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《Therapeutic Advances in Gastrointestinal Endoscopy》

2020, Vol. 13: 1–11

Cap-assisted endoscopic sclerotherapy for  internal hemorrhoids: technique protocol  and study design for a multi-center  randomized controlled trial

Xia Wu, Quan Wen, Bota Cui, Yafei Liu, Min Zhong, Yu Yuan, Lihao Wu, Xiaoyin Zhang,  Yunlian Hu, Muhan Lv, Qianneng Wu, Suyu He, Yan Jin, Shuxin Tian, Rong Wan, Xin Wang,  Long Xu, Jianling Bai, Guangming Huang, Guozhong Ji and Faming Zhang

（ on behalf  of China CAES study group）

中国CAES研究小组代表

Abstract：

Background:Cap-assisted endoscopic sclerotherapy is a new interventional therapy for internal  hemorrhoids and rectal prolapse under colonoscopy. The proper length of the endoscopic  injection needle is the core for performing cap-assisted endoscopic sclerotherapy well with more  benefits and less complications. However, no data are currently available to guide endoscopists to  consider the length of injection needle before cap-assisted endoscopic sclerotherapy. This study  is designed to evaluate the efficacy and safety of cap-assisted endoscopic sclerotherapy with long  or short injection needle in the treatment of internal hemorrhoids.

Methods:This is a nationwide multi-center, prospective, single-blind and randomized controlled  trial. Patients with grade I-II internal hemorrhoids who have failed to conservative treatments  and grade III internal hemorrhoids who are not suitable for surgery or refuse surgery will be  included. Participants will be randomized 1:1 into either long or short injection needle group.  The primary outcome is the recurrence rate of internal hemorrhoids 24weeks after cap-assisted  endoscopic sclerotherapy. The secondary outcomes are as follows: (1) symptom severity  score, (2) three-level EuroQoL five dimensions health scale scores, (3) occurrence of adverse  events and severe adverse events, and (4) patients’ attitudes toward cap-assisted endoscopic  sclerotherapy. Data collection will be conducted before and during operation, the 1st day, 1st  week, 2nd week, and 24th week after cap-assisted endoscopic sclerotherapy.

Discussion:The outcome of this study is expected to provide a practical clinical protocol of  cap-assisted endoscopic sclerotherapy for patients with internal hemorrhoids and promote  the use of this new endoscopic technique.

Trial registration:ClinicalTrials.gov, NCT03917056. Registered on 12 April 2019.

Keywords：

cap-assisted endoscopic sclerotherapy, endoscopy, hemorrhoids, prolapse,  randomized controlled trial, sclerotherapy

DOI：

10.1177/2631774520925636

Hemorrhoids are collection of submucosal, fibro-vascular, arteriovenous sinusoids that are part of  the normal anorectum.1 Symptomatic internal  hemorrhoids are usually characterized by painless  bleeding after defecation, prolapse, anal itching/dampness perianal discomfort and soiling.1 However, the reasons why internal hemorrhoids  become symptomatic remain controversial.  Nowadays, globally recognized that internal hem-orrhoids result from the sliding and deterioration  of the connective tissue of anal cushions, together with the stagnation of blood inside the dilated  hemorrhoidal plexus.2,3 Treatment of internal  hemorrhoids depends on symptoms and the  degree of it, whose substantial progress has been  made in the past few decades.4 Office treatments  or surgical treatments should be considered when  conservative treatments such as dietary modifica-tion, lifestyle changes, and medical therapies do  not respond well.5 To maintain the integrity of  anal cushion, reduce the postoperative pain, save  medical cost, and preserve patients’ working days,  patients prefer to choose the office-based proce-dures like rubber-band ligation (RBL), injection  sclerotherapy, infrared coagulation, laser photo-coagulation, and others.1,5,6 However, clinical tri-als investigating the effectiveness of treatments  for internal hemorrhoids lack uniformity of out-come measurement, which resulted in a wide  variety in outcomes between studies and a debate  regarding the best treatment option for each grade  of internal hemorrhoids.7

The RBL and injection sclerotherapy are the  mainstay of office treatments.5,8 The RBL is cheap  and effective, while the high recurrence rate,  repeat banding, severe late bleeding, and postop-erative pain lower patients’ satisfaction.9–11 Injection sclerotherapy represents as a safe and  simple palliative treatment for internal hemor-rhoids,1,12,13 with a relatively low occurrence of  post-procedural pain and bleeding.1,5,14 However,  misplaced injections may result in iatrogenic risks,  including pain, perianal abscess, impotence, pros-tatitis, mucosal ulcer, prostate abscess, rec-tourethral fistula, and other complications.1,5,15 Importantly, as we know, cap-assisted endoscopic  sclerotherapy (CAES) has not been used in  Europe and North America. The reports on scle-rotherapy from those areas should refer to tradi-tional office procedure. Inverted operation with  anoscope often used in traditional injection sclero-therapy, which has a blind area, affecting precise  operation. Therefore, a novel technique called  CAES was designed for internal hemorrhoids in  virtue of interventional flexible endoscopy.

The CAES is an innovative endoscopic sclerother-apy procedure that is superior to traditional injec-tion sclerotherapy in the following aspects. First,  the cap added to the front of colonoscope can fully  expose the operating field. Second, before or dur-ing the opportunity of CAES, endoscopist can per-form endoscopic differentiation diagnosis (such as  tumors, inflammatory bowel disease, and others  induced hematochezia) and endoscopic therapy within lower gut based on the same colon prepara-tion, thus saving patients’ medical cost, and physi-cal and mental pain. The last but not least, specially  designed length of endoscopic injection needle  (e.g. 14–20mm) that was used in CAES could be  helpful for accurately controlling the injection  angle, direction, and depth under direct vision,  and to avoid iatrogenic injury due to ectopic injec-tion.12,16 Our previous studies have shown that  CAES is effective in treating internal hemorrhoids,  with fewer adverse reactions and higher patient  satisfaction,12,16 and CAES has been carried out in  many hospitals in China. However, the length of  marketing available endoscopic needle generally  ranges 3 to 5mm. Due to the shallow injection  depth, we hypothesize that the sclerosing agents  may cause complications such as artificial ulcer  and secondary bleeding. In addition, using short  injection needle may need retroflection that would  affect precise operation or damage endoscope. In  general, the above shortcomings can be overcome  by CAES based on long injection needle, which  might be conducive to the hemostatic effect and  the improvement of the prolapse symptoms of  hemorrhoids.

However, there is no solid clinical evidence to sup-port the differences between the use of long or  short injection needle during CAES. Therefore, a  nationwide multi-center (centers and participants  involved in the trial were listed in Supplementary  Data), prospective, single-blind, and randomized  controlled trial was designed to evaluate the effi-cacy and safety of CAES with long or short injec-tion needle in the treatment of internal  hemorrhoids, to provide reliable evidence for pop-ularization of this minimally invasive technology.

Methods

This nationwide multi-center, prospective, sin-gle-blind, and randomized controlled trial will be  conducted in China. Medical Center for Digestive  Diseases of the Second Affiliated Hospital of  Nanjing Medical University is the responsible  unit for this study. Flowchart of the trial is shown  in Figure 1. The procedure and checklist of the  protocol are displayed in Figure 2.

Informed consent will be obtained from each  case. A screening visit will be carried out to ensure  the patient eligibility. The participants will  undergo colon cleaning prior to CAES and be  individually randomized to the long injection nee-dle (14mm, 23G, FMT-CAES/1800/14, FMT medical, Nanjing, China) or the short injection  needle (4mm, 23G) group. Data collection will  be conducted before and during operation, the  1st day, 1st week, 2nd week, and 24th week after  CAES. The data will include the recurrence of  internal hemorrhoids after CAES, the intraopera-tive conditions, the incidence of adverse events  (AEs), the patients’ attitudes to CAES, and the  completion/termination of the trial.

Inclusion criteria

Patients of any age with grade I-II internal hem-orrhoids (with or without external hemorrhoids)  that are troublesome to life after conservative  treatment will be eligible to attend the trial.  Patients with grade III internal hemorrhoids who  are not suitable for surgery or reject surgery will  also be included. All patients will be required  total colonic cleaning and undergone colonos-copy following with CAES.

Exclusion criteria

Patients who had preexisting medical conditions,  including history of anal/endoscopic sclerotherapy,  perianal abscess, stricture, fissure, fistula, fecal  incontinence, and inflammatory bowel disease,  will be excluded. Hypertensive patients with  uncontrolled blood pressure and patients with  antiplatelet drugs or anticoagulants, acute diarrhea in the last 24 hours, mental disorders, pregnancy,  decompensated cirrhosis, cerebrovascular acci-dents, any blood coagulation dysfunction, and  other severe complications (such as severe anal  pain with Numerical Rating Scale [NRS] ⩾7) are  unsuitable for inclusion. Patients that diagnosed  acute thrombotic hemorrhoids or grade IV internal  hemorrhoids will be excluded as well.

Proposed sample size

Sample size calculation was carried out using  Stata software system (version 14.0, StataCorp,  College Station, TX, USA). Assuming the pro-portion of patients who experienced recurrence  following CAES with long injection needle is 10%  and with short injection needle is 16% by refer-ence to previous studies using sclerotherapy for  internal hemorrhoids,12,14,16,17 the sample size  required to detect a difference in the recurrence  rates with 80% power and 5% significance is 525  individuals per group. To account for any  between-endoscopic operator variation and follow -up loss, we propose increasing this to 578 per  group (a 10% increase).

Classification of internal hemorrhoids

Internal hemorrhoids are graded based on protru-sion and reducibility, for which the specific crite-ria are as follows5:

Grade I: prominent hemorrhoidal vessels but no  prolapse; Grade II: hemorrhoids prolapse only with strain-ing and spontaneous reduction; Grade III: hemorrhoids prolapse beyond the den-tate line with straining and require manual  reduction; Grade IV: hemorrhoids prolapse beyond the den-tate line with straining and manual reduction  ineffective.

Randomization

A remote, web-based randomization system  (Medical Data, Unimed Scientific, Inc, Wuxi,  China) will be used to generate random numbers  for the participants. Patients will be divided into  the long injection needle group (n = 578) and  the short injection needle group (n = 578) at a  ratio of 1:1 according to the random numbers.  The Medical Data application program (APP;  System developed by Unimed Scientific, Inc,Wuxi, China) will directly display the randomly  assigned treatment group to instruct physicians to  select injection needles for CAES.

Concept and methods of CAES

Figures 3 and 4 showed the concept of CAES.  Table 1 outlined the differences between the  CAES based on long injection needle and short  injection needle.

1. The conventional short and straight trans-parent cap is fixed on the top of endoscope,  which is used for maximizing visibility of  the targeting field for diagnosis and  injection.

2. A disposable endoscopic injection needle  through the endoscopic channel is used to  inject the sclerosing agent into submucosal  layer.

3. The 6 o’clock position under endoscopic  view is the best site for injection. The needle  should be advanced to the targeted points,  which are above the dentate line to prevent  postoperative pain. The sclerosing agent is  injected into submucosal layer during 5sec-onds when the long needle is slowly remov-ing out of tissue. However, the injection  cannot be performed during the withdrawal  of short needle. During the procedure,  proper air is delivered for the proper expo-sure of the endoscopic view. Very quick  injection and more than 2mL injection in  one site are not permitted, because this seems  to increase the risk of huge bump following  with artificial ulcer, bleeding, and pain.

4. Before the needle is taken out of injection  site, it is required to keep needle stable  without moving for at least 5 seconds  for preventing bleeding from needle  track. No bleeding is the indication of  perfect injection.

5. The clockwise order should be followed  for choosing the injection sites, then the  color tracer is not required to differentiate  the injection sites. The methylene blue  tracer is not recommended, but it can be  used for some beginners under CAES  training to differentiate location in case of  getting lost in many injection sites.

6. It is required to have enough suction for  air and residual fluid in the colon before  ending procedure.

7. Both antibiotics and hemostatics generally  are not required during the operation  period.

8. Patients will be required to stay in the hos-pital for bed rest on the first night after  CAES during this trial for safety control.

9. Medications should be administered in  patients complicated with constipation or  chronic diarrhea for preventing recurrence  of internal hemorrhoids. Suppository  drugs are permitted to use when necessary.  Medications used should be recorded  carefully and taken into consideration  when analysis.

10. Patients should be given health education  on fiber and fluid intake, bowel patterns  (including stool frequency), and bathroom  habits (e.g. posture and reading on the  toilet).

The sclerosing agent in the present study is  Lauromacrogol injection (Tianyu Pharmaceutical,  Xi’an, China). Researchers are required to upload  the endoscopy report in details after CAES, includ-ing the description on procedure, type of needle,  and endoscopic images as shown in Supplementary  Table 1 to the Medical Data APP. Since 2014 up  to 2019, the CAES has been used in more than  500 hospitals for hemorrhoids in China.  Researchers involved in the present trial are  required to be advanced endoscopists. All research-ers must be trained by watching the standard  CAES video from Dr Faming Zhang and endos-copy training from advanced CAES experts. At  least 5 cases of CAES were performed prior to  recruiting case to this study for each researcher.

Outcome measures

The outcome measures and the follow-up points  are shown in detail in the Supplementary Tables.

The primary outcome measure is “the recurrence  rate,” defined as the proportion of patients with  recurrent hemorrhoids at 24 weeks post-CAES,  as derived from patients’ self-reported answer to  the following questions simplified by the  Shanmugam and colleagues’18 criteria: “At the  moment, do you feel your symptom (anal pain,  prolapse, itching, soiling and blood loss) from  your hemorrhoids are (1) cured or improved  compared with before starting treatment or (2)  unchanged or worse compared with before start-ing treatment.” Patients will be considered to  have recurrent hemorrhoids when any of the fol-lowing are recorded19: (1) “Unchanged or worse  compared with before starting treatment” at 24th  week as reported by the patient, or (2) seeking  repeat CAES treatment, alternative non-surgical/ surgical treatments for internal hemorrhoids  within 24weeks (except medication treatment),  or (3) presence of any symptoms or events that  strongly indicated recurrent hemorrhoids among patients not meeting (1) or (2). During follow-up,  endoscopic examination will be performed when  the patients develop uncontrollable anal pain,  bleeding, or when repeat CAES is necessary  because of recurrence.

The secondary outcome measures are as follows.  (1) Symptom severity score20 (Supplementary  Table 2): five questions about hemorrhoidal  symptoms (anal pain, prolapse, itching, soiling,  and blood loss) will be self-assessed by patients  by answering how often each symptom was  encountered (never, sometimes, weekly, or  daily). The score is the sum of the points from all  five questions, ranging from 0 to 15 points,  where an increase in number is an increase in  symptom. Specially, anal pain is described using  NRS. Numbers 0 to 10 represent different  degree of pain, with Grade 5: 0=painless,  1~3= mild pain (sleep is unaffected), 4~6= mod-erate pain, 7~9=severe pain (inability to fall  asleep or waking up in sleep), 10=intense pain.  It is worth to note that patients with severe or  intense anal pain should be excluded during  screening. (2) Three-level EuroQoL five dimen-sions (ED-5Q) health scale scores: the ED-5Q  questionnaire includes five dimensions (mobil-ity, self-care, usual activities, pain/discomfort,  anxiety/depression), with three levels in each  dimension (no/moderate/severe problem), which  has been appeared to be sensitive to changes in  patient outcomes in previous studies in this area.19,21 Through the Chinese time trade-off  (TTO) value table, the health status of five  dimensions will be converted into a preference  weight of a ED-5Q index score for further  analysis.22 (3) AEs and SAEs (severe adverse  events): AEs refer to adverse medical events that  occur during or after CAES, including bleeding,  anal pain, having difficulties in passing gas and  defecation, urinary retention, infection, ulcer/ bleeding in the injection points under endo-scopic examination (5–7 days after CAES), and  other symptoms. The SAEs include serious  complications directly or indirectly related to the  CAES, such as death, massive blood loss, incon-tinence, perforation, fistula, anal stenosis,  abscess, and sepsis.23,24 (4) Patients’ attitude  toward CAES: the survey on the satisfaction  with CAES efficacy, the degree of pain relating  to CAES, and the willingness to recommend  CAES to others in the 24th week.

Safety assessment and management

The AEs are classified as mild, moderate, and  severe according to the degree of impact on daily  activity. The relationship between AEs and CAES  is divided into five grades, including absolutely  relevant, possibly relevant, possibly irrelevant,  absolutely irrelevant, and immeasurably, accord-ing to the basis of the occurrence time of AEs,  symptoms and changes in AEs after cassation/ repetition of CAES.

Previous study has shown that CAES using long  needle is a safe technique with very few AEs.12,16 However, possible risks should be considered for  physicians who do not control the angle, direc-tion, and depth of injection under endoscopic  view as well. In general, mild AEs caused by  CAES can be alleviated by themselves without  special intervention. In addition to the following  situations: (1) unexplained large amount of bleed-ing or severe pain after CAES, with ineffective  conservative treatments, endoscopic examination  should be taken to find etiology and do corre-sponding treatments; (2) rational use of antibiot-ics when suspected postoperative infection  aggravates; (3) continuous difficulty in passing  gas after CAES, enema, blinden, subcutaneous,  or intramuscular injection of neostigmine will be  helpful; and (4) repeat CAES or other treatment  options should be adopted if symptoms are not  improved significantly or even worse than before,  or the recurrence of internal hemorrhoids.

In case of SAEs, treatments should be given  according to the patient’s condition. Timely report  to the project sponsor, ethics committee, blinding  unit, regulatory authority in accordance with the  Sponsor’s Standard Operating Procedures (SOPs).  Site staff will be responsible for reporting SAEs  and complete an SAE form. The possible most  important SAEs is deep infection with pain, swol-len, and redness after CAES. Antibiotics should be  used in time to control the infection.

Termination criteria

Completion of the trial or the current data are  sufficient to explain the problem to be verified in  this trial.

Statistical analysis plan

Stata software (version 14.0, StataCorp) will be  used to analyze the data. The data with the nor-mal distribution will be presented as mean±stand-ard deviation, while those with abnormal  distribution will be displayed as median (inter-quartile range [IQR]). Differences in the primary  outcome measure and recurrence rate of internal  hemorrhoids between the two groups will be ana-lyzed by chi-square test. Binary logistic regres-sion, the Wilcoxon rank-sum test, or other tests  will be used to analyze the differences and the  contributing factors to the possible differences  between the two groups. p < 0.05 will be consid-ered statistically significant.

Ethical approval

This trial has been approved by Medical Ethics  Committee of the Second Affiliated Hospital of  Nanjing Medical University and all ethics com-mittee at other participating centers.

Discussion

Injection sclerotherapy dates back at least one  century and has been regarded as a simple and  convenient office procedure for internal hemor-rhoids.25 However, the development of this mini-mally invasive therapy has been used much less  than before because of ectopic injection. The  CAES was coined as an innovation technique for  having advantages in accurately controlling the  injection angle, direction, and depth under direct  vision of flexible endoscope. The core value of  CAES for internal hemorrhoids and rectal pro-lapse is to provide precise therapy, reduce the iat-rogenic injuries, and avoid pain during and after  therapy. Our pilot studies demonstrated that  CAES based on long injection needle is an effec-tive, safe, and convenient operation technique12,16;  100% of participants who underwent CAES  showed sustained clinical efficacy within the  3-month follow-up, with no severe or obvious  complications related to CAES.16 The CAES is  helpful to avoid doctor’s face close to patient’s  anus. Notedly, gastroscope is recommended only  for CAES with short injection needle where retro-flection of the endoscope is necessary, of which  the softer material and thinner diameter make it  more flexible in operation. We have to clarify that  there is no necessary to perform retroflection  when using colonoscope and long needle in  pracitce.

The length of injection needle is controversial in  the process of injection sclerotherapy. Tomiki  and colleagues15 suggested that short needle can  avoid inserting into dangerous areas such as  mucosal muscular layer. They recommend using  3-mm short needle to reduce ectopic injection.15 On the contrary, the short injection needle was  not suggested in CAES because its short length  needs to multiple-site injections, which may lead  to more mucosal injury, potential inflammation,  and complications such as artificial ulcer and sec-ondary bleeding due to the shallow injection  depth and imprecise operation caused by the ret-roflection of endoscope. Reasonably, the long  injection needle would bring more benefit to  patients and endoscopists, which requires data to  prove its authenticity.

Studies on the treatment of hemorrhoid disease  have shown considerable heterogeneity because  of the variety of outcome measurements. The  outcome measurements we chose based on the  Core Outcome Set for hemorrhoid disease devel-oped by Breukink and colleagues and the  European Society of Coloproctology may improve  the quality of our research and enhance the analy-sis of evidence.7 A previous research indicated  that the physical appearance of the postoperative  anal cushions and patients’ symptoms are poorly  correlated, meaning anorectal visualization is not  a reliable surrogate of success.26 Our clinical  experience and principal management for hemor-rhoids shows that there is no need to review colo-noscopy within half a year after CAES treatment.  We therefore used a simple, dichotomized defini-tion of recurrence based on Shanmugam and col-leagues’18 systematic review definition and  measured this at 24weeks post-CAES.

Patients might benefit much more from CAES  than traditional office injection sclerotherapy. The  diagnosis of hemorrhoids is not difficult, but mis-diagnosis and missed diagnosis often exist in clini-cal practice. It is not rare to misdiagnose malignant  tumors as hemorrhoids.1,5,27 Patients with ulcera-tive colitis and Crohn’s disease were reported to  have hemorrhoids, suggesting that colonoscopy  examination before CAES will be conducive to  early diagnosis of inflammatory bowel disease with  hemorrhoid symptoms by determining intestinal  lesions.28 In addition, hematochezia can result  from hemorrhoids, diverticulosis, mucosal abnor-mality/colitis, polyp or multiple polyps, tumor,  solitary ulcers, and other diseases.12,29 Therefore,  CAES was originally designed not only for patients  who had been clearly diagnosed hemorrhoids that  needed therapy but for patients who needed colo-noscopy to clarify a diagnosis and then performed  possible CAES (patients diagnosed of internal  hemorrhoids under this colonoscopy) during the  same opportunity of colonoscopy. Moreover,  30.0% and 41.6% of patients underwent other  endoscopic procedures such as polypectomy, neo-plasia resection, excision of anal papilla fibroma,  biopsy during CAES in our previous studies,12,16 which undoubtedly reduced patients’ medical  costs and the physical and mental pain caused by  anesthesia, intestinal preparation

There are some limitations in this study, which  were not designed to compare the efficacy and  safety of other office-based procedures like RBL.  Furthermore, this is a single-blind design study, because the visualization of the operation cannot  be double-blind.

Conclusion

In summary, we assume that long injection nee-dle for CAES could lead to better efficacy and less  AEs, and achieve higher patient satisfaction than  that observed with short needle. This multi-center  randomized controlled study is expected to pro-vide the solid evidence to guide endoscopists to  perform CAES for internal hemorrhoids and  move CAES forward.

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