Multicenter Randomized Controlled Trial of Doppler Guided Hemorrhoid Artery Ligation (DGHAL) and Mucopexy Versus Mucopexy Alone in the Treatment of Grade III Hemorrhoids
Phase: NA
Conditions: Hemorrhoids Prolapse
Sponsor: Societa Italiana di Chirurgia ColoRettale

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Hamlet  TRIAL  
PROTOCOL 
 
 
Full title: Multicenter randomized controlled trial of Doppler guided Hemorrhoid Artery Ligation 
(DGHAL) and mucopexy versus mucopexy alone in the treatment of grade III Hemorrhoids . 
S 
hort title: Hamlet (Hemorrhoids Artery Mucosal Ligation prospEctive Trial) trial. 
Alternative title: Doppler-guided or non doppler-guided arterial ligation and mucopexy for third 
degree hemorrhoids? That is the question. The Hamlet (Hemorrhoids Artery Mucosal Ligation 
prospEctive Trial) trial. 
 
Developed by Department of Emergency and Organ Transplantation (DETO), University of Bari, 
Italy 
 
 

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Hamlet Trial Management Group 
Surgery 
Prof. Donato F. Altomare, MD, Arcangelo Picciariello, MD 
Dept of Emergency and Organ Transplantation, University of Bari, Italy,  
c/o Azienda Ospedaliero-Universitaria Policlinico di Bari, piazza G Cesare, 11 – 70124 Bari, Italy 
Phone +39.0805478764 Mobile phone:+39.3397593066 
Fax:  +39.0805478735 
e-mail: donatofrancesco.altomare@uniba.it 
 
 
 
 
Randomization 
 
Simple randomization will be centralized and carried out by assigning the 3 treatment options to 
consecutive computer generated random number obtained through the website 
http://www.randomizer.at 
 
The randomization code will be obtained by contacting the number or the Tel number +39 
3492185104/ +39 3397593066 or by the e-mail address arcangelopicciariello@gmail.com or 
donatofrancesco.altomare@uniba.it . 
Clinical queries during office hours should be directed to one of the clinical coordinators or to an 
appropriate member of the Hamlet Management Group 
 
 
 

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Data Monitoring and Ethics Committee 
Clinical data monitoring will be carried out by Ms Angela Accettura: Dept of Emergency and Organ 
transplantation, University of Bari e-mail: angela.accettura@uniba.it  
Tel +39.0805592235 
Independent Ethics Committee of the Azienda Ospedaliero Universitaria Policlinico Consorziale 
Bari 
piazza Giulio Cesare, 11 70124 Bari, Italy   
Tel +39.0805593399 fax +39. 0805575716 e-mail: comitatoetico@policlinico.ba.it 
Protocol approval n. 4555/2014  
Trial Sponsor: University of Bari, Department of Emergency and Organ Transplantation, DETO, 
Section of Surgery, Bari, Italy, Tel: +39 5592107 – +390805478764 
Clinicaltrial.gov ID number:    
 
Protocol version: 14/3/18 
 
Hamlet Study Office 
For general queries, supply of trial materials, and collection of data: 
Trial Coordinator: Prof. Donato F. Altomare,  mobile phone +39.3397593066 – office 
+39.0805478764 e-mail donatofrancesco.altomare@uniba.it 
 
Computing: Dr Arcangelo Picciariello, MD – mobile phone +39 3492185104 – e-mail: 
arcangelopicciariello@gmail.com 
 
 
 
 
 
 

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CONTENTS 
1. INTRODUCTION 
1.1 Background 
Hemorrhoidal disease is one of the most common proctological disease affecting the general 
population from the mid-teens onward with considerable implications for the National Health 
Service (NHS) both from an economic point of view and from surgeon’s workload1. Even if 
hemorrhoids are a benign condition, they severely impact patients’ quality of life. In fact, symptoms 
include bleeding, pain, prolapse, soiling and itch. The treatment of hemorrhoidal disease is directed 
at relieving its related symptoms. 
 
1.2 Management of disease 
While Goligher’s grade I-II hemorrhoids can be readily treated with conservative measures and 
grade IV hemorrhoids find the gold standard treatment in the hemorrhoidectomy, several 
minimally invasive treatment options, including Doppler-guided hemorrhoidal artery ligation and 
mucopexy have been introduced for the management of grade III hemorrhoids with the aim of 
minimizing postoperative pain and sparing the sensitive anoderm 
 
1.3 Doppler guided hemorrhoidal artery ligation 
Improved understanding of the pathogenesis of haemorrhoids and of the complications associated 
with excisional haemorrhoidectomy led to the invention of newer surgical procedures, including 
Doppler guided haemorrhoidal artery ligation (DGHAL).  
This technique was introduced in 1995 by Morinaga et al. and consists in the use of a proctoscope 
with a Doppler transducer that detect the arterial structures[1]. 
Since DGHAL does not involve tissue excision, it is expected to be associated with reduced 
postoperative pain if compared with hemorrhoidectomy[2]. 

5 
 
In the last decade several devices (THD and AMI/ HAL-RAR – Hemorrhoidal Artery Ligation and 
Recto Anal Repair) have been developed in order to improve and facilitate the execution of the 
technique, making easier the procedure [3, 4].   
1.4  Mucopexy 
The addition of suture mucopexy to DGHAL has extended the indication of this technique to III 
degree hemorrhoids with encouraging results in terms of postoperative pain and complication and 
long term recurrences. 
About 6 mucopexy with resorbable sutures are usually performed with this procedure starting 
from 2 o’clock in clockwise direction. 
A RCT and some case series have cast doubts on the usefulness of making DGHAL, claiming that 
mucopexy alone can yield similar results and with less time (Aigner et al). However, these studies 
have some weak points including small sample size and use of different devices. 
2. STUDY HYPOTHESIS  
The hypothesis of the study is that a simple mucopexy procedure by suture-fixation of anal cushion 
without the aim of a Doppler device, could be as effective as DGHAL and mucopexy to manage 
prolapsing grade III hemorrhoids. 
 
3. STUDY DESIGN 
3.1 General Design   
Prospective, multi-centre, parallel-arm randomized controlled equivalence trial. Eligible patients 
will be randomized to either mucopexy without Doppler guided artery ligation or mucopexy with 
doppler guided hemorroidal artery ligation. 
3.2 Endpoints  
3.2.1 Primary  

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Primary aim of the Hamlet trial is to demonstrate that mucopexy without DGHAL for grade III 
haemorrhoids have equivalent recurrence rate at 1 year follow up of DGHAL with mucopexy 
procedure 
3.2.2 Secondary 
- SAFETY: Demonstration that the new treatment will not add related morbidity  
- Comparison of the outcome among the two devices (THD and  AMI/ HAL-RAR) for DGHAL 
-      
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adults with grade III 
Hemorrhoids 
Protocol deviation 
Excluded 
Assessed for eligibility 
Protocol deviation 
Consent 
Not recruited 
Baseline evaluation 
Randomization 
No DGHAL group 
DGHAL group 
1 week follow-up 
1 week follow-up 
Lost to f-up 
Lost to f-up 

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3.2.3 SWOT analysis 
 
 
STRENGHTS 
 
- Possibility to improve patient’s outcome 
and reduce hospital costs 
- Low cost of the new treatment 
 
WEAKNESS 
 
- 
High number of patients to be 
recruited 
- 
Variability of the techniques  
 
OPPORTUNITIES 
 
- 
Applicable to a relevant proportion of 
patients affected by grade III 
hemorrhoids. 
- 
Reduce time of the operation 
- 
Reduce hospital costs  
- 
Improvement of the patients QoL 
 
 
THREATS 
 
- 
Common risks of all surgical 
procedures used for hemorrhoids   
 
 
3.3 Randomization 
Written informed consent will be obtained prior to surgery by the operating surgeon.  Computer-
generated randomization will be used to create an allocation sequence to assign patients to the 
4 weeks follow-up 
4 weeks follow-up 
12 months follow-up 
12 months follow-up 
Lost to f-up 
Lost to f-up 

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different study arms. Randomization will be computer generated and centrally controlled by an 
operator not involved in the study.  
3.4. Subject Recruitment and Screening 
Each patient with grade III hemorrhoids eligible for the inclusion and exclusion criteria will be 
randomized after obtaining written informed consent about the study.  Patients will be given 
information about the risks, discomforts, and potential benefits of both treatments.  The 
randomization protocol will be explained to the patient before consent is obtained. 
 
3.5 Participating Institution and Surgeons  
This multicenter trial is opened to the contribution of surgeons across Europe in order to achieve 
the required number of patient recruitment in the shortest period. 
 All surgeons must have prior experience in the treatment of hemorrhoids with DGHAL and 
mucopexy. 
 All participating institutions must have IRB (Institutional Review Board)/Ethics Committee 
approval in order to enroll patients in the trial. 
 Recruitment of Centers will be by direct invitation or spontaneous proposal of 
Coloproctology Units interested in the study.  
 Surgeons involved MUST have no potential conflict of interests in the procedure 
 
3.6 Definition of Outcome Measures 
Please use the following definitions:  
 duration of the hospital stays (defined as from beginning of surgery to time of discharge, 
measured in hours) 
 questionnaires administered to patients at 1 week, 4 weeks and 1 year follow-up  
 Recurrence is defined as persistent or recurrent hemorrhoid symptoms including prolapse, 
proctorragia, hemorrhoidal thrombosis 
 Hemorrhoidal prolapse is defined as III degree if the prolapse needs to be repositioned into 
the anal canal manually and of II degree if it returns spontaneously into the anal canal.  

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 Hemorrhoid engorgement visible only at control anoscopy but without symptoms will not 
be considered as Hemorrhoidal prolapse 
 Proctorrhagia will be defined as minor if traces of blood can be detected at defecation, 
moderate if there is occasional bleeding at defecation, severe if bleeding occur after any 
defecation 
 
3.6.1 Definition of Adverse Events 
 Urinary retention will be defined as the condition of urinary dysfunction that occurs 
following surgery and requires intervention, including placement of urinary catheter. 
 Pyrexia will be defined as any documented patient temperatures >38.0 C that require any 
treatment intervention such as antipyretics or that result in an increase in hospital stay.   
 Surgical site infection purulent discharge from the wound with positive culture 
 Post operative bleeding  requiring reintervention, or balloon tamponade of the anal mucosa 
or transfusion within 1 month from the operation 
 
3.7 ELIGIBILITY CRITERIA 
3.7.1 Inclusion Criteria 
 Patients over 18 years old 
 Symptomatic grade III hemorrhoids according to Goligher 
 No other source of anal bleeding than hemorrhoids 
 Written informed consent 
 
3.7.2 Exclusion Criteria 
 Any previous hemorrhoid surgery 
 Participants expressing clear preference for one of the interventions 
 Pregnancy 
 Inability to understand the informed consent 
 Oral anticoagulants of congenital defects of the coagulation 
 Patients with immunodepression (i.e.   HIV) 
 Other proctological diseases (fissures, fistulas, condyloma, etc) 
 IBD involving the anus ore the rectum 
 

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3.8 Withdrawal Criteria  
Study participants will be informed of their ability to withdraw from the study or refuse initial 
enrollment at any time. Patients may withdraw without explanation. 
 
4 STUDY INTERVENTION 
4.1 Preoperative work-up 
All the patients will have full proctological examination including anoscopy. Those with familiarity 
for colorectal cancer and those over 50 will be invited to have screening colonoscopy to exclude 
other sources of bleeding 
4.2 Operative protocol 
Patients with symptomatic grade III haemorrhoids will enter the study if they fulfil the entry and 
exclusion criteria and after written informed consent. They will be randomized in 2 groups: DGHAL 
with mucopexy (group A) and DGHAL without mucopexy (group B ). 
A cleansing enemas will be performed early in the morning at least 2 h before the operation. 
Antibiotic prophylaxis was not considered. 
General or epidural anaesthesia will be performed according to the patient or anaesthetist 
preferences. 
A urinary catheter will be inserted in all patients and removed after few hours from the operation. 
The patients will be placed in the lithotomy position. 
 
4.2.1 Technique  
4.2.1.1 Devices: 
THD device produced by THD SpA (Correggio, Italy), consists of a proctoscope equipped with a 
Doppler probe and a light source. The proctoscope model (THD SlideTM, THD SpA) has a sliding part 
comprising the operating window and Doppler probe for better proximal and distal movement 
without repositioning the proctoscope during mucopexy 

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AMI device, HAL-RAR – Haemorrhoidal Artery Ligation and Recto Anal Repair is produced by 
the A.M.I. – Agency for Medical Innovations, Austria. The device includes an illuminated 
proctoscope (RAR Flexi Probe) which is introduced into the rectum, then rotated slowly to search 
for arteries. This proctoscope is connected with a Doppler signal which indicates the position of the 
hemorrhoid arteries. 
 
4.2.1.2 DGHAL 
A lubricating gel is applied to the tip of the THD or the AMI device and, with the patient in the 
lithotomy position, the proctoscope is introduced into the anal canal. The terminal branches of the 
superior rectal artery are detected by the Doppler signal 2–3 cm above the dentate line. The tip of 
the instrument is gently tilted and the arteries are ligated with a figure-of-eight suture using 2 ⁄ 0 
polyglycolic acid inserted using a special needle-holder through an aperture in the operating 
proctoscope.  
4.2.1.3 Mucopexy 
After the haemorrhoid artery ligation, the suture is continued with three to five sutures applied 5 
mm apart, making sure that the last is at least 5 mm above the dentate line. The suture is then tied 
to create a hemorrhoidopexy. The procedure is repeated after all artery ligations (6 ligations). 
In the NON doppler group the mucopexy will start at two o’clock and repeated at 4, 6 8, 10, 12, in 
clockwise direction. 
4.3 Post-Operative Management 
Postoperative care will be according to current standards as directed by the operative surgeon. 
• Pain control will initially be provided using parenteral (intramuscular, intravenous or 
epidural) administration of narcotics or analgesics. 
• bulking agents (psyllium) or osmotic laxatives will be prescribed in order to allow easy 
defecation 
 
 
5.  STATISTICAL ANALYSIS 
5.1 Sample Size Determination: 

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A sample size calculation shows that 100 subjects per arm will suffice for accepting of the equivalent 
hypothesis with power of 0.8 and a type I error probability of 0.05, an equivalent limit of 15% and 
expected percentage of success in both control and experimental group of 90% (sample size 
calculated with R).  
5.2 Statistical Methods: 
Results will be expressed as either mean and standard deviation (SD) or frequency (percentage). 
Between-group comparisons will be performed using Student’s 𝑡 -test (normally distributed data) 
or Mann-Whitney𝑈 test (skew data) for continuous variables or Chi-square test for categorical 
variables. All hypotheses will two-tails with 𝑝 < 0.05 considered as statistically significant.                                       
 
5.3 Subject Population for Analysis 
Data analysis will be performed in accordance with the intention to treat principle. If a violation of 
randomization occurs, all patients will be analyzed according to the original allocation. 
The following information will be prospectively collected and reported: 
 All-randomized population:  Any subject randomized into the study, regardless of whether 
they receive the intervention. 
 Protocol-compliant population:  Any subject who was randomized and received both the 
study intervention and received the required protocol processing. 
 
6. ETHICS 
6.1 Risks of Participation 
Patients in both study arms will be informed of standard risks of hemorrhoid surgery, such as 
bleeding, surgical site infections, thrombotic complications, cardiac, or pulmonary complications.  
6.2 Institutional Review Boards 
This study will be conducted in accordance to the principles of the Declaration of Helsinki and good 
clinical practice guidelines. The study protocol will be approved by the Ethics committee of all 

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participating institutions. Prior to randomization, written informed consent will be obtained from 
all patients.  
6.3 Data Safety Monitoring Committee 
A data safety monitoring board (DSMB) will be established with experts independent of the authors. 
The chairman of the DSMB will receive the clinical data forms continuously from the coordinating 
center and will review data.  The DSMB chair may at any time suggest to the Study Chair to terminate 
the study in case of ethical concerns such as unacceptable complication rates and others. 
 
7. AUTHORSHIP AND PUBLICATION 
The rules described herein apply to any presentation of this study. Members of the Protocol Writing 
Committee as well as Study Chairs qualify for authorship of this study. Vancouver Authorship 
Guidelines 
rules 
shall 
apply 
(for 
full 
document 
please 
see 
full 
article 
at 
http://www.icmje.org/index.html).  Surgeons that include patients will attain authorship through a 
group authorship where names of surgeons will be mentioned. The order of the authors in the group 
authorship according their active contribution to the trial. The study results may only be published 
and/or presented as final analyses after the completion of the study and needs authorization by the 
study chairs. Publication and/or presentation are defined as any article, podium presentation, 
poster, abstract, or any other public presentation of this research. As is generally accepted, 
members of the DSMB should be independent and not involved in the study in any way including 
authorship. 
8. SPONSORSHIP 
The trial is not officially sponsored. 
 
9. APPENDICES 
Consent form  
Form of words 
 

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10.  REFERENCES 
1.  
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2. 
Bursics, A., et al., Comparison of early and 1-year follow-up results of conventional 
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3. 
Ratto, C., et al., Transanal hemorrhoidal dearterialization (THD) for hemorrhoidal disease: a 
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