A Randomised Controlled Trial Comparing Conventional Open Haemorrhoidectomy and Laser Haemorrhoidoplasty in the Treatment of Symptomatic Haemorrhoids: COHLAH Trial
Phase: PHASE2
Conditions: Hemorrhoids
Sponsor: Sengkang General Hospital

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CLINICAL TRIAL PROTOCOL 
 
PROTOCOL TITLE: 
A randomised controlled trial comparing conventional open haemorrhoidectomy and laser 
haemorrhoidoplasty in the treatment of symptomatic haemorrhoids: COHLAH trial 
 
PROTOCOL NUMBER:  
CIRB: 2019/2930 
Clinicaltrials.gov ID:  
 
PROTOCOL VERSION:  
2 
PROTOCOL DATE:  
07/03/2020 
 
PRINCIPAL INVESTIGATOR:  
Foo Fung Joon, Head of Service, Colorectal Division, Sengkang General Hospital 
 
SITE PRINCIPAL INVESTIGATOR:  
NA 
 
 
CO-INVESTIGATORS: 
Chew Min Hoe, Head of Department, General Surgery, Sengkang General Hospital 
Winson Tan Jian Hong, Consultant, Sengkang General Hospital 
Sharmini Su Sivarajah, Consultant, Sengkang General Hospital 
Leonard Ho Ming Li, Consultant, Sengkang General Hospital 
Frederick Koh Hong Xiang, Senior Service Registrar, Sengkang General Hospital  
 
 
 

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Table of Contents 
1 
BACKGROUND AND RATIONALE ............................................................................................. 5 
1.1 
GENERAL INTRODUCTION ................................................................................................................... 5 
1.2 
RATIONALE AND JUSTIFICATION FOR THE STUDY ...................................................................................... 5 
1.2.1 
RATIONALE FOR THE STUDY PURPOSE ................................................................................................... 5 
1.2.2 
RATIONALE FOR DOSES SELECTED ........................................................................................................ 5 
1.2.3 
RATIONALE FOR STUDY POPULATION .................................................................................................... 5 
1.2.4 
RATIONALE FOR STUDY DESIGN........................................................................................................... 6 
2 
HYPOTHESIS AND OBJECTIVES.............................................................................................. 6 
2.1 
HYPOTHESIS ................................................................................................................................... 6 
2.2 
PRIMARY OBJECTIVES ....................................................................................................................... 6 
2.3 
SECONDARY OBJECTIVES ................................................................................................................... 6 
2.4 
POTENTIAL RISKS AND BENEFITS: ........................................................................................................ 7 
2.4.1 
POTENTIAL RISKS ............................................................................................................................ 7 
2.4.2 
POTENTIAL BENEFITS ........................................................................................................................ 7 
3 
STUDY POPULATION .............................................................................................................. 7 
3.1 
LIST THE NUMBER AND NATURE OF SUBJECTS TO BE ENROLLED ................................................................... 7 
3.2 
CRITERIA FOR RECRUITMENT AND RECRUITMENT PROCESS ......................................................................... 8 
3.3 
INCLUSION CRITERIA ........................................................................................................................ 8 
3.4 
EXCLUSION CRITERIA ........................................................................................................................ 8 
3.5 
SUBJECT REPLACEMENT ..................................................................................................................... 8 
4 
STUDY DESIGN ...................................................................................................................... 8 
4.1 
RANDOMISATION AND BLINDING .......................................................................................................... 9 
4.2 
CONTRACEPTION AND PREGNANCY TESTING.......................................................................................... 10 
4.3 
STUDY VISITS AND PROCEDURES ....................................................................................................... 10 
4.3.1 
SCREENING VISITS AND PROCEDURES ................................................................................................. 10 
4.3.2 
STUDY VISITS AND PROCEDURES ....................................................................................................... 10 
4.3.3 
FINAL STUDY VISIT: ....................................................................................................................... 11 
4.3.4 
POST STUDY FOLLOW UP AND PROCEDURES.......................................................................................... 11 
4.4 
DISCONTINUATION/WITHDRAWAL ...................................................................................................... 11 
4.4.1 
DISCONTINUATION CRITERIA ............................................................................................................ 11 
4.4.2 
DISCONTINUATION VISIT AND PROCEDURES ......................................................................................... 11 
5 
TRIAL MATERIALS ............................................................................................................... 11 
5.1 
TRIAL PRODUCT (S) ....................................................................................................................... 11 
5.2 
STORAGE AND DRUG ACCOUNTABILITY ................................................................................................ 11 
6 
TREATMENT ......................................................................................................................... 11 
6.1 
RATIONALE FOR SELECTION OF DOSE .................................................................................................. 11 
6.2 
STUDY DRUG FORMULATIONS ........................................................................................................... 12 
6.3 
STUDY DRUG ADMINISTRATION ......................................................................................................... 12 
6.4 
SPECIFIC RESTRICTIONS / REQUIREMENTS ........................................................................................... 12 
6.5 
BLINDING .................................................................................................................................... 12 
6.6 
CONCOMITANT THERAPY .................................................................................................................. 12 
7 
SAFETY MEASUREMENTS ..................................................................................................... 12 
7.1 
DEFINITIONS ................................................................................................................................ 12 
7.2 
COLLECTING, RECORDING AND REPORTING OF SERIOUS ADVERSE EVENTS (SAES) TO CIRB ............................ 13 

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7.3 
COLLECTING, RECORDING AND REPORTING OF SERIOUS ADVERSE EVENTS (SAES) TO THE HEALTH SCIENCE 
AUTHORITY (HSA) .................................................................................................................................... 13 
7.4 
SAFETY MONITORING PLAN .............................................................................................................. 13 
7.5 
COMPLAINT HANDLING .................................................................................................................... 13 
8 
DATA ANALYSIS................................................................................................................... 13 
8.1 
DATA QUALITY ASSURANCE .............................................................................................................. 13 
8.2 
DATA ENTRY AND STORAGE .............................................................................................................. 14 
9 
SAMPLE SIZE AND STATISTICAL METHODS ......................................................................... 14 
9.1 
DETERMINATION OF SAMPLE SIZE ...................................................................................................... 14 
9.2 
STATISTICAL AND ANALYTICAL PLANS ................................................................................................. 14 
10 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ................................................................. 15 
11 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................................... 15 
12 
ETHICAL CONSIDERATIONS ................................................................................................ 15 
12.1 
INFORMED CONSENT ...................................................................................................................... 16 
12.2 
CONFIDENTIALITY OF DATA AND PATIENT RECORDS ............................................................................... 16 
13 
PUBLICATIONS .................................................................................................................... 16 
14 
RETENTION OF TRIAL DOCUMENTS ..................................................................................... 16 
15 
FUNDING AND INSURANCE ................................................................................................. 17 
LIST OF ATTACHMENTS ............................................................................................................... 18 

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PROTOCOL SIGNATURE PAGE 
 
 
 
Protocol Title: 
A randomised controlled trial comparing conventional open haemorrhoidectomy and 
laser haemorrhoidoplasty in the treatment of symptomatic haemorrhoids: COHLAH trial 
 
Protocol Number: 
CIRB: 2019/2930 
Clinicaltrials.gov ID:  
 
Protocol Version/ Date: 
2 / 07/03/2020 
 
Sponsor Name: 
NA 
 
 
Declaration of Investigator 
 
I confirm that I have read the above-mentioned protocol and its attachments. I agree to conduct the 
described trial in compliance with all stipulations of the protocol, regulations and ICH E6 Guideline for 
Good Clinical Practice (GCP). 
 
  
 
 
Principal Investigator Name:  Foo Fung Joon_____________________________ 
                                                            
 
Principal Investigator Signature:  _______________________________________ 
                                                            
 
Date:  __________________________________________ 
                                                            
 
 
 
 
 
 
 

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1 
BACKGROUND AND RATIONALE 
 
1.1 General Introduction 
 
Haemorrhoids or piles are the most common colorectal condition in the local population. Patients 
often present with bleeding with bowel movement or anal discomfort, both of which causes 
significant anxiety and stress. For symptomatic sizeable piles, the treatment of choice still remains 
the conventional open excision (COH). However, this technique carries with it a significant risk of 
bleeding and pain immediately after the operation, leading to some period of discomfort for the 
patients. The laser haemorrhoidoplasty procedure (LAH) has been shown in preliminary studies to 
have less pain, and less complications compared to COH. This study aims to directly compare these 
two techniques in a local Asian population.  
 
1.2 Rationale and Justification for the Study 
 
We would be conducting a single-centre RCT simultaneously comparing the conventional open 
Milligan-Morgan haemorrhoidectomy (COH) and the laser haemorrhoidoplasty procedure (LAH) for 
the treatment of symptomatic grade ll-lV haemorrhoids. Primary outcomes will be post-operative 
pain while secondary outcomes include post-operative bleeding, readmission and/or reoperations, 
haemorrhoid-related quality of life (QoL) results and recurrence of symptoms up to a year post 
procedure.  
 
1.2.1 Rationale for the Study Purpose 
 
Treatment of haemorrhoids have long been associated with significant postoperative pain as well as 
laden with complications, including bleeding and pelvic sepsis, which usually results in patients’ 
distress and readmission back to hospital. The open Milligan Morgan technique has long been 
regarded as the gold standard treatment for non-circumferential grade ll-IV haemorrhoids.  
 
Newer techniques, including doppler haemorrhoidal dearterialization, has yield mixed results with a 
high recurrence rate.  
 
Laser haemorrhoidoplasty has recently been studied and have shown promising results which has 
addressed the problems of the open Milligan-Morgan technique. These preliminary studies have 
shown a significant decrease in post-operative pain scores, less bleeding risk. There have yet to be 
any well-designed randomised controlled trial (RCT) looking into the longer-term outcomes of this 
technique.   
 
1.2.2 Rationale for Doses Selected 
 
NA 
 
1.2.3 Rationale for Study Population 
 
Patients would be recruited if they are:  
a. between 21-70 years old 
b. presents with symptomatic haemorrhoids as evident from clinical assessment  
c. never had any haemorrhoid-related operations performed on them before  
d. fit for general anaesthesia 

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e. able to give informed consent 
f.   willing to be randomized 
g. willing to fill in post-operative questionnaires and be compliant to follow up 
 
We will be excluding individuals who:  
a. Are pregnant 
b. Are prisoners  
c. Intellectually, mentally or emotionally deemed not able to provide an informed consent and/or 
are unable to fill up the post-procedure questionnaires/VAS score 
d. Have had previous haemorrhoid procedural treatment before (except Rubber Band Ligation) 
e. Declined endoscopic evaluation 
f. Are on anti-platelets and/or anti-coagulation 
g. Have history of thrombophilia 
h. Are on steriods 
i. Have haemorrhoids which are incidentally found on endoscopy/clinical examination but are 
asymptomatic from it 
 
1.2.4 Rationale for Study Design 
 
We would be conducting a single-centre RCT simultaneously comparing the conventional open 
Milligan-Morgan haemorrhoidectomy (COH) and the laser haemorrhoidoplasty procedure (LAH) for 
the treatment of symptomatic grade ll-lV haemorrhoids. Primary outcomes will be post-operative 
pain while secondary outcomes include post-operative bleeding, readmission and/or reoperations, 
haemorrhoid-related quality of life (QoL) results and recurrence of symptoms up to a year post 
procedure.  
 
This would allow us to study this cohort prospectively while comparing the short- and long-term 
outcomes of both techniques in parallel.  
 
2 
HYPOTHESIS AND OBJECTIVES 
 
2.1 Hypothesis 
 
The study team hypothesize that LAH has significantly less pain and bleeding and better QoL scores 
at 1- and 3-months post-operatively.  
 
2.2 Primary Objectives 
 
         Daily visual analogue pain scale (VAS) in the first 10 days after surgery. 
 
2.3 Secondary Objectives 
 
- 
Operative duration 
- 
Incidence of post-operative bleeding 
- 
Incidence 
of 
readmission 
to 
haemorrhoidectomy/haemorrhoidoplasty 
related 
symptoms/condition (pain/pelvic symptoms/bleeding) 
- 
Procedure-related complications (thrombosis, fistulation, incontinence, stenosis) 
- 
Incidence and timing of recurrence of haemorrhoid-related symptoms 
- 
Haemorrhoid-specific QoL questionnaire (Haemorrhoid Severity Score) 
 

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2.4 Potential Risks and Benefits:  
 
2.4.1 Potential Risks 
 
Risk of the participation in the trial include:  
- 
Breach of patient confidentiality and personal data 
 
Risk of General Anaesthesia for both procedures is in keeping with that of those patients not 
involved in the study. These includes but not limited to:  
- 
Major adverse cardiac events (MACE)  
- 
Cerebral vascular accidents (stroke) 
- 
Barotrauma 
- 
Damage or loss of dentition  
 
Risk of Operation:  
a. Conventional open haemorrhoidectomy (COH):  
i. 
Bleeding 
ii. 
Anal sphincter injury which may lead to fecal incontinence 
iii. 
Anal stenosis  
iv. 
Pelvic sepsis 
v. 
Recurrence of haemorrhoids 
b. Laser haemorrhoidoplasty procedure (LAH):  
i. 
Bleeding 
ii. 
Thrombosis 
iii. 
Anal sphincter injury which may lead to fecal incontinence 
iv. 
Pelvic sepsis 
v. 
Bowel injury which may necessitate emergency surgery and/or stoma creation 
vi. 
Intestinal obstruction which may necessitate stoma creation 
 
 
2.4.2 Potential Benefits 
 
The benefits of participation in this trial is that patients will be closely monitored post procedure 
for their pain and symptoms and will receive a phone calls outside the regular follow up period, up 
to a year post-procedure, to follow up on their haemorrhoid-related symptoms.  
 
They will also potentially may receive a procedure that could potentially cause less pain and have a 
lower risk of post-operative bleeding.  
 
3 
STUDY POPULATION 
 
3.1 List the Number and Nature of Subjects to be Enrolled 
 
Based on previous studies, as well as unpublished results from surgeons who have performed LAH 
around the South East Asian region, we are expecting 50% of the patients in the COH arm to have a 
VAS score of more than 7.5. We expect to see 25% patients in the LAH arm having a VAS score of 
more than 7.5.  
 
With a power of 80%, chance of type 1 error (alpha) less than 5% and accounting for 10% of loss to 
follow up rate, the sample size required for the study to be adequate powered is having 64 patients in 

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each arm (N=128).  
 
3.2 Criteria for Recruitment and Recruitment Process 
 
Patients who are seen in the specialist outpatient clinics (SOC) or who are admitted for 
haemorrhoid-related symptoms/complications will be evaluated by one of the PI/co-PIs. All of 
them would need to have the usual clinical and endoscopic assessment of the colon to ascertain that 
the haemorrhoids are the only cause of their symptoms. They also should not have previous 
operation for haemorrhoids, excluding rubber band ligations. Only after the above would they be 
eligible for recruitment into the study.  
 
3.3 Inclusion Criteria 
 
a. between 21-70 years old 
b. presents with symptomatic haemorrhoids as evident from clinical assessment  
c. never had any haemorrhoid-related operations performed on them before  
d. fit for general anaesthesia 
e. able to give informed consent 
f.    willing to be randomized 
g. willing to fill in post-operative questionnaires and be compliant to follow up 
 
 
3.4 Exclusion Criteria 
 
a. Are pregnant 
b. Are prisoners  
c. Intellectually, mentally or emotionally deemed not able to provide an informed consent and/or 
are unable to fill up the post-procedure questionnaires/VAS score 
d. Have had previous haemorrhoid procedural treatment before (except Rubber Band Ligation) 
e. Declined endoscopic evaluation 
f. Are on anti-platelets and/or anti-coagulation 
g. Have history of thrombophilia 
h. Are on steriods 
i. Have haemorrhoids which are incidentally found on endoscopy/clinical examination but are 
asymptomatic from it 
 
3.5 Subject Replacement 
 
Subjects who drop out are accounted for in the sample size calculation and will not be replaced. 
 
 
4 
STUDY DESIGN 
 
This is a single-center, double-blind randomized controlled trial to be conducted in Sengkang General 
Hospital.  
 
All patients presenting to the clinic or admitted for symptomatic haemorrhoids would be assessed for 
recruitment.  
 
Figure 1 shows the enrolment process of the study population in the trial. Patients will be seen in the 

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clinic or in the wards for symptomatic haemorrhoids. All these patients would be approached and be 
introduced to this study but not recruited yet. 
 
Patients older than 40 years-old with no recent colonoscopy (within 5 years) would need to have a 
colonoscopic evaluation of the colon after the index admission/clinic visit.  
 
Those younger than 40 would be advised to have a rigid sigmoidoscopy on the day of the operation 
during the examination under anaesthesia. Only after agreement to the above, the patient would be 
recruited into the study. They would then be educated on the peri-operative questionnaire separately by 
a research administrator after recruitment into the trial.  
 
The peri-operative package is split into pre- and post-operative components and will include basic 
demographics, baseline haemorrhoid-specific QoL questionnaires1-3, VAS scales for POD0-10 and 
details of the intraoperative procedure and intraoperative description of the haemorrhoids.  
 
Patients who fit the inclusion and exclusion criteria would be recruited into the study. We will perform a 
1:1, block-of-4 randomization using a computer-generated programme performed by an independent 
research administrator who is not part of the surgical team.  
 
They will be allocated only after they are examined under anaesthesia. Allocation is provided in a 
concealed opaque envelope that is provided by the research administrator on the day of the operation. 
Thus, the patient is blinded to the procedure. There will also be no cross-over from one study arm to 
another. 
 
 
Potential Difficulties and Alternative Approaches to achieve the aims:  
 
Difficulty of recruitment of patients into the trial may be potentially present especially for a procedure 
that is new in Singapore. Patient counselling and explanation of the procedure would be important and 
offering a short video clip of the procedure may be helpful. The procedurists/co-investigators of the 
study team would also be trained by a regional practitioner of the technique before the initiation of the 
trial to ensure proficiency for reassurance. 
 
Accurately assessing the pain scores and QoL measures may be subjective and laden with the potential 
of recall and interviewer biases. In order to mitigate this, the patients will be instructed on the proper 
way of performing a VAS assessment of their pain before the procedure when they are not bothered by 
any sort of discomfort from the procedure. In addition, our research administrators would be briefed 
and trained to conduct an objective QoL assessment prior to the initiation of the trial.  
 
4.1 Randomisation and Blinding 
 
Patients who fit the inclusion and exclusion criteria would be recruited into the study. We will 
perform a 1:1, block-of-4 randomisation using a computer-generated programme performed by an 
independent research administrator who is not part of the surgical team.  
 
They will be allocated only after they are examined under anaesthesia. Allocation is provided in a 
concealed opaque enveloped that is provided by the research administrator on the day of the 
operation. Thus, the patient is blinded to the procedure. There will also be no cross-over from one 
study arm to another. 
 

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An independent research administrator, not part of the randomisation process, will also contact the 
patient 3 months and 1 year after the procedure as mentioned above.  
 
4.2 Contraception and Pregnancy Testing 
 
For females of childbearing age included in the trial, they will be asked whether they are pregnant 
and for their last menstrual period. They will be offered a UPT to test for pregnancy during 
recruitment into the trial but there are no requirements to perform the test.  
 
4.3 Study Visits and Procedures 
 
 
4.3.1 Screening Visits and Procedures 
 
Patients will be seen in the clinic or in the wards for symptomatic haemorrhoids. All these 
patients would be approached and be introduced to this study but not recruited yet. 
 
Figure 2 illustrates the visits commitment throughout the study process. After the completion of 
surgery, patients typically would already have a follow up appointment at 4-6 weeks after the 
procedure. The clinician will assess the patients progress and examining them for any 
complications. If their recovery is smooth, most of these patients would be discharged from 
follow up. During the same setting, the research administrators would collect back the peri-
operative package from the patient.  
 
Research administrators would then conduct a phone interview with the patients at 3-month 
and 1-year after surgery to perform the QoL survey and also looking out for late-onset 
complications and recurrence of symptoms. If present, they will be offered to have an 
appointment booked with their primary surgeon. Patients would be informed of the allocation at 
the clinic review at 4-6 weeks. As none of the visits are outside of normal practice, no 
remuneration is required. 
 
4.3.2 Study Visits and Procedures 
 
 
Figure 2. Timeline of participation. Those in the 1st row are regarded as within normal clinical 

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practice. Those in the 2nd row are regarded as outside of normal clinical practice. 
 
4.3.3 Final Study Visit: 
 
The final physical study visit for individuals without complications/recurrence will be at 4-6 weeks 
post operatively. As none of the visits are outside of normal practice, no remuneration is required.  
 
4.3.4 Post Study Follow up and Procedures 
 
The phone interview at 3-months and 1-year post-operatively would not be regarded as a visit. 
However, if the patients highlight symptoms suggestive of a complication or recurrence of 
symptoms, they would be offered to return for an evaluation by a colorectal specialist. It would 
then be dependent on the patient if they would like to take up this offer.  
 
4.4 Discontinuation/Withdrawal 
 
4.4.1 Discontinuation Criteria 
 
Discontinuation criteria of the trial would either be due to:  
a. Safety issues of LAH techniques 
b. Significant number and severity of the complications 
c. Statistically overwhelming evidence that 1 method is superior over the other 
 
4.4.2 Discontinuation Visit and Procedures 
 
Upon voluntary withdrawal, participants would resume regular follow up as per clinical 
requirement. These patients would not receive a phone interview at 3-months and a year after the 
procedure. These patients would also be given an open date in the clinic to allow them a year in 
duration to return to the clinic for evaluation if there are recurrence of symptoms or development 
of a previously unrecognised complication from either of the procedures.  
 
5 
TRIAL MATERIALS 
 
5.1 Trial Product (s) 
 
NA 
 
5.2 Storage and Drug Accountability 
 
NA 
 
6 
TREATMENT 
 
6.1 Rationale for Selection of Dose 
 
NA 
 

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6.2 Study Drug Formulations 
 
 
NA 
 
6.3 Study Drug Administration 
 
NA. 
 
6.4 Specific Restrictions / Requirements  
 
NA 
 
6.5 Blinding 
 
Patients will be allocated only after they are examined under anaesthesia. Allocation is provided in a 
concealed opaque enveloped that is provided by the research administrator on the day of the 
operation. Thus, the patient is blinded to the procedure. There will also be no cross-over from one 
study arm to another. 
 
An independent research administrator would conduct a phone interview with the patients at 3-
month and 1-year after surgery to perform the QoL survey and also looking out for late-onset 
complications and recurrence of symptoms. If present, they will be offered to have an appointment 
booked with their primary surgeon. Patients would be informed of the allocation at the clinic review 
at 4-6 weeks. 
 
6.6 Concomitant therapy 
 
NA 
 
 
7 
SAFETY MEASUREMENTS 
 
7.1 Definitions 
 
 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An adverse event (AE) can therefore be any unfavourable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product. 
 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• results in death 
• is life-threatening 
• requires inpatient hospitalisation or prolongation of existing hospitalisation 
• results in persistent or significant disability/incapacity, or 
• is a congenital anomaly/birth defect 
 

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7.2 Collecting, Recording and Reporting of Serious Adverse Events (SAEs) to CIRB  
 
Only related SAEs (definitely/ probably/ possibly) will be reported to CIRB. Related means there is 
a reasonable possibility that the event may have been caused by participation in the clinical trial.  
Please refer to the CIRB website for more information on Reporting Requirement and Timeline for 
Serious Adverse Events.  
 
The investigator is responsible for informing CIRB after first knowledge that the case qualifies for 
reporting. Follow-up information will be actively sought and submitted as it becomes available.  
 
Related AEs will not be reported to CIRB.  However, the investigator is responsible to keep record 
of such AEs cases at the Study Site File. 
 
7.3 Collecting, Recording and Reporting of Serious Adverse Events (SAEs) to the Health 
Science Authority (HSA) 
 
All SAEs that are unexpected and related to the study drug will be reported to HSA. Please refer to 
the HSA website for more information on Safety Reporting Requirements for Clinical Trials.  
 
7.4 Safety Monitoring Plan 
 
The Data Safety Monitoring Plan (DSMP) for this study can be divided into individual events and 
collated events.  
 
Every individual complication will be evaluated by all members of the study team immediately after 
the event has occurred. The study team would review the case and its proceedings to determine 
whether the event was a direct result of the procedure or its technique, and whether this could have 
been prevented. The complication would also be scored for its severity based on the Clavien-Dindo 
Classification of Complications. If there is a severe complication, or if the complication is a direct 
result of the procedure or its technique, a technical pause would be called for in order to re-clarify 
the technical aspects as well as processes to avoid a repeat complication before the trial is resumed.  
 
Interim analysis would also be carried out in a timely fashion (after 50% and 75% of the required 
sample size has been randomised. This would allow statistically significant differences in the 
outcome of the procedures to be identified. If one arm is grossly different from the other, the study 
team would convene to evaluate whether this outcome difference is regarded as a safety hazard to 
subsequent patients. If so, the trial would be halted or terminated prematurely.  
 
7.5 Complaint Handling  
 
All complaints will be handled in accordance with the Sengkang General Hospital Service Quality 
Department policy and aid. They will provide advice on the management strategies in such instances. 
If the complaint is related to a safety issue, the above (7.4) would apply.  
 
 
8 
DATA ANALYSIS 
 
8.1 Data Quality Assurance 
 
All data collected is prospective and the study team members and research administrators will 
convene to go through the peri-operative package, as well as the variables which are going to be 

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collected for the study. This will help standardise the method of assessment and finetune the method 
of administering the phone-based questionnaire.  
 
All the study co-investigators would have also completed the CITI-training workshop and would be 
cognisant of the need for uniformity in terms of assessment of intraoperative and post-operative 
variables.  
 
8.2 Data Entry and Storage 
 
Data will be entered into a data collection sheet by the study team or on the peri-operative package 
by the patient. All these data will be scanned in and images stored in a dedicated encrypted external 
hard-drive for archiving purposes. Hard-copy forms will be stored in a ring-file that is kept under 
lock-and-key by the PI. The data on the 2 data collection forms will be separately entered into an 
password-protected excel document, not having any patient identifiers, and stored in the dedicated 
encrypted hard-drive in a separate folder for the purposes of data analysis.  
 
Only the study administrators and study co-investigators will have access rights for data entry and 
analysis though the PI. 
 
9 
SAMPLE SIZE AND STATISTICAL METHODS 
 
9.1 Determination of Sample Size  
 
Based on previous studies, as well as unpublished results from surgeons who have performed LAH 
around the South East Asian region, we are expecting 50% of the patients in the COH arm to have a 
VAS score of more than 7.5. We expect to see 25% patients in the LAH arm having a VAS score of 
more than 7.5.  
 
With a power of 80%, chance of type 1 error (alpha) less than 5% and accounting for 10% of loss to 
follow up rate, the sample size required for the study to be adequate powered is having 64 patients in 
each arm (N=128).  
 
9.2 Statistical and Analytical Plans 
 
a. General Considerations 
 
All analysis would be conducted with the assistance or validation of a biostatistician. SPSS or Strata 
would be used to conduct the analysis. All categorical data would be analysed using the Fisher Exact 
Test. All continuous variables would be analysed using the Mann-Whitney U test. The level of 
statistical significance would be set as p<0.05.  
 
b. Safety Analyses 
 
Every individual complication will be evaluated by all members of the study team immediately after 
the event has occurred. The study team would review the case and its proceedings to determine 
whether the event was a direct result of the procedure or its technique, and whether this could have 
been prevented. The complication would also be scored for its severity based on the Clavien-Dindo 
Classification of Complications. If there is a severe complication, or if the complication is a direct 
result of the procedure or its technique, a technical pause would be called for in order to re-clarify 
the technical aspects as well as processes to avoid a repeat complication before the trial is resumed.  

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c. Interim Analyses 
 
Interim analysis would also be carried out in a timely fashion (after 50% and 75% of the required 
sample size has been randomised. This would allow statistically significant differences in the 
outcome of the procedures to be identified. If one arm is grossly different from the other, the study 
team would convene to evaluate whether this outcome difference is regarded as a safety hazard to 
subsequent patients. If so, the trial would be halted or terminated prematurely.  
 
 
d. Describe the types of statistical interim analyses, including their timing. 
 
Interim analysis would also be carried out in a timely fashion (after 50% and 75% of the required 
sample size has been randomised. This would allow statistically significant differences in the 
outcome of the procedures to be identified. If one arm is grossly different from the other, the study 
team would convene to evaluate whether this outcome difference is regarded as a safety hazard to 
subsequent patients. If so, the trial would be halted or terminated prematurely.  
 
 
10 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
 
The investigator(s)/institution(s) will permit study-related monitoring, audits and/or IRB review and 
regulatory inspection(s), providing direct access to source data and document. 
 
11 QUALITY CONTROL AND QUALITY ASSURANCE 
 
All data collected is prospective and the study team members and research administrators will 
convene to go through the peri-operative package, as well as the variables which are going to be 
collected for the study. This will help standardise the method of assessment and finetune the method 
of administering the phone-based questionnaire.  
 
All the study co-investigators would have also completed the CITI-training workshop and would be 
cognisant of the need for uniformity in terms of assessment of intraoperative and post-operative 
variables.  
 
12 ETHICAL CONSIDERATIONS 
 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki and that are consistent with the Good Clinical Practice and the applicable 
regulatory requirements. 
 
This final Clinical Trial Protocol, including the final version of the Participant Information Sheet and 
Consent Form, must be approved in writing by the Centralised Institutional Review Board (CIRB) 
and regulatory approval from Health Sciences Authority (HSA), prior to enrolment of any patient 
into the study. 
 
The principle investigator is responsible for informing the CIRB and HSA of any amendments to the 

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protocol or other study-related documents, as per local requirement. 
 
12.1 Informed Consent 
 
Upon satisfaction of the inclusion and exclusion criteria, the primary surgeon (co-investigator) would 
introduce the trial to the patient in their preferred language either themselves or through a proxy. 
Upon interest, the research administrators will provide further details of the trial to the patient in a 
separate room in the clinic/wards. The patient will have ample time to read the patient information 
form (in the language that the patient can read) and consider enrolment into the trial. After the 
decision to participate, he/she would be invited to sign on the recruitment consent forms.  
 
The research administrator and co-investigators would have to document the consult and the risks 
that of participation and of the techniques that were explained. In obtaining and documenting 
informed consent, the investigator should comply with the GCP guidelines and to the ethical 
principles that have their origin in the Declaration of Helsinki.  
 
12.2 Confidentiality of Data and Patient Records 
 
Data will be entered into a data collection sheet by the study team or on the peri-operative package 
by the patient. All these data will be scanned in and images stored in a dedicated encrypted external 
hard-drive for archiving purposes. Hard-copy forms will be stored in a ring-file that is kept under 
lock-and-key by the PI. The data on the 2 data collection forms will be separately entered into an 
password-protected excel document, not having any patient identifiers, and stored in the dedicated 
encrypted hard-drive in a separate folder for the purposes of data analysis.  
 
Only the study administrators and study co-investigators will have access rights for data entry and 
analysis though the PI. 
 
13 PUBLICATIONS 
 
The study team owns the data and analysis. The manuscript would be written by a member of the 
study team and approved by the PI before presentation at an international/regional and local 
scientific 
conference.  
 
The details of analysis would be published in a peer reviewed journal that is also registered in at least  
MEDLINE.  
 
 
14 RETENTION OF TRIAL DOCUMENTS 
 
Records for all participants, including CRFs, all source documentation (containing evidence to study 
eligibility, history and physical findings, laboratory data, results of consultations, etc.) as well as IRB 
records and other regulatory documentation should be retained by the PI in a secure storage facility. 
The records should be accessible for inspection and copying by authorized authorities.  
 
All these data will be scanned in and images stored in a dedicated encrypted external hard-drive 
for archiving purposes. Hard-copy forms will be stored in a ring-file that is kept under lock-and-
key by the PI. The data on the 2 data collection forms will be separately entered into an 
password-protected excel document, not having any patient identifiers, and stored in the 

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dedicated encrypted hard-drive in a separate folder for the purposes of data analysis.  
 
Only the study administrators and study co-investigators will have access rights for data entry 
and analysis though the PI. 
 
15 FUNDING and INSURANCE 
 
En-Life has agreed to sponsor 40 laser probes to initiate the study. Grants will be applied to cover the 
remaining cost of the other 14 laser probes. En-life has agreed to loan the Laser Generator for free.  
Singhealth research indemnity insurance – for utility to cover for the management of any 
complications during the trial 
 
 

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List of Attachments 
 
Appendix 1 
Study Schedule 
 
 
 
Figure 1. CONSORT diagram of patient involvement in COHLAH trial 
 
Appendix 2 
Post-procedure Questionnaire Package 
 
(Attached separately)