safety or interfere with assessment of efficacy; 
or with any clinically significant abnormal laboratory values; or in the Investigator’s 
view to unable to comply fully with the study requirements. 
16. Any previous history of allergy or known intolerance to any of the IMP’s or following 
formulation constituents: macrogol 20,000, mannitol (E421), copovidone, acesulfame 
K, aspartame (E951), mint flavour, carmoisine lake (E122), magnesium stearate, 
xylitol DC (contains carmellose sodium) or the following formulation constituents: 
sodium alginate, calcium carbonate, sodium bicarbonate. 
17. Previously randomised into the study. 
18. Employee at study site. 
19. Partner or first-degree relative of the Investigator. 
20. Patients who failed screening will not be allowed to re-enter the study. 
21. Participation in a clinical study in the previous 6 months or participation in a previous 
Compound Sodium Alginate Double Action Chewable Tablet study.  
22. Unable in the opinion of the Investigator to comply fully with the study requirements.  
 
3.10 
Methodology 
Patients will be recruited by the investigator from out-patient clinics, from the hospital 
database or those patients who respond to advertising. Patients suffering from mild to 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 9 of 76 
moderate symptoms of GERD and who meet all eligibility criteria will be given the 
opportunity by the investigator to participate in the study.  
Potential patients will be provided with the patient information sheets and given ample time 
to read and decide whether they are interested in taking part in the study. If the patient is 
interested, she/he will speak to the investigator or person delegated by the investigator to 
take consent who will explain more about the study and answer any questions the patient 
may have. If the patient feels fully informed and happy to participate in the study they will 
complete, sign and date the informed consent form (ICF). The ICF will then be counter 
signed and dated by the investigator or person delegated by the investigator  to take 
consent. A copy of the ICF and patient information sheet will be provided to the subject for 
their personal records. 
All patients will be given a 5-digit screening number once they have provided consent. The 
first two digits will refer to the centre number and the second three digits to the number of 
patients screened at that centre. For example, screening numbers at centre 01 will start 
01001, 01002 etc.  
The screening process can take up to a maximum of seven days after informed consent. 
The following baseline assessments (Visit 1, screening) will be conducted: demographics, 
laboratory safety data (haematology & biochemistry), vital signs (blood pressure and heart 
rate), 12-lead ECG, endoscopy, medical history and current status, medication and therapy 
history, physical examination and pregnancy testing (women of child-bearing potential will 
undergo urine pregnancy testing).  
At the end of the screening period, patients will return to the clinic (Visit 2, Randomisation) to 
complete the RDQ questionnaire and have any adverse events and concomitant 
medications recorded. If the subject fulfils the eligibility criteria for randomisation, a unique 4-
digit randomisation number will be allocated and study medication dispensed (0001, 0002 
etc.). The numbers available at a site have to be allocated to the subjects in consecutive 
order. Patients will be instructed to start taking their medication the following day for seven 
days (two tablets taken four times a day: 30 minutes after breakfast, 30 minutes after lunch, 
30 minutes after dinner and immediately before lying down for bed). 
Visit 3 will take place preferably on the day following completion of 7-days of study 
treatment, ie, Day 8, or if necessary up to one day before and 2 days after (Day 7 to Day 
10). At this visit, the patient will complete the RDQ questionnaire and answer questions 
relating to overall satisfaction with the trial therapy (OTE) over the previous seven days. All 
unused and empty study medication containers will be returned for assessment of 
compliance with treatment.  The following will be completed:  vital signs (blood pressure and 
heart rate) concomitant medication, adverse events, physical examination, laboratory 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 10 of 76 
investigations (haematology and biochemistry) and pregnancy testing (women of child-
bearing potential will undergo urine pregnancy testing). 
The patient will be instructed to return to the investigator before the end of treatment if they 
require further treatment for their GERD symptoms or have unacceptable adverse events.  If 
the investigator withdraws the patient from the study for these or any other reasons the 
patient will complete the study at this early termination visit and the following will be 
completed. 
The patient will complete the RDQ questionnaire and answer questions relating to overall 
satisfaction with the trial therapy (OTE) over the study treatment period. All unused and 
empty study medication containers will be returned for assessment of compliance with 
treatment.  The following will also be completed: vital signs (blood pressure and heart rate), 
concomitant medication, adverse events, physical examination, laboratory investigations 
(haematology and biochemistry), pregnancy testing (women of child-bearing potential will 
undergo urine pregnancy testing) and reason for early study termination. 
The schedule for assessments for this trial is summarised in the following flowchart.  
 
 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 11 of 76 
Schedule 
FLOW CHART OF STUDY 
Study period 
Visit 1 
Screening 
(up to 7 days)
Visit 2 
Randomisation 
(Day 0) 
Visit 3      End of 
study (Day 8) 
(between Day 7 
and Day 10) 
Visit ET  
Replaces Visit 
3 if early 
termination    
(Day 1 to 6) 
Informed consent 
X 
 
 
 
Assess 
inclusion-/exclusion 
criteria and suitability for 
study 
X 
X 
 
 
Record 
demographics, 
assess 
concomitant 
medication 
and 
relevant 
medical history 
X 
X 
 
 
Physical exam, collection of 
blood 
samples 
for 
haematology & biochemistry, 
vital signs 
X 
 
X 
X 
Urine pregnancy test 
X 
 
X 
X 
12-lead ECG 
X 
 
 
 
Endoscopy 
X 
 
 
 
Investigator’s assessment of 
GERD status 
X 
 
 
 
Make appointment for next 
visit 
X 
X 
 
 
Randomisation 
 
X 
 
 
Dispense study medication & 
emergency card provided 
 
X 
 
 
Patient 
completes 
RDQ 
questionnaire. 
 
X 
X 
X 
Record AEs and concomitant 
medication 
 
X 
X 
X 
Collect returned medication, 
assess 
compliance 
with 
study medication. 
 
 
X 
X 
Complete OTE 
 
 
X 
X 
 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 12 of 76 
3.11 
Statistics 
Sample size 
In a previous pilot study conducted in the UK (GA1203), a least square mean difference 
(Gaviscon – Placebo) of -0.61 was obtained from the ANCOVA model comparing the change 
in the GERD dimension score from the RDQ after 1 week. The root mean squared error 
(RMSE) from the ANCOVA model, which included treatment as a fixed effect and the day 0 
RDQ GERD dimension score as a covariate, was 0.9735. 
In the same study, a least square mean difference (Gaviscon – Placebo) of -0.43 was 
obtained from the ANCOVA model comparing the change in the Dyspepsia dimension score 
from the RDQ after 1 week. The root mean squared error (RMSE) from the ANCOVA model, 
which included treatment as a fixed effect and the day 0 RDQ Dyspepsia dimension score as 
a covariate, was 1.121. 
For the purposes of sample size estimation using the module for a two-group t-test between 
equal means in NQuery Advisor 7.0, the least square means difference and RMSE from 
GA1203 will be used to estimate the effect sizes. The effect sizes using these results would 
be estimated as 0.627 for the GERD dimension and 0.384 for the Dyspepsia dimension. 
In other previous studies, different endpoints to the RDQ were used to demonstrate the 
efficacy of Gaviscon Original Liquid compared to Placebo Liquid. The percentage of patients 
that rated a positive improvement in symptoms were reported. In a study conducted in the 
UK (0900901), 74% of Gaviscon Original patients had a positive improvement of symptoms 
compared to only 44% of Placebo patients. When a similar study was conducted in China 
(GA0917), the corresponding results were 77% for Gaviscon Original and 67% for Placebo, 
thus suggesting an increased Placebo effect in the Chinese population compared to the UK 
population. 
Assuming a reduced effect size of 0.2 for the Dyspepsia dimension, this would require a total 
of 1054 patients with evaluable dyspepsia data from the RDQ to have 90% power to show a 
statistical significant difference at the 5% level using a two-group t-test. The actual analysis 
method to be used would be an ANCOVA model with treatment as a fixed effect, centre as a 
random effect and the day 0 RDQ Dyspepsia dimension score as a covariate.  
If an effect size of 0.4 is assumed for the GERD dimension, a sample size of 1054 patients 
would give more than 99% power to show a statistical significant difference at the 5% level 
using a two-group t-test. The actual analysis method to be used would be an ANCOVA 
model with treatment as a fixed effect, centre as a random effect and the day 0 RDQ GERD 
dimension score as a covariate.  


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 13 of 76 
To allow for 5% drop outs, 1100 patients will be randomised to ensure that 1054 patients 
have evaluable data for the Dyspepsia dimension score. 
Statistical analysis 
All statistical tests performed will be 2-tailed with significance assessed at the 5% 
significance level. The null hypothesis at all times will be the equality of the treatments being 
compared. 
The primary endpoint (change in RDQ GERD dimension score) will be analysed using an 
analysis of covariance (ANCOVA) model with a fixed effect term for treatment, centre as a 
random effect and the day 0 RDQ GERD dimension score as a covariate. Treatment group 
differences will be estimated using the least square means and presented with 95% 
confidence intervals and p-values to make inferences. 
The change in symptom score for each dimension seperately will be analysed identically to 
the primary endpoint although the included covariate will be the relevant dimension day 0 
score rather than the GERD dimension score. 
To preserve the type 1 error rate of 5% for the key secondary endpoint (change from day 0 
in RDQ scores for dyspepsia dimension), a closed testing procedure will be applied. A 
significant comparison at the 5% level (p<0.05) for this key secondary endpoint will only be 
deemed as confirmatory evidence if the primary endpoint is also significant at the 5% 
significance level (p<0.05). All other secondary endpoints and/or any further sensitivity or 
alternate analyses for the primary and key secondary endpoint will serve as supportive 
evidence only and therefore no further adjustment for multiple comparisons will be made. 
The change scores in frequency and intensity for each dimension as well as the two OTE 
responses will be compared between treatments using a Wilcoxon Rank Sum Test stratified 
by centre. 
The incidence of AEs (number and percent of patients reporting each type of AE at least 
once during the study) will be summarised for all AEs, by investigator attribution of 
relationship to IMP and by severity. The incidence of AEs will be compared among 
(between) treatment groups using Fisher’s Exact Test for all AEs, for those AEs classified by 
the Investigator as possibly or probably related to IMP and for severe AEs. 
 
 
 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 14 of 76 
4 
TABLE OF CONTENTS 
1 
STUDY PROTOCOL TITLE PAGE..................................................................... 1 
2 
PROTOCOL APPROVAL ................................................................................... 2 
3 
PROTOCOL SYNOPSIS .................................................................................... 3 
3.1 
Rationale ........................................................................................................ 3 
3.2 
Objective(s) .................................................................................................... 3 
3.3 
Primary Endpoint............................................................................................ 4 
3.4 
Secondary Endpoints ..................................................................................... 4 
3.5 
Design Summary............................................................................................ 4 
3.6 
Sample Size ................................................................................................... 5 
3.7 
Anticipated Study Timings .............................................................................. 5 
3.8 
Inclusion Criteria............................................................................................. 5 
3.9 
Exclusion Criteria............................................................................................ 7 
3.10 
Methodology................................................................................................... 8 
3.11 
Statistics....................................................................................................... 12 
4 
TABLE OF CONTENTS.................................................................................... 14 
4.1 
List of Tables and Figures Contained in the Body of the Protocol................. 19 
4.2 
List of Appendices ........................................................................................ 20 
4.3 
List of Abbreviations ..................................................................................... 20 
5 
INVESTIGATORS AND ADMINISTRATIVE STUCTURE ................................. 21 
5.1 
Reckitt Benckiser Details.............................................................................. 21 
5.2 
Investigational Sites...................................................................................... 22 
5.3 
Laboratories ................................................................................................. 22 
6 
INTRODUCTION.............................................................................................. 22 
7 
STUDY RATIONALE ........................................................................................ 24 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 15 of 76 
8 
STUDY OBJECTIVES ...................................................................................... 24 
8.1 
Primary Objective ......................................................................................... 24 
8.2 
Secondary Objective(s) ................................................................................ 24 
9 
STUDY DESIGN............................................................................................... 25 
9.1 
Study Endpoints ........................................................................................... 25 
9.1.1 
Primary Endpoint ...................................................................................... 25 
9.1.2 
Secondary Endpoints................................................................................ 25 
9.2 
Design Summary.......................................................................................... 25 
9.3 
Discussion of Study Design.......................................................................... 26 
9.4 
Number of Patients....................................................................................... 26 
9.5 
Study Duration.............................................................................................. 27 
9.6 
Patient Commitment to the Study ................................................................. 27 
9.6.1 
Duration of Patient Participation................................................................ 27 
9.6.2 
Invasive Procedures ................................................................................. 28 
9.6.3 
General and Dietary Restrictions .............................................................. 28 
9.7 
End of Study................................................................................................. 28 
10 
STUDY POPULATION ..................................................................................... 29 
10.1 
Inclusion Criteria........................................................................................... 29 
10.2 
Exclusion Criteria.......................................................................................... 30 
10.3 
Patients of Reproductive Potential................................................................ 32 
11 
STUDY METHODOLOGY ................................................................................ 32 
11.1 
Recruitment of Study Patients ...................................................................... 32 
11.2 
Study Visits/Assessments............................................................................. 32 
11.3 
Baseline Visit................................................................................................ 34 
11.3.1 
Screening/Enrolment Procedures ............................................................. 34 
11.3.1.1 
Clinical Assessments Performed at Baseline ........................................ 34 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 16 of 76 
11.3.2 
Clinical Assessments Performed After Baseline ....................................... 36 
11.3.2.1 
Clinical Assessments at Visit 2.............................................................. 36 
11.3.2.2 
Clinical Assessments at Visit 3, End of Treatment................................. 37 
11.3.2.3 
Clinical Assessments at Early Termination (ET) Visit (only if required for 
patient early terminations)..................................................................... 38 
11.4 
Study Variables and Methods of Assessment............................................... 39 
11.4.1 
Efficacy Variables ..................................................................................... 39 
11.4.1.1 
Overview of Efficacy Variables.............................................................. 39 
11.4.1.2 
Methods of Assessment of Efficacy Variables....................................... 39 
11.4.2 
Appropriateness of Measurements ........................................................... 40 
11.5 
Study Specific Supplies ................................................................................ 40 
11.6 
Unscheduled Visits....................................................................................... 41 
11.7 
Patient Withdrawal and Replacement Criteria............................................... 41 
11.7.1 
Patient Withdrawal.................................................................................... 41 
11.7.2 
Replacement of Patients........................................................................... 42 
11.8 
Additional Care of Study Patients Following Completion of the Study........... 42 
11.9 
Treatment Compliance ................................................................................. 42 
11.10 
Premature Termination of the Study ............................................................. 43 
12 
STUDY TREATMENTS .................................................................................... 43 
12.1 
Identity of Investigational Medicinal Products ............................................... 43 
12.2 
Identity of Non-Investigational Medicinal Products........................................ 44 
12.3 
Randomisation and Treatment Allocation ..................................................... 44 
12.3.1 
Randomisation.......................................................................................... 44 
12.3.2 
Blinding..................................................................................................... 45 
12.3.3 
Emergency Unblinding Procedures........................................................... 45 
12.3.4 
IMP allocation for Replacement Patients .................................................. 45 
12.4 
Dosage Instructions...................................................................................... 45 
12.5 
Packaging .................................................................................................... 46 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 17 of 76 
12.6 
Labelling....................................................................................................... 46 
12.6.1 
Investigational Medicinal Product(s) ......................................................... 46 
12.6.2 
Non-Investigational Medicinal Products .................................................... 46 
12.7 
Accountability of Investigational and Non-Investigational Medicinal Product(s)
..................................................................................................................... 47 
12.8 
Disposal of Unused Investigational and Non-Investigational Medicinal 
Product(s)..................................................................................................... 47 
12.9 
Concomitant Therapies ................................................................................ 47 
12.10 
Prohibited Therapies .................................................................................... 48 
13 
SAFETY ASSESSMENTS................................................................................ 49 
13.1 
Adverse Events ............................................................................................ 49 
13.1.1 
Adverse Event Definitions......................................................................... 49 
13.1.2 
Observation Period for Adverse Event Reporting...................................... 50 
13.1.3 
Information to be Collected on Adverse Events ........................................ 51 
13.1.4 
Procedure for Reporting Adverse Events.................................................. 54 
13.1.5 
Procedure for Reporting Serious Adverse Events..................................... 54 
13.1.6 
Reporting to Regulatory Authorities .......................................................... 56 
13.1.7 
Follow-up of Patients Experiencing Adverse Events upon Completion of the 
Study or Withdrawal from the Study.......................................................... 57 
13.1.8 
Procedures for Patients Experiencing Onset of Adverse Events after End of 
the Study .................................................................................................. 57 
13.2 
Overdose...................................................................................................... 57 
13.3 
Pregnancy .................................................................................................... 57 
13.4 
Clinical Laboratory Investigations ................................................................. 58 
13.4.1 
Collection of Laboratory Samples ............................................................. 59 
13.4.2 
Labelling of Laboratory Samples............................................................... 59 
13.4.3 
Reference Ranges.................................................................................... 59 
13.4.4 
Laboratory Results Review....................................................................... 60 
13.4.5 
Good Clinical Laboratory Practice (GCLP) Compliance ............................ 60 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 18 of 76 
13.5 
Vital Signs, Physical Findings and other Observations Related to Safety ..... 60 
14 
STATISTICAL CONSIDERATIONS.................................................................. 60 
14.1 
Sample Size Justification.............................................................................. 61 
14.2 
Data to be Analysed ..................................................................................... 62 
14.3 
Patient Disposition and Characteristics......................................................... 62 
14.4 
Efficacy Analyses ......................................................................................... 63 
14.4.1 
Primary Efficacy Analysis Endpoint........................................................... 63 
14.4.2 
Secondary Efficacy Endpoints .................................................................. 63 
14.4.3 
Statistical Methods for Efficacy Analyses.................................................. 64 
14.5 
Safety Analyses............................................................................................ 65 
14.5.1 
Adverse Events ........................................................................................ 65 
14.5.2 
Laboratory Data........................................................................................ 65 
14.5.3 
Vital Signs ................................................................................................ 66 
14.5.4 
Other Variables Related to Safety............................................................. 66 
14.6 
Interim Analyses........................................................................................... 66 
15 
QUALITY CONTROL AND QUALITY ASSURANCE AUDIT............................. 66 
15.1 
Monitoring .................................................................................................... 66 
15.2 
Source Document Verification ...................................................................... 67 
15.3 
Audit............................................................................................................. 68 
15.4 
RB Policy on Fraud in Clinical Studies.......................................................... 68 
16 
ETHICS ............................................................................................................ 68 
16.1 
Independent Ethics Committee/Institutional Review Board Review .............. 68 
16.2 
Patient Information and Consent .................................................................. 69 
16.3 
Informing General Practitioners .................................................................... 69 
17 
REGULATORY REQUIREMENTS ................................................................... 70 
17.1 
Competent Authority Authorisation ............................................................... 70 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 19 of 76 
17.2 
Curriculum Vitae........................................................................................... 70 
18 
DATA HANDLING AND RECORD KEEPING ................................................... 70 
18.1 
Case Report Forms (CRFs).......................................................................... 70 
18.2 
Retention of Essential Documentation.......................................................... 71 
18.3 
Protocol Amendments .................................................................................. 71 
19 
CLINICAL TRIAL AGREEMENT....................................................................... 72 
20 
COMPENSATION, INDEMNITY AND INSURANCE......................................... 72 
20.1 
Compensation .............................................................................................. 72 
20.2 
Indemnity...................................................................................................... 72 
20.3 
Insurance ..................................................................................................... 73 
21 
REPORTING, PUBLICATION AND PRESENTATION...................................... 73 
22 
REFERENCES................................................................................................. 73 
23 
APPENDICES .................................................................................................. 75 
23.1 
Appendix 1 English version Reflux Disease Questionnaire........................... 75 
23.2 
Appendix 2 Chinese Mandarin version Reflux Disease Questionnaire.......... 76 
 
4.1 
List of Tables and Figures Contained in the Body of the Protocol 
Table 4-1 List of Abbreviations............................................................................................ 20 
Table 5-1 Reckitt Benckiser Details..................................................................................... 21 
Table 11-1 Schedule of Assessments................................................................................. 33 
Table 13-1 Table of Information to be Collected on Adverse Events ................................... 52 
 
Figure 13-1 Procedure for Reporting SAEs......................................................................... 56 
 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 20 of 76 
4.2 
List of Appendices 
Appendix 1  
English version Reflux Disease Questionnaire 
Appendix 2  
Chinese Mandarin version Reflux Disease Questionnaire 
 
4.3 
List of Abbreviations 
Table 4-1 List of Abbreviations 
Abbreviation 
Abbreviation in Full 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
AR 
Adverse Reaction 
CA 
Competent Authority 
CPM 
Clinical Project Manager 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CTA 
Clinical Trial Application 
CV 
Curriculum Vitae 
DSO 
RB Drug Safety Officer 
eCRF 
Electronic Case Report Form 
GCP 
Good Clinical Practice 
GERD 
Gastro-esophageal reflux disease 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
GVG 
Global Vigilance Group 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
ITT 
Intent-to-Treat 
NIMP 
Non-investigational Medicinal Product 
NSAIDs 
Non Steroidal Anti-Inflammatory Drugs 
OTC 
Over-the-counter 
OTE 
Overall Treatment Evaluation 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 21 of 76 
Abbreviation 
Abbreviation in Full 
PFDA 
Provincial Food and Drug Administration (China) 
PPI 
Proton pump inhibitor 
PRO 
Patient Reported Outcome 
QA 
Quality Assurance 
QC 
Quality Control 
RDQ 
Reflux Disease Questionnaire 
R&D 
Research and Development 
RB 
Reckitt Benckiser 
SAE 
Serious Adverse Event 
SDV 
Source Data Verification 
SOP 
Standard Operating Procedure 
SFDA 
State Food and Drug Administration (China) 
UK 
United Kingdom (of Great Britain and Northern Ireland) 
 
5 
INVESTIGATORS AND ADMINISTRATIVE STUCTURE 
5.1 
Reckitt Benckiser Details 
The following RB personnel are responsible for the conduct of the study: 
Table 5-1 Reckitt Benckiser Details 
Name 
Position 
Address and Contact Number 
Clinical Project Manager  
Reckitt Benckiser Healthcare (UK) Ltd, 
Dansom Lane, Hull, HU8 7DS. UK. 
Global Medical Director  
Reckitt Benckiser Healthcare (UK) Ltd, 
Dansom Lane, Hull, HU8 7DS. UK. 
Senior Statistician 
Reckitt Benckiser Healthcare (UK) Ltd, 
Dansom Lane, Hull, HU8 7DS. UK. 
 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 22 of 76 
The names and addresses of the 
 Study Monitors will be provided in the Initiation 
Visit Report.  
 
5.2 
Investigational Sites 
This is a multi-centre, hospital based study in China.  It is anticipated that approximately 30 
hospital centres will participate in this study. 
The Co-ordinating Principal Investigator is 
 
 
 China. 
5.3 
Laboratories 
Local hospital site laboratories will be used for this study. The names and addresses of all 
laboratories involved in the study for safety analyses will be documented in the Initiation Visit 
Reports for each site. 
 
6 
INTRODUCTION 
Gastro-esophageal reflux disease (GERD) is a condition that develops when the backward 
movement of stomach contents into the esophagus causes troublesome symptoms and/or 
complications. The troublesome symptoms of GERD can have significant impact on health-
related quality of life and work productivity [1-4]. GERD is believed to be the most common 
upper gastro-intestinal condition, affecting between 10% and 20% of the Chinese population 
and the prevalence of GERD in Asia is reported to be approximately 5% [5]. 
Dyspepsia (sometimes referred to by the non-medical term indigestion) is defined as pain or 
discomfort centred in the upper abdomen. It is often described as a feeling of fullness, 
bloating, nausea, heartburn or gassy discomfort in the chest or abdomen. 
Heartburn and regurgitation are the two most predominant clinical manifestations of GERD 
[6]. The pain is usually burning in character and felt retrosternally, rising from the epigastrium 
towards or into the throat.   
The over-the-counter (OTC) preparations for treatment of heartburn include antacids, proton 
pump inhibitors (PPIs) and histamine H2-receptor antagonists. While PPIs are effective in 
acid-related conditions, they offer limited benefit for patients whose symptoms are more 
related to regurgitation [6-8]. 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 23 of 76 
Compound Sodium Alginate Double Action Chewable Tablets (also known as Gaviscon® 
Double Action Tablets) are a combination of two antacids (calcium carbonate and sodium 
bicarbonate) and an alginate. On ingestion, the medicinal product reacts rapidly with gastric 
acid to form a raft of alginic acid gel having a near neutral pH and which floats on the 
stomach contents effectively impeding gastro-esophageal reflux. 
Calcium carbonate neutralises gastric acid to provide fast relief from dyspepsia and 
heartburn. This effect is increased by the addition of sodium bicarbonate which also has a 
neutralising action. The total neutralising capacity of the product at the lowest dose of two 
tablets is approximately 10 mEqH+. Compound Sodium Alginate Double Action Chewable 
Tablets are given as two to four tablets four times daily; the minimum dose of two tablets 
four times daily has been selected to be studied. 
No pivotal clinical studies have previously been performed with Compound Sodium Alginate 
Double Action Chewable Tablets to demonstrate relief of symptoms of reflux and dyspepsia 
in patients with GERD.  A symptom relief pilot study in 110 patients with GERD was 
conducted in the UK to provide sufficient data to inform the protocol for this study.  The pilot 
study demonstrated the study design was suitable and robust, and that the Reflux Disease 
Questionnaire (RDQ) [9] was a suitable Patient Reported Outcome (PRO) for use in 
assessing symptom relief in GERD and dyspepsia.  No safety signals or issues were 
identified in the pilot study [10]. 
This study design is based on the pilot study and will examine the efficacy of Compound 
Sodium Alginate Double Action Chewable Tablets compared with matching placebo in 
treating the symptoms of reflux and dyspepsia in patients with GERD. 
The potential risks to patients taking part in the present study are considered to be low.  The 
adverse reactions that occur very rarely (<1/10,000) as a result of taking Compound Sodium 
Alginate Double Action Chewable Tablets and other Gaviscon® products are allergic 
manifestations such as urticaria or bronchospasm, anaphylactic or anaphylactoid reactions 
as a result of a patient being sensitive to any of the active substances (sodium alginate, 
sodium bicarbonate,and calcium carbonate) or any of the excipients.  Other adverse 
reactions include:  
1. Sodium bicarbonate – increased plasma sodium levels especially for those with renal 
and cardiovascular conditions on a highly restricted salt diet. 
2. Calcium carbonate – high doses of calcium may cause alkalosis, hypercalcaemia, 
acid rebound, milk alkali syndrome or constipation. 
For this reason, the risk benefit balance for the current study is considered to be acceptable 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 24 of 76 
This study will be conducted in accordance with the principles set out in the Declaration of 
Helsinki. It will comply with International Conference on Harmonisation (ICH) Good Clinical 
Practice (GCP) and applicable regulatory requirements. 
 
7 
STUDY RATIONALE 
This study is being conducted to provide evidence for inclusion in applications to regulatory 
authorities that the Compound Sodium Alginate Double Action Chewable Tablets are 
effective in managing the symptoms of heartburn, acid regurgitation and dyspepsia in 
patients with GERD. 
 
8 
STUDY OBJECTIVES 
8.1 
Primary Objective 
The primary objective of this study is to assess the efficacy of Compound Sodium Alginate 
Double Action Chewable Tablets (mint-flavoured) compared with a matched placebo in 
reduction of the symptoms of GERD in patients with GERD as assessed using the Reflux 
Disease Questionnaire (RDQ). 
 
8.2 
Secondary Objective(s) 
The secondary objectives of this study are to assess the efficacy of Compound Sodium 
Alginate Double Action Chewable Tablets compared with matching placebo in reduction of 
the symptoms of heartburn, acid regurgitation and dyspepsia in patients with GERD.  Other 
secondary objectives include the efficacy of Compound Sodium Alginate Double Action 
Chewable Tablets compared with placebo in patient responsiveness / satisfaction and 
comparison of safety in terms of adverse events.  
 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 25 of 76 
9 
STUDY DESIGN 
9.1 
Study Endpoints 
9.1.1 
Primary Endpoint 
The primary study endpoint is to compare the change from baseline in RDQ symptom scores 
for the GERD dimension (heartburn and regurgitation) after a 7-day treatment period of a 
regimen of two Compound Sodium Alginate Double Action Chewable Tablets taken four 
times daily compared with a matched placebo. 
 
9.1.2 
Secondary Endpoints 
The key secondary endpoint will compare between the two cohorts (Compound Sodium 
Alginate Double Action Chewable Tablets and matching placebo) for a 7-day treatment 
period for the following parameter: 
• 
Change from baseline in RDQ scores for dyspepsia dimension 
Other secondary endpoints will compare between the two cohorts (Compound Sodium 
Alginate Double Action Chewable Tablets and matching placebo) for a 7-day treatment 
period for the following parameters: 
• 
OTE as a measure for patient’s responsiveness/satisfaction 
• 
Change from baseline in RDQ scores for heartburn dimension. 
• 
Change from baseline in RDQ scores for regurgitation dimension. 
Safety will be assessed in terms of the overall proportion of patients with adverse events 
(AEs). 
 
9.2 
Design Summary 
This is a multi-centre, randomised, double blind, two arm, placebo-controlled, parallel group, 
study. After signing a written informed consent, patients will undergo a screening period of 
up to 7 days.  Patients who satisfy the study entry requirements within 7 days of consent, will 
be randomised to receive either Compound Sodium Alginate Double Action Chewable 
Tablets (2 tablets four times daily) or matching placebo tablets (2 tablets four times daily), for 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 26 of 76 
a 7-day treatment period. At the beginning and end of the treatment period, patients will be 
required to complete the RDQ. 
In addition, at the end of the 7-day treatment period, patients will be required to complete the 
overall treatment evaluation (OTE). 
 
9.3 
Discussion of Study Design 
The primary endpoint and some of the secondary endpoints are assessed using information 
collected in the Reflux Disease Questionnaire (RDQ).  The choice of the RDQ is based on 
this being a validated questionnaire which collects patient assessments of their heartburn, 
acid regurgitation and dyspepsia. The RDQ is validated in English (Appendix 1) and Chinese 
Mandarin (Appendix 2).  It comprises a 12-item self-administered questionnaire which was 
designed to assess the frequency and severity of heartburn, acid regurgitation and 
dyspepsia symptoms. The heartburn and acid regurgitation subscales can be combined into 
a GERD dimension [9]. Response options are scaled as Likert-type with scores ranging from 
0 to 5 for frequency (not present to daily) and severity (not present to severe).   
Other secondary endpoints are assessed using the Overall Evaluation of Treatment (OTE). 
The OTE is a validated scale that rates the overall change in clinical status on a 15-point 
scale (-7 to -1 = worse; 0 = no change or about the same; and +1 to +7 = better).  It then 
categorises the change with a second question asking how patients perceive the importance 
of the change on a 7-point scale from: 1 = not important, 2 = slightly important, 3 = 
somewhat important, 4 = moderately important, 5 = important, 6 = very important, 7 = 
extremely important [11-13]. 
9.4 
Number of Patients 
The sample size calculation, based on the UK pilot study date [10] and a previous pivotal 
China study, shows that 1054 evaluable patients need to complete the study (with the aim of 
having approximately 527 patients in each treatment group). An evaluable patient is defined 
as a randomised patient who completes the study treatment period and attends the end of 
treatment visit. In order to achieve this, it is estimated that approximately 1222 patients will 
have to be screened and approximately 1100 patients will have to be randomised.  
Patients will receive a screening number on signing the informed consent.  Patients will 
receive a separate randomisation number on being randomised to the study. 
It is anticipated that between 25 and 50 sites will take part in the study. Each site will be 
asked to recruit between 10 and 200 patients. 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 27 of 76 
Further details are provided in Section 14.1. 
 
9.5 
Study Duration 
It is estimated that it will take 9 months to recruit the required number of patients. 
The duration of each patient’s participation in the study will be a maximum of 17 days (from 
screening visit to end of treatment visit) and involve 3 visits. 
Patients can enter the study, if eligible, as soon as all screening results are available 
following informed consent at Visit 1. A maximum of 7 days will be allowed to screen a 
patient at Visit 1. If eligible, the patient will be randomised and will commence the 7-day 
treatment period at Visit 2 (Day 0). 
The patients will be randomised to receive either Compound Sodium Alginate Double Action 
Chewable Tablets or matching placebo tablets for 7 days. Visit 3, the End of study visit, will 
occur on Day 8 (between Day 7 and Day 10). 
The anticipated overall duration of study conduct is expected to be approximately one year. 
9.6 
Patient Commitment to the Study 
9.6.1 
Duration of Patient Participation 
Up to 7 days will be allowed to screen a patient at Visit 1 following informed consent. The 
pre-study procedures will consist of a medical history and physical examination, endoscopy, 
12-lead ECG, haematology and biochemistry and urine pregnancy test for female patients of 
child-bearing potential. 
Visit 2 (Day 0) will take place immediately after all screening results are available and within 
7 days after Visit 1. Patients will be required to complete a baseline RDQ which will ask the 
patient to rate their symptoms over the previous 7 days and have any adverse events and 
concomitant medications recorded. Patients meeting the entry criteria will be randomised 
and then issued with either Compound Sodium Alginate Double Action Chewable Tablets or 
matching placebo tablets to take for 7 days. 
At Visit 3, End of treatment period (Day 8, between Day 7 and day 10), unused 
investigational medicinal product (IMP) will be collected. Patients will be required to 
complete the RDQ questionnaire and OTE (overall treatment evaluation) as a measure of 
the responsiveness to the study therapy and undergo assessment by the Investigator for 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 28 of 76 
compliance and safety (AEs, haematology and clinical biochemistry and urine pregnancy 
test for female patients).  
Further details on the timing of study visits are provided in Section 11.2. 
 
9.6.2 
Invasive Procedures 
Blood samples will be taken for haematology and biochemistry at Visit 1 and Visit 3.  The 
volume of blood samples for a patient will not exceed 30 ml in total for all visits. 
An endoscopy will be performed at screening or results may be used if conducted prior to 
consent within 28 days of giving consent if the examination was conducted at the same 
hospital. 
Further details on the study assessments are provided in Section 11.2. 
 
9.6.3 
General and Dietary Restrictions 
Patients will be instructed to follow their routine meal pattern, avoiding food not normally 
consumed, such as excessively spicy food. There should be an interval of at least three 
hours between meals. 
 
9.7 
End of Study 
The end of the study is defined as the last visit of the last patient undergoing the study. 
 will notify SFDA within 90 days of the end of the study (within 15 days if the study is 
terminated prematurely). 
The Investigator will notify the IEC within 90 days of the end of the study (within 15 days if 
the study is terminated prematurely). 
 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 29 of 76 
10 
STUDY POPULATION 
10.1 
Inclusion Criteria 
Only patients to whom all of the following conditions apply will be included: 
1. Informed consent has been obtained. 
2. Age: ≥ 18 to ≤ 65 years 
3. Sex: male or female. 
4. Primary diagnosis: Current evidence of symptomatic GERD in accord with the 
Montreal definition [1,14]. This evidence can be based solely on symptom 
characteristics. Patients should have a GERD history of frequent episodes of GERD-
related symptoms during the last 3 months and also during 5 of the last 7 days prior to 
study screening. 
5. GERD Status: Patients will be patients at the clinic or members of the public who 
respond to an advertisement or via their doctor.  Patients must have had troublesome 
heartburn and/or regurgitation (with or without dyspepsia symptoms) of at least mild or 
moderate intensity* on at least five days during the week before the start of screening. 
If the patient also has other symptoms, the heartburn, regurgitation or dyspepsia 
should be the predominant symptoms.  
*Symptom intensity should be assessed using the following scale; 
• 
Mild: awareness of symptom but easily tolerated  
• 
Moderate: discomforting symptom sufficient to cause interference with normal 
activities including sleep 
• 
Severe: incapacitating symptom with inability to perform normal activities, 
including sleep 
6. Patients who have not taken any antacids within 24 hours before randomisation (Visit 
2) and be instructed not to take antacids throughout the remainder of the study. 
7. Patients taking mucous membrane protection drugs or prokinetics may enter the 
study provided that these are discontinued for at least 5 days before screening and 
throughout the remainder of the study. 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 30 of 76 
8. Systemic glucocorticosteroids or non-steroidal anti-inflammatory drugs (NSAIDs, 
except for low dose aspirin which can be given for cardioprotection) can only be taken 
for up to 3 consecutive days in the 28 days prior to screening 
9. Absence of relevant abnormalities in the physical examination, endoscopy, ECG and 
laboratory safety results. 
10. Patients must be sufficiently literate to be able to complete the RDQ unaided. 
 
10.2 
Exclusion Criteria 
Patients to whom any of the following conditions apply must be excluded: 
1. Patients who have a history of drug, solvent or alcohol abuse (weekly alcohol intake ≥ 
140g). 
2. Patients who have suffered cardiac chest pain within the last year. 
3. Patients who have suffered a recent, significant unexplained weight loss of more than 
6 Kg in the last 6 months. 
4. Female patients of childbearing potential who, for the duration of the study, are either 
unwilling or unable to take adequate contraceptive precautions (as defined in 
Section 10.3) or are unwilling to be sexually abstinent (as defined in Section 10.3).  
5. Pregnancy or lactating mother.  
6. Patients with a history and/or symptom profile and/or discovered on endoscopy 
suggestive of the following:  any other gastrointestinal (GI) disease, erosive GERD 
(Los Angeles [LA] classification grades C-D), Barrett’s esophagus, acute peptic ulcer 
and/or ulcer complications, Zollinger-Ellison syndrome, gastric carcinoma, pyloric 
stenosis, oesophageal or gastric surgery, intestinal obstruction, current pernicious 
anaemia, indication for H-pylori eradication therapy, known gastro-intestinal bleeding 
(hematochezia or hematemesis) within the last 3 months, and severe diseases of 
other major body systems. 
7. Patients who are observed on endoscopy to have a hiatus hernia with a diameter 
which exceeds 3cm. 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 31 of 76 
8. Patients who have taken anti-cholinesterase drugs, traditional Chinese medicines for 
treating gastrointestinal disease, ulcerlmin or misoprostol preparations within 7 days 
prior to screening or throughout the study. 
9. Patients who have taken PPIs during the 10 days prior to screening, prokinetics or H2 
antagonists during the 5 days prior to screening or systemic glucocorticosteroids, non-
steroidal anti-inflammatory drugs (NSAIDs, except for low dose aspirin which can be 
given for cardioprotection) on more than 3 consecutive days or PPI-based triple or 
quadruple therapy for eradication of H-pylori during the last 28 days. 
10. Patients taking or requiring to take macrolide antibiotics, such as erythromycin, 
azithromycin, from the day before screening. 
11. Patients with difficulty in swallowing. 
12. Patients with known hypophosphataemia, phenylketonuria or hypercalcaemia. 
13. Patients with severe constipation, or history of intestinal obstruction. 
14. In the opinion of the Investigator, patients with damaged heart or kidney diseases and 
patients who require a low sodium diet. 
15. Patients either with any co-existing condition which, in the opinion of the Investigator, 
would be likely to compromise patient safety or interfere with assessment of efficacy; 
or with any clinically significant abnormal laboratory values; or in the Investigator’s 
view to unable to comply fully with the study requirements. 
16. Any previous history of allergy or known intolerance to any of the IMP’s or following 
formulation constituents: macrogol 20,000, mannitol (E421), copovidone, acesulfame 
K, aspartame (E951), mint flavour, carmoisine lake (E122), magnesium stearate, 
xylitol DC (contains carmellose sodium) or the following formulation constituents: 
sodium alginate, calcium carbonate, sodium bicarbonate. 
17. Previously randomised into the study. 
18. Employee at study site. 
19. Partner or first-degree relative of the Investigator. 
20. Patients who failed screening will not be allowed to re-enter the study. 
21. Participation in a clinical study in the previous 6 months or participation in a previous 
Compound Sodium Alginate Double Action Chewable Tablet study.  


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 32 of 76 
22. Unable in the opinion of the Investigator to comply fully with the study requirements.  
 
10.3 
Patients of Reproductive Potential 
Woman of childbearing potential must take adequate contraceptive precautions for the entire 
duration of study participation. Adequate contraceptive precautions include oral or injectable 
contraceptives; approved hormonal implants or topical patches; intrauterine devices; barrier 
methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with 
spermicidal foam/gel/film/cream/suppository; true abstinence (true abstinence: when this is 
in line with the preferred and usual lifestyle of the patient. Periodic abstinence e.g., calendar, 
ovulation, symptothermal, post-ovulation methods and withdrawal are not acceptable 
methods of contraception. Should the patient become sexually active while participating in 
the study, she must agree to use a double barrier method or condoms/diaphragms with 
spermicidal foam/gel/film/cream/suppository. Patients are to be informed that a female 
condom and male condom should not be used together as friction between the two can 
result in either product failing. A woman of childbearing potential is defined as any female 
who is less than 2 years post-menopausal or who has not undergone a hysterectomy or 
surgical sterilisation, e.g. bilateral tubal ligation, bilateral ovariectomy (oophorectomy). 
The procedures to be followed if a patient becomes pregnant while enrolled in the study are 
described in Section 13.3. 
 
11 
STUDY METHODOLOGY 
11.1 
Recruitment of Study Patients 
Patients will be recruited by the investigator from out-patient clinics, from the hospital 
database or those patients who respond to advertising. Patients suffering from mild to 
moderate symptoms of GERD and who meet all eligibility criteria will be given the 
opportunity by the investigator to participate in the study.  
 
11.2 
Study Visits/Assessments 
A patient is enrolled into a study when he or she (or a legal representative as defined 
in Section 16.2) has signed the informed consent form, i.e. prior to any study-specific 
assessments being performed.  


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 33 of 76 
The schedule for assessments for this trial is summarised in the following flowchart: 
Table 11-1 Schedule of Assessments 
Schedule 
FLOW CHART OF STUDY 
Study period 
Visit 1 
Screening 
(up to 7 days)
Visit 2 
Randomisation 
(Day 0) 
Visit 3      End of 
study (Day 8) 
(between Day 7 
and Day 10) 
Visit ET  
Replaces Visit 
3 if early 
termination    
(Day 1 to 6) 
Informed consent 
X 
 
 
 
Assess 
inclusion-/exclusion 
criteria and suitability for 
study 
X 
X 
 
 
Record 
demographics, 
assess 
concomitant 
medication 
and 
relevant 
medical history 
X 
X 
 
 
Physical exam, collection of 
blood 
samples 
for 
haematology & biochemistry, 
vital signs 
X 
 
X 
X 
Urine pregnancy test 
X 
 
X 
X 
12-lead ECG 
X 
 
 
 
Endoscopy 
X 
 
 
 
Investigator’s assessment of 
GERD status 
X 
 
 
 
Make appointment for next 
visit 
X 
X 
 
 
Randomisation 
 
X 
 
 
Dispense study medication & 
emergency card provided 
 
X 
 
 
Patient 
completes 
RDQ 
questionnaire. 
 
X 
X 
X 
Record AEs and concomitant 
medication 
 
X 
X 
X 
Collect returned medication, 
assess 
compliance 
with 
study medication. 
 
 
X 
X 
Complete OTE 
 
 
X 
X 
 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 34 of 76 
* Previous endoscopy results may be used if conducted prior to consent within 28 days of 
giving consent and if the examination was conducted at the same hospital 
** OTE: Overall Treatment Evaluation. 
 
11.3 
Baseline Visit 
11.3.1 
Screening/Enrolment Procedures 
Potential patients will be provided with the patient information sheets and given ample time 
to read and decide whether they are interested in taking part in the study. If the patient is 
interested, she/he will speak to the investigator or person delegated by the investigator to 
take consent who will explain more about the study and answer any questions the patient 
may have. If the patient feels fully informed and happy to participate in the study then they 
will complete, sign and date the informed consent form (ICF). The ICF will then be counter 
signed and dated by the investigator or person delegated by the investigator  to take 
consent. A copy of the ICF and patient information sheet will be provided to the patient for 
their personal records. 
All patients will be given a 5-digit screening number once they have provided consent. The 
first two digits will refer to the centre number and the second three digits to the number of 
patients screened at that centre. For example, screening numbers at centre 01 will start 
01001, 01002 etc.  
The screening process can take up to a maximum of seven days after informed consent. 
 
11.3.1.1 
Clinical Assessments Performed at Baseline 
The following baseline assessments (Visit 1, screening) will be conducted: 
Demographic data: 
• 
Sex 
• 
Race (categorised as: Caucasian, Asian, Afro-Caribbean and Other) 
• 
Date of birth 
• 
Height (cm)  


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 35 of 76 
• 
Weight (kg)  
• 
Smoking/alcohol/drugs of abuse history/use 
Laboratory safety data: 
• 
Haematology 
• 
Biochemistry 
• 
Details are listed in section 13.4 
Vital signs: 
• 
Blood pressure (after sitting for 5 minutes; mmHg) 
• 
Heart rate (radial pulse counted for 30 seconds after resting for 5 minutes; beats/minute) 
• 
12-lead ECG 
Medical history and current status: 
• 
Primary diagnosis 
• 
Duration of disease 
• 
Medical history and current status 
• 
GERD status as assessed by the investigator 
Medication and therapy history: 
• 
Current medication and therapy (including any OTC or traditional Chinese medicines) 
• 
Medication and therapy in the previous 30 days (including any OTC or traditional 
Chinese medicines) 
Physical examination 
• 
A standard physical examination will be conducted 
Pregnancy testing  


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 36 of 76 
• 
Women of child-bearing potential will undergo urine pregnancy testing.  Pregnancy tests 
will be performed with urine pregnancy kits using standard urine pregnancy testing 
methods. 
Endoscopy examination  
• 
A standard hospital endoscopy examination will be conducted to indicate whether the 
patient meets inclusion/exclusion criteria.  
 
• 
Endoscopy diagnosis examinations conducted prior to consent may be used if patients 
were examined within 28 days of giving consent, only if the examination was conducted 
at the same hospital and if the endoscopy results are available for study monitoring 
purposes. 
 
11.3.2 
Clinical Assessments Performed After Baseline 
11.3.2.1 
Clinical Assessments at Visit 2 
At the end of the screening period, within 7 days of consent, patients will return to the clinic 
to complete the RDQ questionnaire and have any changes in medical history and 
concomitant medications recorded.  
If the patient fulfils the eligibility criteria (check inclusion / exclusion criteria) for 
randomisation, a unique 4-digit randomisation number will be allocated and study medication 
dispensed (0001, 0002 etc.). The randomisation number will be pre-printed on the 
medication assigned to that patient. Randomisation numbers will not be site-specific. The 
numbers available at a site will be allocated to the patients in consecutive order. Patients will 
be instructed to start taking their medication the following day for seven days (two tablets 
taken four times a day: 30 minutes after breakfast, 30 minutes after lunch, 30 minutes after 
dinner and immediately before lying down for bed).  Patients will be instructed to chew 
tablets thoroughly and swallow.  Patients will be instructed to follow their routine meal 
pattern, avoiding food not normally consumed, such as excessively spicy food. There should 
be an interval of at least three hours between meals. 
Emergency cards will be issued to patients before they leave the centre. The emergency 
card will be the size of a credit card and will contain the following information: 
• 
Study number.  
• 
Patient (randomisation) number. 
• 
Statement that patient is participating in a clinical trial. 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 37 of 76 
• 
Statement that the patient is taking either two Compound Sodium Alginate Double 
Action Chewable Tablets or two matching placebo tablets four times per day. 
• 
Instructions to non-investigator staff to ring a 24-hour telephone number in case of 
emergency. This will be the number of the investigator site. 
 
11.3.2.2 
Clinical Assessments at Visit 3, End of Treatment 
Visit 3 will take place preferably on the day following completion of 7-days of study 
treatment, ie, Day 8, or if necessary up to 1 day before and 2 days after that (Day 7 to Day 
10). At this visit, the patient will complete the RDQ questionnaire and answer questions 
relating to overall satisfaction with the trial therapy (OTE) over the previous seven days. All 
unused and empty study medication containers will be returned for assessment of 
compliance with treatment.  The following will be completed: 
Vital Signs 
• 
Blood pressure (after sitting for 5 minutes; mmHg). 
• 
Heart rate (radial pulse counted for 30 seconds after resting for 5 minutes; 
beats/minute). 
 
Concomitant Medication 
• 
All concomitant medication usage including any OTC medications and traditional 
Chinese medicines will be recorded. 
 
Adverse Events 
• 
All adverse events will be recorded. 
 
Physical examination 
• 
A standard physical examination will be conducted. 
 
Laboratory investigations 
• 
Haematology 
• 
Biochemistry 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 38 of 76 
• 
Details are listed in section 13.4. 
 
Pregnancy testing  
• 
Women of child-bearing potential will undergo urine pregnancy testing. 
 
11.3.2.3 
Clinical Assessments at Early Termination (ET) Visit (only if 
required for patient early terminations) 
The patient will be instructed to return to the investigator before the end of treatment if they 
require further treatment for their GERD symptoms or have unacceptable adverse events.  
Early termination applies to study Days 1 to 6.  If the investigator withdraws the patient from 
the study for these or any other reasons the patient will complete the study at this early 
termination visit and the following will be completed. 
The patient will complete the RDQ questionnaire and answer questions relating to overall 
satisfaction with the trial therapy (OTE) over the study treatment period. All unused and 
empty study medication containers will be returned for assessment of compliance with 
treatment.  The following will be completed: 
Vital Signs 
• 
Blood pressure (after sitting for 5 minutes; mmHg). 
• 
Heart rate (radial pulse counted for 30 seconds after resting for 5 minutes; 
beats/minute). 
 
Concomitant Medication 
• 
All concomitant medication usage including any OTC medications and traditional 
Chinese medicines will be recorded. 
 
Adverse Events 
• 
All adverse events will be recorded. 
 
Physical examination 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 39 of 76 
• 
A standard physical examination will be conducted. 
 
Laboratory investigations  
• 
Haematology 
• 
Biochemistry 
• 
Details are listed in section 13.4. 
 
Pregnancy testing  
• 
Women of child-bearing potential will undergo urine pregnancy testing 
 
Early Study Termination 
• 
The investigator will assess the reason for early termination AE; lack of efficacy; lost to 
follow-up; no further need for IMP; protocol violation; death; withdrawal of consent; 
other. 
 
11.4 
Study Variables and Methods of Assessment 
11.4.1 
Efficacy Variables 
11.4.1.1 
Overview of Efficacy Variables 
The primary and some secondary efficacy variables are derived from the RDQ.  OTE is also 
a secondary efficacy variable. 
11.4.1.2 
Methods of Assessment of Efficacy Variables 
The following assessments of symptoms will be used: 
• 
RDQ (Appendix 1 & 2) is a self-assessed patient questionnaire which is designed to 
measure and evaluate specific GERD symptoms of heartburn, regurgitation and 
dyspepsia. The items that constitute the three dimensions of heartburn, regurgitation 
and dyspepsia are listed in Table 1 (Sub-dimensions of the symptoms). The Scoring 
system of the RDQ is shown in the Table 2 (Scoring system of RDQ). 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 40 of 76 
Table 1. Sub-dimensions of the symptoms 
Regurgitation 
Heartburn 
Dyspepsia 
Acid in the mouth. 
Burning 
behind 
the 
breastbone. 
Burning 
in 
the 
upper 
stomach. 
Unpleasant movement of 
material upwards from the 
stomach. 
Pain 
behind 
the 
breastbone. 
Pain in the upper stomach. 
 
 
Table 2. Scoring system of RDQ 
Score
Frequency 
Intensity/Severity 
0 
None 
None 
1 
Less than one day a week 
Very mild 
2 
Once day a week 
Mild 
3 
2-3 days a week 
Moderate 
4 
4-6 days a week 
Moderately severe 
5 
Daily 
Severe 
 
The Overall Treatment Evaluation (OTE): patients will be prompted by the question “Thinking 
over the last 7 days and the medication you received, how would you rate the change in your 
symptoms?” and “How important was the change in the symptoms to you?”. 
 
11.4.2 
Appropriateness of Measurements 
The RDQ is an accepted reflux disease questionnaire that also assesses dyspepsia and is 
therefore an appropriate method of assessing the efficacy of Compound Sodium Alginate 
Double Action Chewable Tablets on symptoms of GERD and dyspepsia in this study.  It has 
been validated in Chinese Mandarin and is therefore appropriate for use in this study. 
 
11.5 
Study Specific Supplies 
Not applicable. 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 41 of 76 
 
11.6 
Unscheduled Visits 
If unscheduled visits occur, the Investigator must record the following in the patient’s CRF: 
• 
Reason for unscheduled visit 
• 
Any AEs. 
• 
Concomitant medication and therapy changes. 
• 
Withdrawal (if deemed appropriate). 
• 
Any clinical assessments deemed appropriate for the clinical care of the patient. 
If the dosage regimen of study medication has been changed, the Investigator must contact 
the RB Clinical Project Manager in order to determine if the patient should be withdrawn 
from the study or may be allowed to continue. The Clinical Project Manager will advise the 
Investigator of how information should be recorded on the CRF. 
Unscheduled visits should not alter the timing of the routine study schedule. 
 
11.7 
Patient Withdrawal and Replacement Criteria 
11.7.1 
Patient Withdrawal 
The Investigator may withdraw the patient from the study at any time. Reasons for removing 
a patient from the study include, but are not limited to: 
• 
AEs that in the judgement of the Investigator may cause severe or permanent harm 
(significant clinical deterioration is an AE). 
• 
Violation of the study protocol. 
• 
In the Investigator’s judgement, it is in the patient’s best interest. 
• 
Patient declines further study participation. 
• 
Randomisation code is broken. 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 42 of 76 
The primary reason for withdrawal will be documented as one of the following: AE; lack of 
efficacy; lost to follow-up; no further need for IMP; protocol violation; death; withdrawal of 
consent; other. The Investigator must make reasonable attempts to contact patients who are 
lost to follow-up - a minimum of 2 documented telephone calls or a letter is considered 
reasonable. 
If a patient is withdrawn prematurely from the study, the assessments listed in section 
11.3.2.3 will be carried out. 
 
11.7.2 
Replacement of Patients 
Patients who withdraw from the study will not be replaced. 
 
11.8 
Additional Care of Study Patients Following Completion of the 
Study 
Patients who experience AEs at the end of the study, or experience the onset of an AE after 
the end of the study, will be followed up as described in Sections 13.1.7 and 13.1.8. 
No other additional care of study patients will take place following the end of the study. The 
treatment of the patient’s condition will follow normal clinical practice. 
 
11.9 
Treatment Compliance 
Treatment compliance will be assessed on the basis of tablet counts. Patients will be 
instructed to bring their unused IMP and any empty containers with them at each visit. For 
the time period between each visit, the number of unused tablets returned will be recorded. 
For the entire treatment period of the study, the proportion of tablets taken relative to the 
expected number of tablets that should have been taken will be calculated. A compliance to 
IMP intake of less than 75% will be considered a major protocol deviation. Patients with 
compliance of less than 75% will be excluded from the per protocol population. 
 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 43 of 76 
11.10 
Premature Termination of the Study 
RB may prematurely terminate the conduct of the study specific study sites or the entire 
study.  Reasons for early termination include, but are not limited to: 
• 
Inability to recruit or slow recruitment of patients 
• 
Unacceptable data quality 
• 
Concerns regarding the risk/benefit ratio 
• 
Withdrawal of CA or IEC approval 
• 
Recall of a batch of IMP where replacement medication will not be provided 
• 
Results from an interim statistical or safety analysis 
• 
Inability to remedy a clinical hold or suspension 
• 
Unresolved non-compliance with GCP or the protocol that compromises patient rights 
or safety or the study data 
The CPM will inform all investigators in writing at specific study sites relevant to the decision.  
A suitable course of action will be agreed for existing patients.  The investigator will inform 
the IEC in writing and provide a copy to RB for filing in the TMF.  
 inform the 
SFDA within 15 days of the date of termination of the study and file a copy of the 
correspondence in TMF. 
 
12 
STUDY TREATMENTS 
12.1 
Identity of Investigational Medicinal Products 
The following medication will be supplied. 
 
Compound Sodium Alginate Double Action Chewable Tablets  
 
Matching placebo tablets.  
Compound Sodium Alginate Double Action Chewable Tablets will be manufactured to Good 
Manufacturing Practice (GMP) by Reckitt Benckiser Healthcare (UK) Limited, Dansom Lane, 
Hull, HU8 7DS, UK (Product Licence 00063/0157).  The matching placebo tablets will be 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 44 of 76 
manufactured to Good Manufacturing Practice (GMP) by 
 
 for RB. 
The active and placebo treatments will be shipped to 
 
 where both 
will be blister packed.   
The blister packs will be shipped to the Investigational Material Supplies Unit (IMSU), Reckitt 
Benckiser Healthcare UK Ltd, Dansom Lane, Hull, HU8 7DS UK. The supplies will be 
assembled and labelled to GMP standards by the Investigational Material Supplies Unit 
(IMSU), Reckitt Benckiser Healthcare UK Ltd, Dansom Lane, Hull, HU8 7DS.  They will be 
shipped directly from IMSU to be distributed to the investigator sites from a distribution 
centre in China. 
Labels and all packaging will be matching for both active and placebo packs and will not 
identify which of the two treatments (active or placebo) the patient’s pack contains. 
 
12.2 
Identity of Non-Investigational Medicinal Products 
NIMPs are not used in this study. 
 
12.3 
Randomisation and Treatment Allocation 
12.3.1 
Randomisation 
Drug supplies will be randomised by the RB Investigational Material Supply Unit, according 
to a computer-produced randomisation schedule. On entry, patients will be allocated a 
unique patient number in numerical sequence based on the patient numbers supplied to that 
site. Issue of the IMP at the site in this numerical sequence will ensure correct 
randomisation. 
The IMSU will hold the master code for the randomisation schedule and will supply the 
Investigator with the randomisation code for each patient as individually sealed envelopes. 
The code will only be broken for an individual patient in an emergency such as a serious AE 
(SAE) for which it is necessary to know the study treatment in order that the SAE be treated 
appropriately. If the code for a patient is broken, the Investigator should withdraw the patient 
from the study, document the details of the event in the patient’s CRF and promptly inform 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 45 of 76 
the RB/
 Clinical Project Manager. If, for any reason, the code is broken the patient 
will be withdrawn from the study. 
The 
 study monitor will check the randomisation code-break envelopes on a regular 
basis at monitoring visits, to ensure the above procedures are being followed. All code-break 
envelopes, whether sealed or opened, will be returned to RB at the end of the study. 
 will break the code for all patients only after all data queries have been answered 
and the database has been locked. 
 
12.3.2 
Blinding 
The study is blinded using matching placebo and active tablets, identically packaged and 
labelled. 
 
12.3.3 
Emergency Unblinding Procedures 
The randomisation code envelopes will be provided to the unit providing a 24 hour blind 
breaking service (either Investigator Unit or Pharmacy). 
The randomisation code will only be broken for an individual patient in an emergency such 
as an SAE that requires knowledge of which IMP was taken so that the SAE can be treated 
appropriately. If the code for a patient is broken, the Investigator must withdraw the patient 
from the study, document the details of the event in the patient’s CRF, and promptly inform 
the RB and 
 Clinical Project Managers. 
 
12.3.4 
IMP allocation for Replacement Patients 
Patients will not be replaced. 
 
12.4 
Dosage Instructions 
Each patient will be instructed to thoroughly chew and swallow Compound Sodium Alginate 
Double Action Chewable Tablets or matching placebo tablets as a multiple dose regimen. 
Prior to dosing, all patients will be instructed by the Investigator on how they will take the 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 46 of 76 
medication, ie, on each occasion take two tablets simultaneously, thoroughly chew and 
swallow both tablets. Patients will be instructed to start taking their medication the day after 
their randomisation visit for seven days (two tablets taken four times a day: 30 minutes after 
breakfast, 30 minutes after lunch, 30 minutes after dinner and immediately before lying down 
for bed).  
Medication errors are reportable to RB irrespective of the presence of an associated 
AE/SAE, including: 
• 
Medication errors involving subject exposure to a medicinal product  
• 
Potential medication errors or uses outside of what is foreseen in the protocol that do or 
do not involve the participating subject. 
Whether or not the medication error is accompanied by an AE/SAE, as determined by the 
investigator, the medication error and any associated AE/SAEs will be captured on an AE 
CRF page /SAE form (refer to Adverse Event Reporting section 13.1 for further details).  
 
12.5 
Packaging 
Sufficient IMP supplies will be packaged and labelled initially for 2000 patients (1000 
patients per treatment group).  This will allow for the initial allocation of 60 patients to each 
site. Each patient pack will contain 64 tablets (allowing 7 days study treatment and one days’ 
overage). 
 
12.6 
Labelling 
12.6.1 
Investigational Medicinal Product(s) 
Supplied IMP(s) will be labelled according to GCP and GMP requirements and any other 
applicable national/state legislation. 
Each patient pack will be labelled and each blister pack in the patient pack will be labelled.  
 
12.6.2 
Non-Investigational Medicinal Products 
NIMPs are not used in this study. 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 47 of 76 
 
12.7 
Accountability of Investigational and Non-Investigational 
Medicinal Product(s) 
The Investigator will keep all IMPs in a pharmacy or a secure storage facility, accessible only 
to those individuals authorised by the Investigator to dispense the medication. 
The Investigator or designated individual will maintain an inventory. This will include the 
description and quantity of IMPs received during the course of this study, as well as a record 
of the materials that are dispensed and returned (how much, to whom, and when). This 
inventory (“Drug Dispensing Log”) will be subject to review by the study monitor during 
monitoring visits. 
The Investigator agrees not to supply IMPs to any person except study personnel and 
patients enrolled in this study. 
The study drug should be stored between 4°C and 30°C. Temperatures must be monitored 
using a minimum / maximum thermometer and recorded in a temperature log on a daily 
basis on working days. The temperature log will be reviewed by the study monitor. 
 
12.8 
Disposal of Unused Investigational and Non-Investigational 
Medicinal Product(s) 
The Investigator agrees to conduct a drug supply inventory, to record the results of this 
inventory (“IMP/NIMP Removal from Site” form) and to return it and all original IMP/NIMP 
containers, whether empty or containing IMP or NIMP, to 
 at the end of the study or 
in stages during the course of the study. 
 and RB will arrange for the appropriate and timely destruction of all returned IMP(s) 
and NIMP(s) following the end of the study (on finalisation of the study report).  
 
12.9 
Concomitant Therapies 
Concomitant therapies are defined as prescribed medications, physical therapies, and over-
the-counter preparations, including herbal preparations licensed for medicinal use, other 
than IMP(s) that the patient receives during the course of the study. 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 48 of 76 
The Investigator will record any medications given for treatment of AEs on the concomitant 
medication page in the patient’s CRF. Any medication taken by the patient from the time of 
giving informed consent through to the end of the study should also be recorded in the CRF. 
Any changes in concomitant therapy during the study will be documented, including 
cessation of therapy, initiation of therapy, and dose changes. 
 
12.10 
Prohibited Therapies 
The use of the following therapies will not be permitted: 
 
PPIs during the 10 days prior to screening and throughout the study. 
 
Prokinetics or H2 antagonists during the 5 days prior to screening and throughout the 
study. 
 
Systemic glucocorticosteroids or non-steroidal anti-inflammatory drugs (NSAIDs except 
low dose aspirin given for cardioprotection) on more than 3 consecutive days in the 28 
days prior to screening and are not allowed throughout the study. 
 
PPI-based triple or quadruple therapy for eradication of H-pylori during the 28 days prior 
to screening and throughout the study. 
 
Mucous membrane protection drugs for 5 days prior to screening and throughout the 
study. 
 
Patients who have taken anti-cholinesterase drugs, traditional Chinese medicines for 
treating gastrointestinal disease / symptoms, ulcerlmin or misoprostol preparations within 
7 days prior to screening or throughout the study. 
 
Macrolide antibiotics, such as erythromycin, azithromycin, from the day before screening 
and throughout the study. 
 
Any antacids within 24 hours before randomisation (Visit 2) and throughout the 
remainder of the study. 
 Patients who use any of these above medications during the study will be withdrawn. 
The Investigator Brochure indicates that due to the presence of calcium carbonate which 
acts as an antacid, a time-interval of 2 hours should be considered between IMP intake and 
the administration of other medicinal products, especially H2-antihistaminics, tetracyclines, 
digoxine, fluoroquinolone, iron salt, ketoconazole, neuroleptics, thyroxine, penicilamine, 
beta-blockers 
(atenolol, 
metoprolol, 
propranolol), 
glucocorticoid, 
chloroquine 
and 
diphosphonates.  
 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 49 of 76 
13 
SAFETY ASSESSMENTS 
13.1 
Adverse Events 
13.1.1 
Adverse Event Definitions 
Adverse Event (AE): Any untoward medical occurrence in a patient participating in a clinical 
study administered an IMP, which does not necessarily have a causal relationship with 
administration of the IMP. 
Comment: An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
IMP, whether or not considered related to the IMP. 
AEs do not include the following: 
• 
Medical or surgical procedures; the condition requiring a medical or surgical procedure is 
an AE. 
• 
Elective surgery or pre-existing conditions requiring planned procedures outside the 
scope of the study. 
Adverse Reaction (AR) to an IMP: All untoward and unintended responses to an IMP 
related to any dose administered. 
Comment: All AEs judged by either the Investigator or the sponsor as having a reasonable 
causal relationship to an IMP qualify as AR’s. The expression “reasonable causal 
relationship” means to convey in general that there is evidence or argument to suggest a 
causal relationship. 
Serious Adverse Event (SAE): Any untoward medical occurrence (i.e. AE) that at any 
dose: 
• 
Results in death. 
• 
Is life-threatening. 
• 
Requires hospitalisation or prolongation of existing hospitalisation. 
• 
Results in persistent or significant disability/incapacity. 
• 
Is a congenital anomaly/birth defect. 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 50 of 76 
• 
Is otherwise considered to be medically significant. 
Comments: Life-threatening in the definition of an SAE or serious AE refers to an event in 
which the patient was at risk of death at the time of the event; it does not refer to an event 
which hypothetically might have caused death if it were more severe. 
Medical judgement should be exercised in deciding whether an AE or AR is otherwise 
considered to be medically significant. Important AEs or AR’s that are not immediately life-
threatening or do not result in death or hospitalisation but may jeopardise the patient or may 
require intervention to prevent 1 of the other outcomes listed in the definition above should 
also be considered serious. 
Examples of such medically significant events are: 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm. 
• 
Blood dyscrasias or convulsions that do not result in hospitalisation. 
• 
Development of drug dependency or drug abuse. 
Unexpected Adverse Reaction: An AR, the nature or intensity of which is not consistent 
with the applicable product information (e.g. Investigator’s Brochure for an unauthorised IMP 
or SmPC for an authorised IMP). 
Comment: When the outcome of the AR is not consistent with the applicable product 
information this AR should be considered as unexpected. 
Suspected Unexpected Serious Adverse Reaction (SUSAR): An SAE considered to have 
a causal relationship with administration of the IMP, and the nature or intensity of which is 
not consistent with the applicable product information (e.g. Investigator’s brochure for an 
unauthorised IMP or SmPC for an authorised IMP). 
Intensity:  The term “severe” is often used to describe the intensity (severity) of a specific 
event.  This is not the same as “serious,” which is based on patient/event outcome or action 
criteria. 
 
13.1.2 
Observation Period for Adverse Event Reporting 
The observation period for an individual patient will start after giving informed consent and 
will finish at the last visit defining the end of the study for the given individual patient.  


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 51 of 76 
Any SAEs occurring after Informed Consent must be reported. 
Any untoward medical events occurring after Informed Consent but prior to IMP 
administration should be recorded in the patient’s medical history and not reported as an AE. 
 
13.1.3 
Information to be Collected on Adverse Events 
Each AE will be recorded according to the criteria given below. “Relationship to IMP” must 
be determined by the Investigator (if medically qualified) or by a medically qualified Co-
Investigator. 
 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 52 of 76 
Table 13-1 Table of Information to be Collected on Adverse Events 
Variable 
Category 
Definition 
AE reported 
term 
 
Any untoward medical occurrence in a patient 
administered an IMP and which does not 
necessarily have to have a causal relationship with 
this treatment. 
An AE can therefore be any unfavourable and 
unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease 
temporally associated with the use of a medicinal 
product, whether or not considered related to the 
IMP. 
Date AE 
started 
 
The date on which the AE started. 
Date of 
change in 
severity of AE 
 
The date on which the AE changed in severity. 
This date equates to the finish date of the old 
severity and the onset date of the new severity. 
Intensity 
 
Intensity will be determined by the Investigator. For 
symptomatic AEs the following definitions will be 
applied, but medical experience and judgement 
should also be used in the assessment of intensity. 
 
Mild 
The AE does not limit usual activities; the patient 
may experience slight discomfort. 
 
Moderate 
The AE results in some limitation of usual 
activities; the patient may experience significant 
discomfort. 
 
Severe 
The AE results in an inability to carry out usual 
activities; the patient may experience intolerable 
discomfort or pain. 
Actions taken 
None 
No action was taken in relation to this AE. 
 
IMP dose changed 
The dose of IMP was changed due to this AE, i.e. 
increase, decrease, or temporary discontinuation. 
 
IMP permanently 
discontinued 
The IMP was permanently discontinued due to this 
AE. 
 
Symptomatic therapy 
Symptomatic therapy was added or changed due 
to this AE. 
 
Patient hospitalised 
or hospitalisation 
prolonged 
The patient was hospitalised or hospitalisation was 
prolonged due to this AE. 
 
Other action (specify)
Other action was taken due to this AE, e.g. 
diagnostic tests, laboratories and procedures. 
Relationship 
to IMP 
Unassessable/ 
Unclassifiable 
Insufficient information to be able to make an 
assessment. 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 53 of 76 
Variable 
Category 
Definition 
 
Conditional/ 
Unclassified 
Insufficient information to make an assessment at 
present (causality is conditional on additional 
information). 
 
Unrelated 
No possibility that the AE was caused by the IMP. 
 
Unlikely 
Slight, but remote, chance that the AE was caused 
by the IMP, but the balance of judgment is that it 
was most likely not due to the IMP. 
 
Possible 
Reasonable suspicion that the AE was caused by 
the IMP. 
 
Probable 
Most likely that the AE was caused by the IMP. 
 
Certain 
The AE was definitely caused by the IMP. 
Is the AE 
serious? 
Results in death 
Life-threatening 
Requires or prolongs 
hospitalisation  
Results in persistent 
or significant 
disability/incapacity  
Congenital 
anomaly/birth defect 
Otherwise 
considered to be 
medically significant 
See Section 13.1.1. 
Date resolved 
 
The date on which the AE ceased to be present.  
Outcome 
Not recovered/not 
resolved 
The AE still persists. 
 
Recovered/resolved 
The AE is resolved. 
 
Recovered/resolved 
with sequelae 
The patient is stabilised, but with sequelae from 
this AE. 
 
Recovering/resolving 
The patient is recovering from this AE/this AE is 
resolving 
 
Fatal 
The patient died whilst this AE was ongoing or as a 
result of it. 
 
Unknown 
The outcome of this AE is not known. 
Has the 
patient ever 
experienced 
this AE 
before? 
Yes/No 
A query confirming whether the patient has a 
previous medical history of the AE at any time 
before entering into the study. If the patient has 
experienced this AE before, brief details should be 
given under additional information. 
Additional 
information 
 
Additional information regarding the AE. 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 54 of 76 
 
13.1.4 
Procedure for Reporting Adverse Events 
All AEs that arise after the patient has had IMP administered will be recorded in the patient’s 
CRF. AEs can be reported spontaneously by the patient or in response to non-leading 
questioning or observation by the Investigator, or be a significant laboratory abnormality. 
The Investigator will ask the patient: “Are you experiencing any symptoms or complaints?” at 
the baseline visit and “Have you had any symptoms or complaints since the last visit?” 
during the study.  
Assessments of the relationship of AEs to IMP must be made by the Investigator (if 
medically qualified) or by a medically qualified Co-Investigator. 
 
13.1.5 
Procedure for Reporting Serious Adverse Events 
In the event of a Serious Adverse Event (SAE), the Investigator should telephone the Clinical 
Project Manager (CPM) within 24 hours of knowledge of the event. The name and contact 
number of the CPM will be provided to the Investigator in the study protocol and/or at the 
Study Initiation Visit. To allow timelines to be met the Investigator can report the event to the 
Global Vigilance Group (GVG) simultaneously by contacting GVG by email: 
 
The CPM will also forward any SAE information/forms to the RB Global Vigilance Group 
within the same day using the email address: 
  
Out of hours emergency contacts will be provided to the Investigator in the study protocol 
and/or at the Study Initiation Visit. If notification is via telephone the CPM will ensure that a 
SAE Form is completed but the Investigator will be requested to make a detailed written 
report by sending a follow-up SAE Form as soon as possible. The CPM will be responsible 
for reporting the event to the Global Vigilance Group (
. All the SAE forms will 
be provided to the CPM function via email, and a copy filed in the TMF. Any inconsistencies 
in the information received from the Investigator will be clarified using the Adverse Event 
Data Clarification Form.  
If the case does require reporting, a CIOMS (Council for International Organizations of 
Medical Sciences) form will be produced. A copy of this will be sent to the RB Drug Safety 
Officer (DSO) in China who will complete the SFDA SAE Form in Chinese and submit to the 
SFDA within 7 days for fatal or life-threatening events, or 15 days for all events. 
If the event requires expedited reporting (event classified as a SAE): 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 55 of 76 
1. The IEC/IRB, SFDA and PFDA will be notified by the Investigator within 24 hours of 
awareness 
2. All other investigators participating in the study will be informed by the CPM 
The Investigator will be instructed to retain a copy of all the SAE Forms in the Investigator 
Site File, and must inform his/her local ethics committee/institutional review board of all 
SAEs occurring in the study. 
The Investigator should not break the randomisation code except when it is necessary to do 
so in order to ensure the patient receives appropriate medical care (see Section 12.2). 
The overall procedure for reporting SAEs is illustrated in the flowchart below. 
 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 56 of 76 
Figure 13-1 Procedure for Reporting SAEs 
 
 
13.1.6 
Reporting to Regulatory Authorities 
SAEs and non-serious AEs will be reported to the appropriate regulatory authorities by RB, 
in accordance with the authorities’ requirements. 
 
 
GVG database event  
SAE
 
Not SAE
Fatal or life 
threatening 
Not Fatal or life 
threatening 
Request to CPM for 
additional information if 
required
SAE Form signed 
copy filed in the 
TMF
No further action 
details kept on record. 
Listing of drug related 
SAEs to CA and EC as 
part of annual safety 
report  
Expedited Reporting within 7 
days of knowledge of the event
 
and follow-up information 
within an additional 8 days 
Expedited Reporting within 15 
days of knowledge of the event
Investigator informs EC, SFDA, PFDA, CPM
& GVG  within 24 hours 
Additional/follow up 
information 
AE Identified 
Investigator records 
AE in patient CRF 
Is the event serious? 
No  
Final AE listings 
to 
 
 
GVG
Yes 
 
SAE form filed in Site File 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 57 of 76 
13.1.7 
Follow-up of Patients Experiencing Adverse Events upon 
Completion of the Study or Withdrawal from the Study 
All SAEs, and all AEs that cause premature withdrawal of the patient from the study, that 
have not resolved by the end of the study will be followed up by the Investigator until 
resolution or until the Investigator believes there will be no further change. This may involve 
the patient making additional visits to the site. 
All other AEs will be followed up where possible to resolution or until the Investigator 
believes there will be no further change, whichever is the earlier.  
The minimum data required are the final outcome and date, which may be obtained by the 
Investigator in a documented telephone conversation with the patient or patient’s medical 
practitioner. 
 
13.1.8 
Procedures for Patients Experiencing Onset of Adverse Events 
after End of the Study 
As the active study drug in this study is not absorbed, a serious adverse event that occurs 
within a day of the final dose of study medication should be reported and followed to 
resolution or until the Investigator believes there will be no further change (refer to Adverse 
Event Reporting section 13.1.4 for further details). 
 
13.2 
Overdose 
In the event of an overdose of the trial medication, symptomatic treatment should be given. 
The patient may notice abdominal distension.  
 
Overdoses are reportable to RB irrespective of the presence of an associated AE/SAE. The 
overdose and any associated AE/SAE will be captured on an AE CRF page/SAE form. 
 
13.3 
Pregnancy 
If a patient is found to be pregnant after being dosed with IMP: 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 58 of 76 
• 
Promptly notify RB (i.e. Clinical Project Manager) or CRO monitor (if CRO is 
Investigator’s first port of call for reporting SAEs).  
• 
Withdraw the patient from the study. 
• 
Perform study completion assessments. 
• 
Collect details of due date, etc.  
Pregnancy follow-up will be conducted by RB GVG personnel as part of their drug safety 
monitoring responsibilities and will not form part of the study dataset.  
Pregnancy should be reported to RB as an AE. 
 
13.4 
Clinical Laboratory Investigations 
All blood samples will be collected and prepared according to the standard procedures of the 
hospital laboratory conducting the analyses at each of the study sites. Laboratory safety 
parameters will be analysed using standard validated methods. 
The following investigations will be made: 
Haematology 
• 
Haemoglobin 
• 
Red blood cells 
• 
Mean cell haemoglobin concentration 
• 
White blood cells 
• 
Platelet count 
 
Biochemistry 
• 
Electrolytes: sodium, potassium, calcium 
• 
Urea 
• 
Creatinine 
• 
Uric acid 
• 
Glucose 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 59 of 76 
• 
Inorganic phosphorous 
• 
Alanine transaminase 
• 
Aspartate transaminase 
 
Pregnancy testing  
• 
Women of child-bearing potential will undergo urine pregnancy testing (positive or 
negative). 
The total volume of blood expected to be sampled for clinical laboratory safety investigations 
from an individual patient in the course of the study is not expected to exceed 30 ml. 
 
13.4.1 
Collection of Laboratory Samples 
Blood samples will be collected and labelled in tubes provided by the local laboratory.  
Urine samples will be collected mid-stream. 
 
13.4.2 
Labelling of Laboratory Samples 
The site’s standard labels will be used. 
 
13.4.3 
Reference Ranges 
Up-to-date reference ranges for the above investigations must be obtained for each site 
performing analyses prior to the start of the study and be updated as appropriate during the 
course of the study. 
 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 60 of 76 
13.4.4 
Laboratory Results Review 
The Investigator will review the results and comment, on the laboratory results sheet, upon 
all abnormal values, identifying those that are clinically significantly abnormal. The 
Investigator will sign and date the laboratory results sheet, to indicate that the review has 
taken place. 
A copy of these results will be provided to the 
 monitor. 
 
13.4.5 
Good Clinical Laboratory Practice (GCLP) Compliance 
Confirmation of compliance with GCLP will be required from the laboratories involved prior to 
the start of the study. 
The laboratories will be requested to provide documented evidence of GCLP compliance. 
This may be a statement of compliance issued by the appropriate national authority, or 
details of accreditation by a recognised organisation. 
An independent inspection of the laboratories by 
 or RB may be conducted. 
 
13.5 
Vital Signs, Physical Findings and other Observations Related to 
Safety 
Vital signs and physical examinations will be conducted at screening and final or early 
termination visits. A 12-lead ECG and endoscopy will be conducted and the results will be 
reviewed by the investigator at screening as part of the screening procedures. Patients will 
be asked about adverse events at follow-up visits. 
 
14 
STATISTICAL CONSIDERATIONS 
The statistical analysis will be undertaken in collaboration with Quintiles. 
A detailed Statistical Analysis Plan will be finalised before the code for all patients is broken 
and prior to analysis of the study being carried out.  
Any deviations from the analyses described below will be included in the Statistical Analysis 
Plan, which will form Appendix 16.1.9 of the clinical study report. 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 61 of 76 
14.1 
Sample Size Justification 
In a previous pilot study conducted in the UK (GA1203), a least square mean difference 
(Gaviscon – Placebo) of -0.61 was obtained from the ANCOVA model comparing the change 
in the GERD dimension score from the RDQ after 1 week. The root mean squared error 
(RMSE) from the ANCOVA model, which included treatment as a fixed effect and the day 0 
RDQ GERD dimension score as a covariate, was 0.9735. 
In the same study, a least square mean difference (Gaviscon – Placebo) of -0.43 was 
obtained from the ANCOVA model comparing the change in the Dyspepsia dimension score 
from the RDQ after 1 week. The root mean squared error (RMSE) from the ANCOVA model, 
which included treatment as a fixed effect and the day 0 RDQ Dyspepsia dimension score as 
a covariate, was 1.121. 
For the purposes of sample size estimation using the module for a two-group t-test between 
equal means in NQuery Advisor 7.0, the least square means difference and RMSE from 
GA1203 will be used to estimate the effect sizes. The effect sizes using these results would 
be estimated as 0.627 for the GERD dimension and 0.384 for the Dyspepsia dimension. 
In other previous studies, different endpoints to the RDQ were used to demonstrate the 
efficacy of Gaviscon Original Liquid compared to Placebo Liquid. The percentage of patients 
that rated a positive improvement in symptoms were reported. In a study conducted in the 
UK (0900901), 74% of Gaviscon Original patients had a positive improvement of symptoms 
compared to only 44% of Placebo patients. When a similar study was conducted in China 
(GA0917), the corresponding results were 77% for Gaviscon Original and 67% for Placebo, 
thus suggesting an increased Placebo effect in the Chinese population compared to the UK 
population. 
Assuming a reduced effect size of 0.2 for the Dyspepsia dimension, this would require a total 
of 1054 patients with evaluable dyspepsia data from the RDQ to have 90% power to show a 
statistical significant difference at the 5% level using a two-group t-test. The actual analysis 
method to be used would be an ANCOVA model with treatment as a fixed effect, centre as a 
random effect and the day 0 RDQ Dyspepsia dimension score as a covariate.  
If an effect size of 0.4 is assumed for the GERD dimension, a sample size of 1054 patients 
would give more than 99% power to show a statistical significant difference at the 5% level 
using a two-group t-test. The actual analysis method to be used would be an ANCOVA 
model with treatment as a fixed effect, centre as a random effect and the day 0 RDQ GERD 
dimension score as a covariate.  


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 62 of 76 
To allow for 5% drop outs, 1100 patients will be randomised to ensure that 1054 patients 
have evaluable data for the Dyspepsia dimension score. 
 
14.2 
Data to be Analysed 
The following defined populations will be used for the analysis of the study data. 
All patient population: includes all patients recruited into the study. Data presentation will 
comprise information on patient disposition, withdrawals and protocol deviations as well as 
baseline data. 
Safety population:  includes those recruited into the study and receive at least one dose of 
the study medication. Summaries and analyses for all safety endpoints will be conducted on 
this population. 
Intent to treat (ITT) population: includes those recruited into the study and have at least 
partially completed RDQ questionnaire for the trial therapy period or are known to have 
withdrawn from the study due to poor efficacy. Summaries and analyses for all primary and 
secondary endpoints will be conducted on this population. 
Per protocol (PP) population: includes all patients from the ITT population who have 
adequate compliance with the treatment during the study (defined as > 75% study 
medication used from return tablet count) and no major protocol deviations. This PP 
population will be defined based upon a review of blinded data prior to database lock. All 
summaries and analyses for all primary and secondary endpoints will be additionally 
conducted using this population to support the corresponding ITT results. 
If there is a discrepancy in patient numbers between the all patient population and any other 
population, then baseline data will be summarised additionally for that population and for 
those patients that are excluded from that population. 
 
14.3 
Patient Disposition and Characteristics 
Descriptive summary statistics will be provided for demographic characteristics for each 
treatment group and all patients. For continuous parameters, mean, standard deviation, 
median, minimum, and maximum will be provided. For categorical parameters, the cell 
frequencies and percentage of patients in each demographic category will be provided. 
 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 63 of 76 
14.4 
Efficacy Analyses 
Efficacy data will be recorded from the RDQ questionnaire and the patient overall treatment 
evaluation (OTE). 
All efficacy data will be listed in the appendices of the study report and summarised for the 
ITT and PP populations by treatment group (n as the number of observations, mean, 
median, SD, minimum and maximum). Categorical variables will be summarised by 
treatment group using frequency distributions (showing cell frequencies and percentages). 
For those patients that do not return for Visit 3 because of confirmed poor efficacy from the 
treatment between Day 1 and Day 6, all efficacy data at Visit 3 will be imputed as no change 
from the day 0 values (BOCF). All other withdrawn patients that do not have the reason of 
withdrawal confirmed as poor efficacy and do not complete the Visit 3 assessments will be 
treated as missing. If the number of such patients is high, a sensitivity analysis will be 
conducted to assess the robustness of this imputation and the effect on results. 
 
14.4.1 
Primary Efficacy Analysis Endpoint 
The primary study endpoints are to compare the change from day 0 in RDQ symptom scores 
for the GERD dimension (heartburn and regurgitation) after a 7-day treatment period of a 
regimen of two Compound Sodium Alginate Double Action Chewable Tablets taken four 
times daily compared with a matched placebo. 
 
14.4.2 
Secondary Efficacy Endpoints 
The key secondary endpoint will compare between the two cohorts (Compound Sodium 
Alginate Double Action Chewable Tablets and placebo) for a 7-days treatment period for the 
following parameter: 
• 
Change from day 0 in RDQ scores for dyspepsia dimension 
Other secondary endpoints will compare between the two cohorts (Compound Sodium 
Alginate Double Action Chewable Tablets and placebo) for a 7-days treatment period for the 
following parameters: 
• 
OTE as a measure for patient’s responsiveness/satisfaction 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 64 of 76 
• 
Change from day 0 in RDQ scores for heartburn dimension. 
• 
Change from day 0 in RDQ scores for regurgitation dimension. 
 
14.4.3 
Statistical Methods for Efficacy Analyses 
All statistical tests performed will be 2-tailed with significance assessed at the 5% 
significance level. The null hypothesis at all times will be the equality of the treatments being 
compared. 
Normality assumptions will be evaluated by an examination of the residual plots. Depending 
on the degree of departure from these assumptions, an alternate nonparametric approach 
may be used for supportive purposes. 
The primary endpoint (change in RDQ GERD dimension score) will be analysed using an 
analysis of covariance (ANCOVA) model with a fixed effect term for treatment, centre as a 
random effect and the day 0 RDQ GERD dimension score as a covariate. Treatment group 
differences will be estimated using the least square means and presented with 95% 
confidence intervals and p-values to make inferences. 
The change in symptom score for each dimension seperately will be analysed identically to 
the primary endpoint although the included covariate will be the relevant dimension day 0 
score rather than the GERD dimension score. 
To preserve the type 1 error rate of 5% for the key secondary endpoint (change from day 0 
in RDQ scores for dyspepsia dimension), a closed testing procedure will be applied. A 
significant comparison at the 5% level (p<0.05) for this key secondary endpoint will only be 
deemed as confirmatory evidence if the primary endpoint is also significant at the 5% 
significance level (p<0.05). All other secondary endpoints and/or any further sensitivity or 
alternate analyses for the primary and key secondary endpoint will serve as supportive 
evidence only and therefore no further adjustment for multiple comparisons will be made. 
For the primary and key secondary endpoint, two additional separate exploratory ANOVA 
models will be conducted identical to those stated above but with one additional interaction 
term for the treatment by centre interaction (random effect) and treatment by baseline 
covariate interaction respectively. 
The change scores in frequency and intensity for each dimension as well as the two OTE 
responses will be compared between treatments using a Wilcoxon Rank Sum Test stratified 
by centre. 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 65 of 76 
 
14.5 
Safety Analyses 
14.5.1 
Adverse Events 
All AEs will be coded using the most up-to-date version of MedDRA. For an individual 
patient, AEs that began prior to the first dose of IMP or more than one day after the final 
dose of IMP will not be included in the analysis.  
The incidence of AEs (number and percent of patients reporting each type of AE at least 
once during the study) will be summarised for all AEs, by investigator attribution of 
relationship to IMP and by severity. The incidence of AEs will be compared among 
(between) treatment groups using Fisher’s Exact Test for all AEs, for those AEs classified by 
the Investigator as possibly or probably related to IMP and for severe AEs. 
  
14.5.2 
Laboratory Data 
For the purpose of analysing laboratory data, “baseline” is defined as the baseline 
assessments at Visit 1, screening and “last visit” is defined as the final visit, Visit 3 or the 
Early Termination Visit. 
Each pre-study baseline laboratory value will be categorised as low, normal, or high based 
on the reference range. Each post-baseline value will be classified in a similar manner, 
producing a 3 x 3 table for each treatment group at each post-baseline visit. Scores of “1” 
will be assigned to low values, “2” to normal values, and “3” to high values. Using these 
scores, shifts from baseline will also be assigned a score. For example, a laboratory value 
that shifts from low to high will be assigned a score of 2, whilst a laboratory value that 
remains at a low value will be assigned a score of 0. Shifts between these categories 
between baseline and subsequent timepoints will be compared using the Wilcoxon Signed-
Rank test within each treatment group. Statistical testing will be performed at last visit. 
At each visit, summary statistics for the absolute laboratory value and the changes from 
baseline will be presented by treatment group. The significance of within-treatment changes 
from baseline will be assessed using the Wilcoxon Signed-Rank Test. The significance of 
between treatment changes from baseline will be assessed using the Wilcoxon Rank-Sum 
Test. Statistical testing will be performed at last visit. 
Scatter plots of end of treatment values versus baseline values will be provided for all 
laboratory tests. 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 66 of 76 
 
14.5.3 
Vital Signs 
At each visit, summary statistics for the absolute vital sign value and the changes from 
baseline will be presented by treatment group. The significance of within-treatment changes 
from baseline will be assessed at the last visit, using the Wilcoxon Signed-Rank Test. The 
significance of between treatment changes from baseline will be assessed at the last visit 
using the Wilcoxon Rank-Sum. 
14.5.4 
Other Variables Related to Safety 
No further variables related to safety will be analysed. 
 
14.6 
Interim Analyses 
No interim analysis is planned for this study. 
 
15 
QUALITY CONTROL AND QUALITY ASSURANCE AUDIT 
15.1 
Monitoring 
The study will be monitored by site visits and meetings with the Investigator and co-
workers(s) at intervals agreed with the Investigator. The anticipated monitoring frequency will 
be stated in the Monitoring Plan. Monitoring will also involve, as appropriate, 
correspondence and telephone contacts. 
The Investigator, or a designated member of the Investigator’s staff, must be available at 
some time during the monitoring visit to review the data and resolve any queries and to allow 
direct access to the patient’s records for source data verification. 
At a site visit the CRFs forms should be made available in order that the accuracy of their 
completion may be checked. Each completed set of CRFs for each visit must be signed and 
dated by the Investigator, or a designated member of the Investigator’s medical staff, to 
verify the data and statements submitted. Similarly all alterations must be initialled and dated 
by the Investigator or a designated person, explained as necessary, with the original mistake 
left legible. 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 67 of 76 
 
15.2 
Source Document Verification 
On-site monitoring will also include source document verification (SDV). SDV is the 
procedure whereby the data contained in the CRFs are compared with the primary source 
data (e.g. patient notes, original recordings from automated instruments, X-ray films, ECG 
tracings, laboratory results) contained in the patient records held at the investigational site, 
and thereby verified as accurate. 
The Investigator must be aware that: 
• 
SDV is a part of the normal monitoring process. It will be carried out by designated study 
personnel and will be done in such a way as to preserve patient confidentiality, taking 
into account all ethical and legislative requirements. 
• 
SDV will be carried out by direct comparison of entries made in the CRF with appropriate 
source data. Direct access to source data requires that the patient gives written, 
documented consent to this.  
• 
Where source data are in the form of a computer print-out (e.g. medical records, ECG 
tracings) they will be made available by the Investigator to the monitor. Each will be 
signed and dated by the Investigator or a designated person, confirming that the print-out 
is a true and faithful record of the data for that patient. These print-outs will be filed in the 
CRF. 
• 
The 
 Clinical Project Manager/Study Monitor will write an SDV Plan, specifying 
which data require SDV and what constitutes source data. This plan will also include the 
identification of any data to be recorded directly on the CRF and therefore considered 
source data. The SDV Plan will be agreed with the Investigator and documented in the 
Initiation Visit Report.  For all patients, patient identity (date of birth, sex, initials and 
patient number), record of entry into the study and signature of informed consent must 
be verified from source documents as a minimum. In addition the following will be 
verified: 
o Endoscopy results 
o Details of SAEs. 
It is important that the patient’s notes record important details about their participation in the 
study. The Investigator or designated person will agree, as a minimum requirement, to 
record the following information in the patient’s notes: 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 68 of 76 
• 
Study number, brief description or title of study. 
• 
Date that the patient gave written consent. 
• 
All visit dates. 
• 
All SAEs. 
• 
All concomitant medications. 
 
15.3 
Audit 
In accordance with the standards defined in ICH GCP, clinical studies sponsored by RB may 
be subject to an independent audit at the study site which will be conducted by personnel 
from an appropriate Quality Assurance Unit. Full consultation with the Investigator will be 
made prior to and during such audit, which will be conducted according to Quality Assurance 
Unit Standard Operating Procedures. 
 
15.4 
RB Policy on Fraud in Clinical Studies 
In accordance with GCP, it is RB’s policy always to follow up suspected cases of fraud. 
 
16 
ETHICS 
16.1 
Independent Ethics Committee/Institutional Review Board Review 
Written approval of the study by an independent and appropriately constituted IEC/IRB must 
be obtained and a copy provided to RB before any protocol-related procedures that do not 
form part of the patient’s normal clinical treatment are performed. 
The approval letter must contain: 
• 
Name and address of the IEC/IRB. 
• 
Date of meeting. 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 69 of 76 
• 
Sufficient information to identify the version of both the protocol and patient 
information/informed consent. 
• 
Sufficient information to identify the version of other documents reviewed. 
 
The investigator must also provide RB with a list of IEC/IRB members that includes each 
member’s name, sex, and institutional affiliation. 
The Investigator must submit all protocol amendments to the IEC/IRB for approval and notify 
them of any administrative changes. 
 
16.2 
Patient Information and Consent 
Prior to entering the study, the Investigator or designated assistant will explain to each 
patient or legally acceptable representative, the nature of the study, its purpose, procedures, 
expected duration, alternative therapy available, and the benefits and risks involved in study 
participation. Patients will be given information and consent documents and the opportunity 
to ask questions. They will be informed of their right to withdraw from the study at any time 
without prejudice. After this explanation and before any study-specific procedures have been 
performed, the patient, or legally acceptable representative, will voluntarily sign and date the 
informed consent form. The person conducting the informed consent discussion and 
providing the information to the patient will also sign and date the consent form. Prior to 
participation in the study, the patient will receive copies of the written information and their 
signed and dated consent document, plus any other written information provided to them. 
 
16.3 
Informing General Practitioners 
Not applicable. 
 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 70 of 76 
17 
REGULATORY REQUIREMENTS 
17.1 
Competent Authority Authorisation 
This study proposal was submitted to the SFDA and approved on 4 June 2010.   The 
approval number is 2010L02452. 
17.2 
Curriculum Vitae 
A current curriculum vitae (CV) will be obtained from all personnel with significant study 
responsibilities, i.e. the Investigator and those to whom he or she has delegated some of 
his/her responsibilities as well as those whose names appear on the signature and 
delegation of duties forms (see below).  
The CV will contain as a minimum the following information: name, current work address, 
qualifications, current position and previous positions. It will be signed and dated within 2 
years of the start of the study. The CVs will be maintained on file by RB. 
The Investigator and individuals to whom the Investigator has delegated some of his or her 
responsibilities as an investigator will be asked to provide sample signatures. The duties 
delegated to them will also be recorded on the signature and delegation of duties forms. 
 
18 
DATA HANDLING AND RECORD KEEPING 
18.1 
Case Report Forms (CRFs) 
Electronic CRFs (eCRFs) will be used in this study. The Investigator is responsible for the 
quality of the data recorded in the eCRF. The data recorded should be a complete and 
accurate account of the patient’s record collected during the study. The Investigator and 
study monitor will identify any data that will be recorded directly into the eCRF such that the 
eCRF will be considered the source document (i.e. no prior written or electronic record of the 
data). The study monitor will document this on the Initiation Visit Report. 
The Investigator and other staff who have been delegated responsibility for entering data 
into the CRF at each visit will be trained in the use of the eCRFs before the first patient at 
that site is enrolled. The Investigator must review all entries for completeness and 
correctness. Data management will be conducted by Quintiles. The eCRF system will keep 
an audit trail of all changes made after the eCRF pages are initially completed and 
submitted. 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 71 of 76 
The Investigator agrees to complete and sign the eCRFs in a timely fashion after completion 
of each patient and make them available to the study monitor for full inspection. In addition, 
any data queries prepared after the original eCRF has been completed should be answered 
promptly. Following monitoring of each patient’s eCRF, the investigator will electronically 
sign the eCRF. Re-signature by the Investigator may be required prior to database lock after 
resolution of interim data queries. 
Before acceptance, the study monitor will review the eCRFs for completeness and 
adherence to the protocol..Following completion of the study, the Investigator will no longer 
be able to access the eCRFs.  They will therefore be provided with a CD with all of the 
eCRFs from their site by the data management group. 
 
18.2 
Retention of Essential Documentation 
The Investigator should retain all essential documents (as defined in ICH E6 or according to 
other national and international regulations) until at least 5 years after the completion of the 
study. These documents should be retained for a longer period, however, if required by the 
applicable regulatory requirements or by an agreement with RB. It is the responsibility of RB 
to inform the Investigator when these documents no longer need to be retained. 
Patient files and other source data must be kept for the maximum period of time permitted by 
the hospital, institution or private practice. The Investigator must notify RB if his/her 
institution’s policy is to retain documents for a shorter period of time. 
 
18.3 
Protocol Amendments 
The investigator must abide by the agreed protocol as approved by the IEC/IRB. 
No change will be made to the agreed protocol without the prior written approval of the 
Investigator, the Clinical Project Manager, the R&D Manager Clinical (Healthcare) and the 
Global Medical Director, except in circumstances where the immediate safety of the patient 
is at risk. Written approval will also be obtained from other functions if appropriate, for 
example the Statistician if the amendment relates to a change in endpoints. 
All substantial protocol amendments require IEC/IRB and regulatory approval. Protocol 
amendments will be submitted to the same IEC/IRB and regulatory authority as the study 
protocol. 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 72 of 76 
 
19 
CLINICAL TRIAL AGREEMENT 
Before the study commences, a Clinical Trial Agreement be will signed in which financial 
aspects of the study (including financial disclosure) as well as responsibilities and obligations 
are described. This will take the form of: 
• 
A contract between 
 and the Investigator/healthcare organisation. 
 
20 
COMPENSATION, INDEMNITY AND INSURANCE 
20.1 
Compensation 
Appropriate treatment and/or compensation will only be provided and/or paid to the patient 
by the Sponsor to the extent that a patient suffers injury or death directly attributable to 
participation in the study without: 
• 
Fault on the part of the investigator or the CRO or its employees or agents. 
• 
The investigator or the CRO failing to comply with the protocol. 
• 
The investigator or the CRO failing to notify the Sponsor of the claim or denying the 
Sponsor full conduct of the claim.  
In any event, such compensation and treatment shall only be provided by the Sponsor to the 
extent required by the applicable law. 
 
20.2 
Indemnity 
RB will provide appropriate indemnity for the Investigator and staff who conduct part or all of 
this study, upon request. The request must be received before the first patient is recruited. 
 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 73 of 76 
20.3 
Insurance 
If required, and in accordance with applicable regulatory and legal requirements, RB will take 
out appropriate insurance policies on behalf of the Investigator and staff who conduct part or 
all of this study, and/or on behalf of the patients participating in the study. 
 
21 
REPORTING, PUBLICATION AND PRESENTATION 
A clinical study report will be prepared according to ICH E3 (Structure and Content of 
Clinical Study Reports) as part of RB’s commitment to Good Clinical Practice. The report will 
be a record of the total study conduct and findings, and will be subject to approval by the Co-
ordinating Investigator who will sign the final report. 
The study data will be owned by RB. RB retains the right to publish the data independently 
of the Investigator. RB agrees that before it publishes the results, it will provide the 
Investigator with at least 30 days for full review prior to submission of the manuscript to the 
publisher. The Investigator must submit any proposed manuscript to RB for approval prior to 
submission for publication. 
Any publication must state that it is a part of a multicentre study. Where it would be 
impractical to send the manuscript to every Investigator in a multicentre study, a copy will be 
sent to the Co-ordinating Investigator. In such a study, RB may wish to publish the results of 
the study and this may be done without all participants having the opportunity to review the 
manuscript. 
 
22 
REFERENCES 
1. Vakil N, Veldhuyzen van Zanten S, Kahrilas P, Dent J, Jones R. The Montreal definition 
and classification of gastro-esophageal reflux disease (GERD)- a global evidence-based 
concensus. Am J Gastrolenterol 2006, 101: 1900-1920.  
2. Armstrong D. Systematic review: persistence and severity in gastroesophageal reflux 
disease. Aliment Pharmacol Ther 2008, 28: 841-853. 
3. Liker H, Hungin AP, Wiklund I. Management of reflux disease in primary care: the 
subject perspective. J Am Boar Fam Pract 2005, 18: 393-400. 
4. Wahqvist P, Reilly M, Barkun AN. Systematic review: the impact of gastro-oesophageal 
reflux disease on work productivity. Aliment Pharmacol Ther 2006, 24: 259-272. 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 74 of 76 
5. Dent J, El-Serag HB, Wallander MA, Johansson S. Epidemiology of gastro-oesophageal 
reflux disease: a systematic review. Gut 2005, 54: 710-717. 
6. Kahrilas PJ, Howden CW, Hughes, N. Response of Regurgitation to Proton Pump 
Inhibitor Therapy in Clinical Trials of Gastroesophageal Reflux Disease. Am J 
Gastroenterol 2011, 106:1419–1425. 
7. Moayyedi P, Delaney BC, Vakil N, Forman D, Talley NJ. The efficary of proton pump 
inhibitors in nonulcer dyspepsia: A systematic review and economic analysis. 
Gastroenterology 2004, 127: 1329-1337. 
8. Fass R, Tougas G. Functional heartburn: The stimulus, the pain, and the brain. Gut 
2002, 51: 885-892. 
9. Shaw MJ, Talley NJ, Beeble TJ, Rockwood T, Carisson R, Addis S, Fendrick AM, Jones 
R, Dent J, Bytzer P.  Initial validation of a diagnostic questionnaire for gastroesophageal 
reflux disease. Am J Gastroenterol 2001, 96: 52-57.  
10. GA1203 study data on file. 
11. Jaeschke R, Singer J, Guyatt G: Measurement of health status. Ascertaining the minimal 
clinically important difference. Control Clin Trials 1989, 10:407-415. 
12. Juniper EF, Guyatt GH, Willan A, Griffith LE: Determining a minimal important change in 
a disease-specific quality of life questionnaire. J Clin Epidemiol 1994, 47:81-87. 
13. Lydick E, Epstein RS: Interpretation of quality of life changes. Qual Life Res 1993, 2:221-
226. 
14. Rubin G, Uebel P, Brimo-Hayek A, Hey KH, Doerfler H, Heading RC. Validation of a brief 
symptom questionnaire (ReQuest in Practice) for patients with gastro-oesophageal reflux 
disease. Aliment Pharmacol Ther 2008 May; 27 (9):846-51. Epub 2008 Feb 09. 
 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 75 of 76 
23 
APPENDICES 
23.1 
Appendix 1 English version Reflux Disease Questionnaire 
 


Investigational Study Protocol Template 
Study No: GA1210 
 
SOP D0365585, Version 4.0 
Protocol Version Final v 2.0, 28 February 
2013 
 
 
Study Sponsor: Reckitt Benckiser UK Ltd, Dansom Lane, HU8 7DS; Telephone No: +44 (0) 1482 326151; Fax 
No: +44 (0) 1482 582172 
Template vs_4.0, 23-Jan-2013                             Page 76 of 76 
23.2 
Appendix 2 Chinese Mandarin version Reflux Disease 
Questionnaire 
 

SAP_001.pdf: 
 
Study Title: A Multi-centre, Randomised, Double-blind, Two Arm, Parallel Group, 
Placebo-controlled Study to Assess the Effect of Compound Sodium Alginate Double Action 
Chewable Tablets in Patients with Gastro-esophageal Reflux Disease 
ClinicalTrials.gov ID: NCT01869491 
 
Final Statistical Analysis Plan, dated 29-Jul-2014 
Changes to Planned Statistical Analyses Form, dated 01-Sep-2014  


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STATISTICAL ANALYSIS PLAN: PROTOCOL GA1210 
STATISTICAL ANALYSIS PLAN 
GA1210 
A MULTI-CENTRE, RANDOMISED, DOUBLE-BLIND, TWO ARM, PARALLEL GROUP, 
PLACEBO-CONTROLLED STUDY TO ASSESS THE EFFECT OF COMPOUND SODIUM 
ALGINATE DOUBLE ACTION CHEWABLE TABLETS IN PATIENTS WITH GASTRO-
ESOPHAGEAL REFLUX DISEASE 
AUTHOR: 
VERSION NUMBER AND DATE: V2.0, 29JUL2014 


Q QUINTILES" 
II' Reck•tt 
Benckiser 
STATISTICAL ANALYSIS PLAN: PROTOCOL GA1210 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Statistical Analysis Plan Final V2.0 (Date 29Jul2014) for Protocol Version Final v 2.0 Amendment l, Dated 
04Jun2013 
Author: 
Position: 
Company: 
Name -
AD, Biostatistics 
Quintiles 
Upon review of this document, the undersigned approves this version of the Statistical Analysis Plan, authorizing 
that the content Is acceptable for the reporting of this study. 
Name 
Approved By: 
Position: 
Statistical Manager 
Company: 
Reckitt Benckiser Brands Limited 
Document: 
Reckitt Benckiser GA1210 Statistical Analysis Plan 
Author: 
-
Version Number: 
Version Date: 
Template No: CS_TP _0SO16- Revision 3 
Effective Date: O1May2O12 
2.0 
29Jul2O14 
Reference: CS_WI_BSOOS 
Page 2 of24 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL GA1210 
MODIFICATION HISTORY 
 
Unique 
Identifier 
for 
this Version 
Date of the 
Document 
Version 
Author 
Significant 
Changes 
from  
Previous Authorized Version 
0.1 
30Dec2013 
Not Applicable – First Version 
0.2 
08Apr2014 
Updated per sponsor’s comments 
1.0 
24Apr2014 
Updated per sponsor’s comments and 
version up.  
1.1 
12May2014 
Updated per new sensible findings. 
1.2 
18Jun2014 
Updated per Dry run 1’s comments and 
findings.  
1. Updated compliance section for clarity.  
2. Concomitant medications are to be 
presented by indication and ATC class in 
addition to by preferred term.  
3. Added subgroup analyses for GERD status 
and Endoscopy Findings.  
1.3 
23Jul2014 
Updated per Dry run 2’s comments and 
findings.  
1. Revised the definition of PP population.  
2. Updated time on treatment derivation to 
account for missing visit date.  
3. 
Further 
clarified 
on 
missing 
data 
imputation. 
4. Refined subgroup analysis to only include 
by GERD status. 
2.0 
29Jul2014 
 Version up to 2.0 for finalization 
 
 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL GA1210 
TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS .......................................................................................................... 7 
2. 
INTRODUCTION ............................................................................................................................ 7 
3. 
STUDY OBJECTIVES ..................................................................................................................... 8 
3.1. 
Primary Objective..................................................................................................................................... 8 
3.2. 
Secondary Objectives ............................................................................................................................... 8 
3.3. 
Safety Objectives ..................................................................................................................................... 8 
4. 
STUDY DESIGN .............................................................................................................................. 8 
4.1. 
General Description .................................................................................................................................. 8 
4.2. 
Schedule of Events ................................................................................................................................... 9 
5. 
FINAL ANALYSIS ........................................................................................................................... 9 
6. 
ANALYSIS SETS .............................................................................................................................. 9 
6.1. 
All Patient [AP] Population ....................................................................................................................... 9 
6.2. 
Safety Population [SAF] ............................................................................................................................ 9 
6.3. 
Intent-to-treat [ITT] Population .............................................................................................................. 10 
6.4. 
Per Protocol [PP] Population .................................................................................................................. 10 
7. 
GENERAL CONSIDERATIONS ................................................................................................. 10 
7.1. 
Reference Start Date and Study Day ....................................................................................................... 10 
7.2. 
Baseline ................................................................................................................................................. 10 
7.3. 
Retests, Unscheduled Visits and Early Termination Data ......................................................................... 11 
7.4. 
Statistical Tests ...................................................................................................................................... 11 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL GA1210 
7.5. 
Common Calculations ............................................................................................................................. 11 
7.6. 
Software Version .................................................................................................................................... 11 
8. 
STATISTICAL CONSIDERATIONS .......................................................................................... 11 
8.1. 
Multicenter Studies ................................................................................................................................ 11 
8.2. 
Missing data ........................................................................................................................................... 12 
8.3. 
Examination of Subgroups ...................................................................................................................... 12 
8.4. 
Multiple Comparisons/ Multiplicity ........................................................................................................ 12 
9. 
OUTPUT PRESENTATIONS ..................................................................................................... 12 
10. 
DISPOSITION AND WITHDRAWALS .................................................................................... 13 
11. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ...................................... 13 
12. 
MEDICAL HISTORY AND CONCOMITANT ILLNESS ......................................................... 14 
13. 
PRIOR AND CONCOMITANT MEDICATION AND THERAPIES ...................................... 14 
14. 
STUDY MEDICATION EXPOSURE & COMPLIANCE .......................................................... 14 
14.1. 
Derivations ......................................................................................................................................... 14 
15. 
EFFICACY OUTCOMES .............................................................................................................. 15 
15.1. 
Primary Efficacy .................................................................................................................................. 15 
15.1.1. 
Primary Efficacy Variable ..........................................................................................................................15 
15.1.2. 
Missing Data Methods for Primary Efficacy Variable ...............................................................................15 
15.1.3. 
Primary Analysis of Primary Efficacy Variable ..........................................................................................16 
15.1.4. 
Sensitivity Analysis of Primary Efficacy Variable .......................................................................................16 
15.1.5. 
Exploratory Analysis of Primary Efficacy Variable ....................................................................................16 
15.1.6. 
Subgroup Analysis of Primary Efficacy Variable .......................................................................................16 
15.2. 
Secondary Efficacy .............................................................................................................................. 16 
15.2.1 
Secondary Efficacy Variables ....................................................................................................................16 
15.2.2 
Missing Data Methods for Secondary Efficacy Variables ..........................................................................17 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL GA1210 
15.2.3 
Analyses of Secondary Efficacy Variables .................................................................................................17 
15.2.4 
Sensitivity Analyses of Secondary Efficacy Variables ................................................................................18 
15.2.5 
Subgroup Analyses of Key Secondary Efficacy Variables ..........................................................................18 
16 
SAFETY OUTCOMES .................................................................................................................. 18 
16.1 
Adverse Events ....................................................................................................................................... 18 
16.1.1 
Adverse Events .........................................................................................................................................19 
16.1.1.1 
Severity .............................................................................................................................................19 
16.1.1.2 
Relationship to Study Medication ....................................................................................................19 
16.1.2 
Adverse Events leading to Dose Change or Discontinuation of Study Medication ..................................19 
16.1.3 
Serious Adverse Events .............................................................................................................................20 
16.1.4 
Adverse Events Leading to Death .............................................................................................................20 
16.2 
Death ..................................................................................................................................................... 20 
16.3 
Laboratory Evaluations ........................................................................................................................... 20 
16.4 
Vital Signs .............................................................................................................................................. 21 
16.5 
Physical Examination .............................................................................................................................. 21 
17 
REFERENCE ................................................................................................................................. 21 
APPENDIX 1 LIST OF LABORATORY ASSESSMENTS ................................................................. 22 
APPENDIX 2 REFLUX DISEASE QUESTIONNAIRE (RDQ) ......................................................... 23 
 
 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL GA1210 
1. LIST OF ABBREVIATIONS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis of efficacy and 
safety data for Protocol GA1210. It describes the data to be summarized and analyzed, including specifics of the 
statistical analyses to be performed.  
 
This statistical analysis plan (SAP) is based on clinical study protocol (CSP) version Final v 2.0 Amendment 1, 
dated 04Jun2013. 
Abbreviation 
Definition 
AE 
Adverse event 
ANOVA 
Analysis of Variance 
BLQ 
Below the lower limit of quantification
CI 
Confidence Interval 
CRF 
Case report form 
CSP 
Clinical Study Protocol 
FAS 
Full analysis set 
GERD 
Gastro-esophageal reflux disease
IMP 
Investigational medicinal product
ITT 
Intention-to-Treat  
MedDRA 
Medical Dictionary for Regulatory Activities
NIMP 
Non-investigational medicinal product
OTE 
Overall treatment evaluation
PP 
Per protocol 
PT 
Preferred term 
RDQ 
Reflux Disease Questionnaire
SAE 
Serious adverse event 
SOC 
System organ class 
SAP 
Statistical analysis plan
SI 
International System 
ULQ 
Upper limit of quantification
WHO 
World Health Organization


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL GA1210 
3. STUDY OBJECTIVES 
3.1. PRIMARY OBJECTIVE 
The primary objective is to assess the efficacy of Compound Sodium Alginate Double Action Chewable Tablets 
compared with a matched placebo in reduction of the symptoms of Gastro-esophageal reflux disease (GERD) in 
patients with GERD as assessed using the Reflux Disease Questionnaire (RDQ). 
3.2. SECONDARY OBJECTIVES 
The secondary objectives of this study are to assess the efficacy of Compound Sodium Alginate Double Action 
Chewable Tablets compared with matching placebo in reduction of the symptoms of heartburn, acid regurgitation 
and dyspepsia in patients with GERD.   
 
Other secondary objectives include the efficacy of Compound Sodium Alginate Double Action Chewable Tablets 
compared with placebo in patient responsiveness / satisfaction and comparison of safety in terms of adverse 
events.  
3.3. SAFETY OBJECTIVES 
Safety will be assessed in terms of the overall proportion of patients with adverse events (AEs). 
 
 
4. STUDY DESIGN 
4.1. GENERAL DESCRIPTION 
This is a multi-centre, randomised, double blind, two-arm, placebo-controlled, parallel group study. After signing 
a written informed consent, patients will undergo a screening period of up to 7 days.  Patients who satisfy the 
study entry requirements within 7 days of consent, will be randomised to receive either Compound Sodium 
Alginate Double Action Chewable Tablets (2 tablets four times daily) or matching placebo tablets (2 tablets four 
times daily), for a 7-day treatment period. At the beginning and end of the treatment period, patients will be 
required to complete the RDQ. 
In addition, at the end of the 7-day treatment period, patients will be required to complete the overall treatment 
evaluation (OTE).  
The sample size calculation, based on the UK pilot study and a previous pivotal China study, shows that 1054 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL GA1210 
evaluable patients need to complete the study (with the aim of having approximately 527 patients in each 
treatment group). An evaluable patient is defined as a randomised patient who completes the study treatment 
period and attends the end of treatment visit. In order to achieve this, it is estimated that approximately 1222 
patients will have to be screened and approximately 1100 patients will have to be randomized.  
Patients can enter the study, if eligible, following informed consent at Visit 1. A maximum of 7 days will be 
allowed to screen a patient at Visit 1.  If eligible, the patient will be randomised and will commence the 7-day 
treatment period at Visit 2 (Day 0) to receive either Compound Sodium Alginate Double Action Chewable Tablets 
or matching placebo tablets.  Visit 3, the End of study visit, will occur on Day 8 (between Day 7 and Day 10). 
4.2. SCHEDULE OF EVENTS 
Schedule of assessments can be found in Section 3.10 of the protocol.  
 
 
5. 
FINAL ANALYSIS  
All final, planned analyses identified in this SAP will be performed by Quintiles Biostatistics following Reckitt 
Benckiser’s Authorization of this SAP, Database Lock and Sponsor Authorization of Analysis Sets. 
 
6. ANALYSIS SETS 
Agreement and authorization of patients included/excluded from each analysis set was conducted at a blind data 
review meeting on 23rd July 2014, prior to database lock.  
6.1. ALL PATIENT [AP] POPULATION 
All patients recruited (e.g. those with eligibility confirmed at screening visit and assigned randomization number) 
into the study will be included in the All Patient Population. 
6.2. SAFETY POPULATION [SAF] 
All patients who are recruited into the study and receive at least one dose of study medication will be included in 
safety population.   


 
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6.3. INTENT-TO-TREAT [ITT] POPULATION 
All patients who are recruited into the study and have at least partially completed RDQ questionnaire for the trial 
therapy period or are known to have withdrawn from the study due to poor efficacy will be included into intent-
to-treat (ITT) population. 
6.4. PER PROTOCOL [PP] POPULATION 
The inclusion/exclusion from per protocol (PP) population was confirmed during a blind data review meeting on 
23rd July 2014, and will include all patients from the ITT population who have no major protocol deviations or 
other circumstances that may be relevant to efficacy assessment during the study.  
A major protocol deviation that affects efficacy assessment is defined as any deviation of the protocol that is 
considered to affect the efficacy results and will include the following:  
• 
Patient did not satisfy an inclusive/exclusive criteria that was deemed to have potential to affect efficacy; 
• 
Patient took prohibited medication which would interfere with evaluation of drugs in the study period; 
• 
Patient had inadequate treatment compliance. Adequate compliance with the treatment is defined as ≥ 75% of 
study medication used from return tablet count.  
Additionally, a patient will be excluded from the PP population if they returned for Visit 3/Early termination visit 
outside the 7 – 10 day window and did not withdraw for lack of efficacy 
7. 
GENERAL CONSIDERATIONS 
7.1. REFERENCE START DATE AND STUDY DAY 
Study Day will be calculated from the reference start date, and will be used to show start/stop day of 
assessments and events.  
Reference start date (Day 0) is defined as the day of randomisation.  
• 
Study Day = (date of event – reference start date). 
In the situation where the event date is partial or missing, Study Day, and any corresponding durations will 
appear partial or missing in the listings. 
Randomization date will be considered as the same date of randomization visit, that is, visit 2.  
7.2. BASELINE 
Unless otherwise specified, baseline value refers to the tests or measurements recorded at Visit 1, screening 


 
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visit. If a particular test or measurement was repeated after Visit 1, screening visit, then the baseline value is 
defined as the last non-missing measurement taken prior to Visit 2, Day 0 (including unscheduled assessments). 
Baseline for RDQ scores are collected on Day 0.  In the case where the last non-missing measurement and the 
reference start date coincide, that measurement will be considered pre-baseline, but Adverse Events (AEs) and 
medications commencing on the reference start date will be considered post-baseline. 
7.3. RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION DATA 
In general, for by-visit summaries, data recorded at the nominal visit will be presented. Unscheduled 
measurements will not be included in by-visit summaries. In the case of a retest (same visit number assigned), 
the latest available measurement for that visit will be used for by-visit summaries.  
Early termination data will be mapped to the next available visit number, i.e., Visit 3, for by-visit summaries. 
Listings will include scheduled, unscheduled, retest and early discontinuation data. 
7.4. STATISTICAL TESTS 
The default significant level will be (5%); confidence intervals (CIs) will be 95% and all tests will be two-sided, 
unless otherwise specified in the description of the analyses. 
7.5. COMMON CALCULATIONS 
For quantitative measurements, change from baseline will be calculated as: 
 
• 
Test Value at Visit X – Baseline Value 
7.6. SOFTWARE VERSION 
All analyses will be conducted using SAS version 9.2 or higher.  
 
8. STATISTICAL CONSIDERATIONS 
8.1. MULTICENTER STUDIES 
This study will be conducted at multiple hospital sites.  Allocation to treatment arms is stratified by centre. 
Centre pooling will be carried out across all centres for use in statistical summaries for this study.  Centre will be 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL GA1210 
included in the statistical models to adjust for centre effect.  Treatment by centre interaction may also be 
explored using additional analyses.  Refer to Section 15 for more details.  
8.2. MISSING DATA 
Patients who withdraw from the study will not be replaced.  
Unless otherwise specified, all analysis will be based on the number of non-missing observations. If relevant for 
categorical tabulations, missing values will be treated as another category, so that all tabulations involving this 
variable will also include a row or column as appropriate to indicate the number of patients for whom the 
variable was recorded as a missing value.  
For AEs, partial or missing dates and times will not be imputed, and this will be listed as originally reported in the 
Case Report Form (CRF). 
8.3. EXAMINATION OF SUBGROUPS 
No subgroup analyses will be performed for this study. 
8.4. MULTIPLE COMPARISONS/ MULTIPLICITY 
To preserve the type 1 error rate of 5% for the key secondary endpoint (change from baseline in RDQ scores for 
dyspepsia dimension), a closed testing procedure will be applied. A significant comparison at the 5% level 
(p<0.05) for this key secondary endpoint will only be deemed as confirmatory evidence if the primary endpoint is 
also significant at the 5% significance level (p<0.05). All other secondary endpoints and/or any further sensitivity 
or exploratory analyses for the primary and key secondary endpoint will serve as supportive evidence only and 
therefore no further adjustment for multiple comparisons will be made.  
 
9. OUTPUT PRESENTATIONS 
The templates provided with this SAP describe the presentations for this study and therefore the format and 
content of the summary tables, figures and listings to be provided by Quintiles Biostatistics. 
Continuous variables will be summarized using descriptive statistics, i.e., number of subjects (n), mean, median, 
standard deviation, minimum and maximum.  
Qualitative variables will be summarized by counts and percentages. Unless otherwise stated, the calculation of 
proportions will be based on the sample size of the population of interest.  
 


 
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10. DISPOSITION AND WITHDRAWALS 
All subjects who provide informed consent will be accounted for in this study. The number of patients who 
provided informed consent, as well as those who were eligible will be summarized overall.   
The number of patients who completed the study, the number of patients who withdrew prematurely from the 
study, the reasons for withdrawals and the number of patients in the AP, Safety, ITT and PP population will be 
summarized for each treatment group and overall.   
Listings on patient completion/withdrawal information, as well as eligibility details will be reported.  
Major protocol deviation will be summarized by treatment group and overall. Furthermore the number of 
patients to be excluded from each population together with reasons of exclusion will be summarized.  Details on 
major protocol deviation as well as population classification information will be listed. 
 
11. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data and other baseline characteristics will be summarized by treatment group and overall for all 
patients in AP.  If there is a discrepancy in patient numbers between the AP and any other population, then 
baseline data will be summarised additionally for that population. 
The following demographic and other baseline characteristics will be reported for this study:  
• 
Age (years) –relative to date of consent  
• 
Race 
• 
Sex 
• 
Height (cm) 
• 
Weight (kg) 
• 
Body mass index (BMI) (kg/m2) 
• 
Smoking status – Yes, No, Former smoker 
• 
Smoking years and amount (cigarettes per day) 
• 
Alcohol use – Yes, No  
• 
Drinking years and amount (gram per day) 
• 
Drug of abuse history – Yes, No 
 
Summary statistics will be presented for Investigator’s assessment of patients’ baseline GERD-related symptoms, 
including the severity of heartburn, regurgitation and dyspepsia.  
In addition, interpretation of the 12-lead ECG results and abnormalities present in a standard hospital endoscopy 
examination will be reported at baseline as part of the screening procedures.  
 


 
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12. MEDICAL HISTORY AND CONCOMITANT ILLNESS 
Medical History conditions are defined as those conditions which stopped prior to or at screening visit. Medical 
history information will be coded using version 17.0 of Medical Dictionary for Regulatory Activities (MedDRA) 
and presented for all patients in safety population by system organ class (SOC) and preferred term (PT), by 
treatment group and overall.  
Concomitant illnesses are conditions other than GERD which are ongoing before or on the day of last dose of 
study drug, or stopped after screening visit but before or on the day of last dose of study drug. Concomitant 
illnesses will be captured from “Medical History and Current Status (excluding GERD)” form in eCRF, and will be 
coded using MedDRA version 17.0 and presented for all patients in safety population by SOC and PT, by 
treatment group and overall.  
 
13. PRIOR AND CONCOMITANT MEDICATION AND THERAPIES  
Medications will be coded using World Health Organization (WHO) Drug Dictionary Enhanced version dated 
01Mar2013 and tabulated by indication collected on the eCRF(AE, Medical History, GERD, Endoscopy Related, 
Other), Anatomical Therapeutic Chemical (ATC) class and Standardized Medication Name for the safety 
population (for prior and concomitant medications separately) 
• 
‘Prior’ medications are medications which started and stopped prior to first dose of study medication.  
• 
‘Concomitant’ medications are medications which:  
o 
started prior to, on or after first dose of study medication 
o 
AND ended on or after first dose of study medication or were ongoing at the end of the study. 
 
14. STUDY MEDICATION EXPOSURE & COMPLIANCE 
The extent of exposure and compliance with study treatment will be presented for the safety population.  
Patients will receive Compound Sodium Alginate Double Action Chewable Tablets (two tablets four times daily) 
or matching placebo tablets for a period of 7 days.    
14.1. DERIVATIONS  
The date of first treatment administration will be the day after “date of dispense” on the eCRF “Drug Dispense” 
at Visit 2. The date of last treatment administration will be the day before the date of Visit 3 or Early 
Termination; for patients who do not have a Visit 3 or Early Termination date, the drug return date on the eCRF 
“Drug Return” will be used.  Time on treatment in days will be derived from the following formula: 


 
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Time on treatment (days) = (date of Visit 3 or Early Termination or drug return date-1) – (date of dispense at 
Visit 2 +1) + 1 
 
Compliance with study treatment is based on the drug accountability data recorded on the eCFR “Drug Dispense” 
and “Drug Return” forms and will be calculated as the number of tablets taken (total dispensed – total returned) 
divided by the prescribed number of tablets expressed as a percentage, see calculations below:  
Ѳ = Prescribed number of tablets required to be taken per day, i.e., 8 tablets in this study.   
 
Compliance (%) =  
ሾ୒ ୭୤ ୲ୟୠ୪ୣ୲ୱ ୢ୧ୱ୮ୣ୬ୱୣୢ ୟ୲ ୚୧ୱ୧୲ଶሿିሾ୒ ୭୤ ୲ୟୠ୪ୣ୲ୱ ୰ୣ୲୳୰୬ୣୢ ୟ୲ ୚୧ୱ୧୲ଷ ୭୰ ୉ୟ୰୪୷ ୘ୣ୰୫୧୬ୟ୲୧୭୬ሿ
୘୧୫ୣ ୲୰ୣୟ୲୫ୣ୬୲ሺୢୟ୷ୱሻ∗Ѳ
x 100 
 
15. EFFICACY OUTCOMES  
15.1. PRIMARY EFFICACY 
15.1.1. PRIMARY EFFICACY VARIABLE  
The primary efficacy endpoint is the change from baseline  RDQ symptom scores for the GERD dimension 
(heartburn and regurgitation) after a 7-day treatment period of a regimen of two Compound Sodium Alginate 
Double Action Chewable Tablets taken four times daily compared with a matched placebo. This variable is 
derived from the data collected on the “Reflux Disease Questionnaire” form in eCRF. 
The RDQ is a self-administered questionnaire in which subjects are asked to report the frequency and severity of 
their upper gastrointestinal symptoms (refer to Appendix 1 and 2 of the Protocol).  There are three subscales 
that evaluate regurgitation, heartburn and dyspepsia. The heartburn and regurgitation subscales can be 
combined into a GERD dimension. Refer to Appendix 2 for RDQ scoring instructions for deriving the RDQ 
symptom scores for the GERD dimension.  
15.1.2. MISSING DATA METHODS FOR PRIMARY EFFICACY VARIABLE 
For those patients that do not return for Visit 3 because of confirmed poor efficacy from the treatment between 
Day 1 and Day 6, all efficacy data at Visit 3 will be imputed as no change from the day 0 values (BOCF) if Early 
Termination visit is missing. If there is missing data for a patient in the RDQ questionnaire at an occasion and the 
missing data is less than or equal to 50% of the item scores within a dimension, the missing items will be imputed 
using the mean score of the non-missing item scores. If more than 50% of the item scores are missing, no 
imputation will be performed and the dimension score will be excluded from the analysis.  


 
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15.1.3. PRIMARY ANALYSIS OF PRIMARY EFFICACY VARIABLE 
The primary endpoint will be performed for the ITT population primarily using a linear mixed model with a fixed 
effect term for treatment, centre as a random effect and the baseline RDQ GERD dimension score as a covariate.  
The primary analysis is to test the null hypothesis that there is no difference between treatment, least square 
means (with 95% CI) corresponding to the two treatments will be presented.  Descriptive statistics will also be 
presented for the primary endpoint by treatment.   
The following SAS core code will be used: 
proc mixed data=XXX method=REML; 
  class treatment center; 
  model chg = base treatment / DDFM=KR; 
  random center; 
  lsmeans treatment/diff cl; 
run; 
15.1.4. SENSITIVITY ANALYSIS OF PRIMARY EFFICACY VARIABLE 
A sensitivity analysis will be conducted on the primary endpoint using the PP population. 
15.1.5. EXPLORATORY ANALYSIS OF PRIMARY EFFICACY VARIABLE 
Two additional separate exploratory mixed models will be conducted identical to those stated above but with 
additional interaction terms for the treatment by centre interaction (random effect) and treatment by baseline 
covariate interaction respectively.  
15.1.6. SUBGROUP ANALYSIS OF PRIMARY EFFICACY VARIABLE 
The analysis will be repeated within each of the subgroups separately as indicated below:  
GERD status: Erosive vs Non-erosive.  
15.2. SECONDARY EFFICACY 
15.2.1 SECONDARY EFFICACY VARIABLES  
The key secondary endpoint is:  


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL GA1210 
• 
Change from baseline in RDQ scores for dyspepsia dimension 
Other secondary endpoints are: 
• 
Overall treatment evaluation (OTE) as a measure for patient’s responsiveness/satisfaction; 
• 
Change from baseline in RDQ scores for heartburn dimension;  
• 
Change from baseline in RDQ scores for regurgitation dimension. 
The secondary efficacy analyses will be performed for the ITT population. 
Refer to Appendix B for RDQ scoring instructions for deriving the RDQ symptom scores for the dyspepsia, 
heartburn and regurgitation dimension.  
The two OTE responses are collected on the “Overall Treatment Evaluation” form in eCRF as responses to 
questions 1) thinking over the last 7 days and the medication you received, how would you rate the change in 
your symptoms; and 2) how important was the change in the symptoms to you.  
15.2.2 MISSING DATA METHODS FOR SECONDARY EFFICACY VARIABLES 
For those patients that do not return for Visit 3 because of confirmed poor efficacy from the treatment between 
Day 1 and Day 6, all efficacy data concerning RDQ scores at Visit 3 will be imputed as no change from the day 0 
values (BOCF) if Early Termination visit is missing. If there is missing data for a patient in the RDQ questionnaire at 
an occasion and the missing data is less than 50% of the item scores within a dimension, the missing items will be 
imputed using the mean score of the non-missing item scores. If more than 50% of the item scores are missing, no 
imputation will be performed and the dimension score will be excluded from the analysis.  
15.2.3 ANALYSES OF SECONDARY EFFICACY VARIABLES 
The analysis methods for the key secondary endpoint will be identically to those described for the primary 
endpoint in 15.1.3, 15.1.4 and 15.1.5 except that the included covariate will be the baseline RDQ score for the 
relevant dimension.  
The difference in the two OTE responses will be compared between treatment groups using a Wilcoxon Rank 
Sum Test stratified by centre.  
The following SAS core code will be used: 
proc freq data=XXX; 
  tables center*treatment*ote_resp/cmh2 scores=modridit ; 
run; 
 
The second OTE response (i.e., how important was the change in symptoms) will also be examined in the 
subgroup of patients who have reported an improvement in the first OTE response.   
The change scores in frequency and intensity for each dimension, i.e., the 12 items asked on the RDQ 
questionnaire, will be compared between treatment groups using a Wilcoxon Rank Sum Test stratified by centre. 
The analysis methods for the other two secondary endpoints (heartburn and regurgitation dimensions) will be 


 
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identical to those described for the primary endpoint in 15.1.3 and 15.1.4 except that the included covariate will 
be the baseline RDQ score for the relevant dimension. 
15.2.4 SENSITIVITY ANALYSES OF SECONDARY EFFICACY VARIABLES 
Sensitivity analyses will be conducted on the secondary endpoints using the PP population. 
15.2.5 EXPLORATORY ANALYSIS OF KEY SECONDARY EFFICACY VARIABLES 
Two additional separate exploratory mixed models will be conducted identical to those stated above but with 
additional interaction terms for the treatment by centre interaction (random effect) and treatment by baseline 
covariate interaction respectively.  
16 SAFETY OUTCOMES 
All outputs for safety outcomes will be based on the Safety population. 
16.1 ADVERSE EVENTS 
Adverse Events (AEs) will be coded using MedDRA version 17.0. For an individual patient, only adverse events 
commencing after first dose of IMP and no later than last dose of IMP+1day will be included in the AE and 
serious adverse event (SAE) summaries.  AEs that began prior to the first dose of IMP or more than one day after 
the final dose of IMP will not be included in the analysis. Where an AE start date is partially or completely 
missing, and it is unclear using partial dates as to whether the AE is treatment-emergent, it will be assumed that 
it is.   


 
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16.1.1 ADVERSE EVENTS 
An overall AE summary presenting the number and percentage of patients within the following categories by 
treatment  group and total will be provided.  
• 
Total number of AEs (each patient might be counted more than once within this item) 
• 
Patients with AEs 
• 
Patients with SAEs 
• 
Patients with AEs with a relationship to IMP as “Possible”, “Probable” and “Certain” 
• 
Patients with severe AEs 
• 
Patients with AEs leading to IMP dose change 
• 
Patient with AEs leading to IMP permanently discontinued 
In addition, an analysis using Fisher's exact test to compare the AE incidence between treatment groups will be 
presented for the following categories: 
• 
Patients with AEs 
• 
Patients with AEs with a relationship to IMP as “Possible”, “Probable” and “Certain” 
• 
Patients with severe AEs 
In addition, the following tables will be reported by treatment groups:  
• 
AEs, by SOC, PT and severity 
• 
Related AEs, by SOC, PT and severity 
16.1.1.1 
Severity 
Severity is classified as mild/ moderate/ severe. AEs with a missing severity will be counted in a separate missing 
category.  If a patient reports an AE more than once within that SOC/ PT, the AE with the worst case severity will be 
used in the corresponding severity summaries. 
16.1.1.2 
Relationship to Study Medication 
Relationship, as indicated by the Investigator, is classed as “Unassessable/Unclassified”, “Conditional/Unclassified”, 
“Unrelated”, “Unlikely”, “Possible”, “Probable”, and “Certain”. Adverse events with a relationship of “Possible”, 
“Probable” and “Certain” to IMP will be considered as related to study medication.  AEs with a missing relationship 
to study medication will be counted in a separate missing category.  If a patient reports the same AE more than 
once within that SOC/ PT, the AE with the worst case relationship to study medication will be used in the 
corresponding relationship summaries.  
16.1.2 ADVERSE EVENTS LEADING TO DOSE CHANGE OR DISCONTINUATION OF STUDY MEDICATION 
If the action taken for an AE is recorded as “IMP permanently discontinued” on the “Adverse Events” form of the 
eCRF, it will be considered as an AE leading to permanent discontinuation. If the action taken for an AE is recorded 
as “IMP dose changed” on the “Adverse Events” form of the eCRF, it will be considered as an AE leading to dose 
change.  These will be summarized by SOC and PT by treatment group and also listed. 


 
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16.1.3 SERIOUS ADVERSE EVENTS 
SAEs are those events a response of “Yes” for the item “Is the Adverse Event serious?” on the “Adverse Events” 
form of the eCRF.  A summary of SAEs by SOC, PT and severity, as well as a summary of related SAEs by SOC, PT, 
and severity will be reported by treatment group.  Summaries will also be provided for SAEs leading to dose change 
as well as study discontinuation.  These data will also be listed. 
16.1.4 ADVERSE EVENTS LEADING TO DEATH 
AEs leading to Death are those events with outcome reported as “Fatal” on the “Adverse Events” form of the eCRF. 
A summary of AEs leading to death by SOC and PT will be prepared.  This information will also be listed. 
16.2  DEATH 
Only AEs leading to death are recorded for this study, please refer to Section 16.1.4. 
16.3 LABORATORY EVALUATIONS 
Clinical assessments on hematology and clinical chemistry are to be measured at Visit 1 and Visit 3 or Early 
Termination Visit.  A list of laboratory assessments to be included in the outputs is provided in appendix 1. Local 
laboratories will be used for the assessment of hematology and clinical chemistry data and these data will be 
converted to the International System (SI) of units by Data Management Team using standard conversion factors.  
Quantitative laboratory measurements reported as “< X”, i.e. below the lower limit of quantification (BLQ), or 
“> X”, i.e. above the upper limit of quantification (ULQ), will be converted to X for the purpose of quantitative 
summaries, but will be presented as recorded, i.e. as “< X” or “> X” in the listings. 
At each visit, summary statistics for the absolute laboratory value and the changes from baseline will be 
presented by treatment group.  The significance of within-treatment changes from baseline will be assessed 
using the Wilcoxon Signed-Rank Test. The significance of between treatment changes from baseline will be 
assessed using the Wilcoxon Rank-Sum Test. Statistical testing will be performed at last visit.  
Each pre-study baseline laboratory value will be categorised as low, normal, or high based on the reference 
range of the local laboratories:  
• 
Low: Below the lower limit of the laboratory reference range.  
• 
Normal: Within the laboratory reference range (upper and lower limit included). 
• 
High: Above the upper limit of the laboratory reference range. 
Each post-baseline value will be classified in a similar manner, producing a 3 x 3 table for each treatment group 
at each post-baseline visit.  Scores of “1” will be assigned to low values, “2” to normal values, and “3” to high 
values.  Using these scores, shifts from baseline will also be assigned a score.  For example, a laboratory value 
that shifts from low to high will be assigned a score of 2, whilst a laboratory value that remains at a low value will 
be assigned a score of 0.  Shifts between these categories between baseline and subsequent timepoints (Visit 3 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL GA1210 
or Early Termination Visit) will be compared using the Wilcoxon Signed-Rank test within each treatment group. 
Statistical testing will be performed at last visit.  
In addition to the high and low quantitative laboratory assignments (as identified by means of the laboratory 
reference ranges), clinically significant quantitative laboratory assessments will be identified by investigator and 
the result will be recorded in the eCRF. The number and percentage of patients with abnormal or clinically 
significant results will be tabulated by treatment groups by visit. The results will also be listed.  
Women of child-bearing potential will undergo urine pregnancy testing (positive or negative). The results will be 
listed. 
16.4  VITAL SIGNS  
Vital signs including systolic/diastolic blood pressure (mmHg) and heart rate (beats/min) will be conducted at Visit 1 
and Visit 3 or early termination visit. 
At each visit, summary statistics for the absolute vital sign value and the changes from baseline will be presented 
by treatment group. The significance of within-treatment changes from baseline will be assessed at the last visit, 
using the Wilcoxon Signed-Rank Test. The significance of between treatment changes from baseline will be 
assessed at the last visit using the Wilcoxon Rank-Sum Test. 
A complete listing on all patients’ vital sign result will be presented.  
16.5 PHYSICAL EXAMINATION  
A physical examination is to be performed at Visit 1 and Visit 3 or Early Termination Visit. The following 
summaries will be provided for physical examination data: 
Incidence of clinically significant abnormalities at each visit will be presented and a shift table on clinically 
significant abnormalities between baseline and Visit 3 (or early termination visit) will be presented by treatment 
group.  
A listing on clinical significant abnormalities will be reported.  
 
17 REFERENCE 
Reckitt Benckiser GA1210 Study Protocol Final Version 2.0, Amendment 1, 4Jun2013 
Reckitt Benckiser GA1210 Annotated Study Book_Version 04_ 28Mar2014 
 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL GA1210 
APPENDIX 1 LIST OF LABORATORY ASSESSMENTS 
Assessment 
SI Unit 
Haematology 
Haemoglobin 
g/L
Red blood cells 
10^12/L
Mean cell haemoglobin concentration
g/L
White blood cells 
10^9/L
Platelet count 
10^9/L
Clinical chemistry 
Sodium 
mmol/L
Potassium 
mmol/L
Calcium 
mmol/L
Urea 
mmol/L
Creatinine 
µmol/L
Uric Acid 
µmol/L
Glucose 
mmol/L
Inorganic phosphorous 
mmol/L
Alanine transaminase 
U/L
Aspartate transaminase 
U/L
 
 
 
 
 
 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL GA1210 
APPENDIX 2 REFLUX DISEASE QUESTIONNAIRE (RDQ) 
Description  
The RDQ is a self-administered questionnaire. It has been used to assess treatment induced changes over time and 
will be validated as a diagnostic tool of gastroesophageal reflux disease for use in primary care.  
 
Scoring  
The questionnaire, which contains 12 items, uses a six-graded Likert scale, where 0 represents the most positive 
option and 5 the most negative one. A raw score is calculated.  
 
A mean value for the items in each dimension should be calculated:  
Heartburn:   1a. A burning feeling behind your breastbone  
1b. Pain behind your breastbone  
2a. A burning feeling behind your breastbone  
2b. Pain behind your breastbone  
Regurgitation:   1e. An acid taste in your mouth  
1f. Unpleasant movement of material upwards from the stomach  
2e. An acid taste in your mouth  
2f. Unpleasant movement of material upwards from the stomach  
GERD dimension:   1a. A burning feeling behind your breastbone  
1b. Pain behind your breastbone  
2a. A burning feeling behind your breastbone  
2b. Pain behind your breastbone  
1e. An acid taste in your mouth  
1f. Unpleasant movement of material upwards from the stomach  
2e. An acid taste in your mouth  
2f. Unpleasant movement of material upwards from the stomach  
Dyspepsia:   1c. A burning feeling in the centre of the upper stomach  
1d. A pain in the centre of the upper stomach  
2c. A burning feeling in the centre of the upper stomach  
2d. A pain in the centre of the upper stomach  
 
References:  
- 
Shaw MJ, Talley NJ, Beebe TJ, Rockwood T, Carlsson R, Adlis S, Fendrick M, Jones R, Dent J, Bytzer P. Initial 
validation of a diagnostic questionnaire for gastroesophageal reflux disease. Am J Gastroenterol 2001;96:52-57.  
- 
Shaw MJ, Crawley JA. Improving health-related quality of life in gastro-oesophageal reflux disease. Drugs 
2003;63:2307-2316.  
- 
Ofman JJ, Shaw M, Sadik K, Grogg A, Emery K, Lee J, Reyes E, Fullerton S. Identifying patients with 
gastroesophageal reflux disease – Validation of a practical screening tool. Dig Dis Sci 2002;47:1863-1869.  
- 
Shaw M. Diagnostic utility of reflux disease symptoms. Gut 2004;53(Suppl IV):iv25-iv27.  
- 
Nocon M, Kulig M, Leodolter A, Malfertheiner P, Willich SN. Validation of the Reflux Disease Questionnaire for 
a German population. European Journal of Gastroenterology & Hepatology 2005;17:229-233.  
- 
Shaw M, Dent J, Beebe T, Junghard O, Wiklund I, Lind T, Johnson F, Carlsson R. The Reflux Disease 
Questionnaire: A new measure to assess treatment response in clinical trials (submitted).  
 


QOUINTILES 
Changes to Planned Statistical Analyses Form 
Customer: 
rrotocol No.: 
Project Code: 
Date: 
RB Healthcare 
GAl2IO 
QVJ\96909 
01/SEP/2014 
The timing of the changc{s) was: 
After unhlinding (or database lock for an open-label study) but before completion of the 
final Statistical Report/Clinical Study Report 
After completion of the final Statistical Report/Clinical Study Report 
Describe Che clmngc(s) req11ircd: 
Page 1 of 1 
Table 14.2.3.3, the site and sitc•trentment interaction initially entered the model as random effect. During 
review of the finul unhlindcd output, it was found that the p-vnlue for the site•treatrncnt interaction term 
was not calculated due to non positive definite variance matrix. Thus for this table, the analysis will be 
uodated with site, and site•treatment entered into the model as fixed effects. 
Desci-ibe the process used to decide on the chanl!C.-s) and who was involved: 
As the key intention of this analysis was to test the null hypothesis of equal treatment differences across 
centres, it was decided by the RB Statistical Manager (
) to change the analysis presented because 
this could not be assessed from the planned analysis using random effects. Although this change may not 
have the same level of power to detect a significant treatment by centre interaction as the previously planned 
analysis and relics on different assumptions about the centre effect, it at least provides some unbiased 
information on the homogeneity of the treatment di ffcrence across centres. Due to negative variance 
components in the planned analysis (and setting the centre x treatment variance as zero), in the nsscssment o 
the treatment effect the calculated dc~rees of freedom are not valid. 
The RB Statislical Manager (
) is responsible for requesting this change and Quintile 
Statisticians are responsible for updating the affected output and ensuring appropriate documentation and 
explanation in the Statistical and Clinical Reports. 
Form completed by: 
Title 
AD, Biostatistics 
Form approved hy: 
Title --
Form approved by Customer Representative {if applicable): 
Name 
Statistical Mannger 
-
Form No: CS FM B5006 - Revision 4 
Effective Date: 01Feb2010 
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• 
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