Protocol

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achalasia. Alternatively, LES pressure can be reduced by forceful endoscopic stretching or by surgical myotomy. Forceful endoscopic dilation of the LES can be ...
Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Boeckxstaens GE, Annese V, Bruley des Varannes S, et al. Pneumatic dilation versus laparoscopic Heller’s myotomy for idiopathic achalasia. N Engl J Med 2011;364:1807-16.

Academic Medical Center Amsterdam The Netherlands

A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

STUDY PROTOCOL

Central site Academic Medical Center Meibergdreef 9 1105 AZ Amsterdam The Netherlands Phone : +31 20 566 91 11 Fax : +31 20 691 07 33 E-mail : [email protected] Central site team Principal Investigators: Guy E.E. Boeckxstaens, MD, PhD (Dept. of Gastroenterology) Olivier R.C. Busch, MD, PhD (Dept. of Surgery) Trial nurse : Aaltje Lei (Dept. of Gastroenterology) Research technician : Cynthia B. Verkleij (Dept. of Gastroenterology)

January 2003

A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

Background and study objectives Achalasia is a rare esophageal motor disorder with an annual incidence of 1 per 100 000 persons, clinically characterized by dysphagia, chest pain and regurgitation of undigested food. These symptoms result from esophageal aperistalsis combined with a defective relaxation of the lower esophageal sphincter (LES), leading to impaired propulsion of the bolus and stasis of food in the esophagus. Abundant evidence illustrates that degeneration and dysfunction of the intrinsic inhibitory innervation of the esophagus, with absence of nitric oxide releasing neurons is the underlying abnormality. The exact cause remains to be determined, although a genetic, auto-immune or an infectious origin of the neural damage has been suggested. As the neural damage is irreversible, treatment is aimed at reducing the resistance to flow at the level of the esophagogastric junction, rather than to restore esophageal motility. This can be achieved by relaxing the LES with pharmacological agents such as nitroderivatives or Ca2+ channel blockers, or by endoscopic injection of botulinum toxin. The clinical benefit of these approaches is however short-lasting or only successful in the early stage of achalasia. Alternatively, LES pressure can be reduced by forceful endoscopic stretching or by surgical myotomy. Forceful endoscopic dilation of the LES can be accomplished with a balloon dilator designed to distend the LES to a diameter of 30-40 mm aimed at reducing LES pressure by disrupting the sphincteric muscle. Several types of dilators have been described, of which pneumatic dilation using the Rigiflex balloon is most commonly used. The success rate of this technique varies widely between 60 and 85 %. Clearly, such figures strongly depend on the criteria used to define success, but also on the length of

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A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

follow up, especially as it is well documented that symptoms in patients with achalasia often relapse after treatment. The other most commonly used treatment is surgical myotomy. With the introduction of the laparoscopic technique, the surgical approach has gained a lot of interest, especially since the morbidity has significantly improved and the results so far are excellent, ranging between 90-95 %. These data have given rise to a continuously increasing enthusiasm especially for the laparoscopic Heller myotomy combined with a Dor fundoplication. In the past, gastroenterologists were not enthousiastic about the surgical approach due to the invasiveness and the concurrent morbidity. Therefore, since the introduction of endoscopic pneumodilation more than 30 years ago, this technique has been the treatment of choice in many centers. It should be stressed though that a large proportion, if not the majority of patients requires retreatment during the course of their disease. Furthermore, this technique can be complicated by esophageal perforation in 1-3 %, and the success rates are lower than those reported for surgery. To date, the choice of treatment is largely dictated by the experience of the physician, rather than on evidence-based data. So far, only one randomized study has compared the endoscopic and the surgical approach. The outcome of this trial favored surgery, but it should be emphasized that the endoscopic technique used was certainly not optimal. The excellent results recently reported in the literature on the laparoscopic approach and the low morbidity however seriously question the endoscopic approach, mainly as it requires re-treatment, each time exposing patients to potential risks such as aspiration and esophageal perforation. Unfortunately, no randomized comparative data are available identifying the optimal treatment for patients

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A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

with achalasia. Therefore, the major aim of this multi-center study is to compare the two state-of-the-art treatments, namely pneumatic dilation and laparoscopic Heller myotomy according to Dor in a randomized prospective manner. In addition, the scale of the present study provides an ideal opportunity to collect a significant number of DNA samples allowing the evaluation of the contribution of possible genetic factors in achalasia. Details of this study protocol will be described elsewhere.

1. Specific study objectives 1.1. Primary study objectives 1.1.1. Symptom control 1.1.2. Therapeutic success This study is designed to evaluate which of the two treatment modalities under study results in the best symptom control and thus in the highest success rate after 1 year. Thereafter, follow-up will continue and similar analyses will be performed yearly to determine the long-term outcome of both treatment arms. As described in more detail later, symptoms will be evaluated using the Eckardt scoring system. Therapeutic success is defined as a reduction of at least 2 points leading to an Eckardt score of 3 or less. This implies that only patients with a Eckardt score > 3 will be included in order to be able to detect a relevant drop in symptom score. Six months and 1 year after treatment, the number of patients with a successful symptom control will be determined for both groups of treatment. If symptoms

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A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

recur within the first year of follow-up in patients randomized for pneumatic dilation, retreatment with pneumatic dilation is allowed. If retreatment however does not result in reduction of the symptom score below 4, the patient will be considered as a failure. In case of a failure, patients will be offered the choice to undergo an alternative treatment (surgery, botox), and will be excluded from the study. When patients successfully treated with pneumatic dilation develop recurrent symptoms during the longer (> 1 year) follow-up period, retreatment is allowed. Treatment is started with a 35 mm balloon, and symptoms are evaluated 4 weeks later. In case the Eckardt score is still above 3, redilation with a 40 mm balloon will be performed. After this second series of pneumodilation, symptoms should be controlled for at least 2 year before a third and last session is allowed. If symptoms occur before this 2 year interval, the patient is considered as a failure. In total, only three dilation sessions will be allowed. If symptoms recur after the third series of dilations, this patient is considered as a failure. If symptoms recur after surgery, the patient should be considered as a failure and other treatment options are discussed with the patient. 1.1.3 – Follow-up of failures If treatment fails (pneumatic dilation or myotomy), other treatment options are to be considered. The investigator/attending physician will judge (in consultation with the subject) which treatment modality should be used in case of re-treatment. There are no obligatory re-treatment modalities.

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A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

For all failures the follow-up visits should be scheduled with regard to the date of alternative treatment instead of to the date of initial treatment, starting with visit 3 (1 month after alternative treatment). All data should be filled out in a new, blanc CRF.

1.2. Secondary study objectives 1.2.1. Quality of life 1.2.2. Complication rate (related to the procedure, GERD) 1.2.3. Need for retreatment 1.2.4. Costs 1.2.5. LESP (Lower esophageal sphincter pressure) The quality of life will be determined using a general QoL questionnaire, namely the SF36 questionnaire. In addition, a more disease specific questionnaire, i.e. the EORTC QLQ-OES24 questionnaire, will be filled out. These questionnaires will score the QoL at fixed time points during follow-up (3 months, yearly). As discussed in detail in section 3.1. and 3.2, complications (perforation, bleeding, aspiration, infection, sepsis, …) occurring during or immediately following the procedure will be recorded. In addition, reflux symptoms will be scored using a disease-specific questionnaire (HRQL) and gastroesophageal reflux will be measured using 24h pHmetry after 1 year. As described above, retreatment is allowed to some degree. The number of retreatment sessions after the initial therapy (pneumodilation or surgery) will be compared between the two groups.

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A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

Costs will be calculated for each procedure in each center separately.

2. Patient selection criteria 2.1. Inclusion criteria:  Between 18 and 75 yr of age  Manometric diagnosis of achalasia  Eckardt score > 3  Informed consent

2.2. Exclusion criteria:  Severe cardio-pulmonary disease or other serious disease leading to unacceptable surgical risk  previous treatment, except treatment with nitroderivatives, Ca++ channel blockers or sildenafil, or dilation with Savary bougies or balloons of 2 cm diameter or smaller.  Pseudo-achalasia  Mega-esophagus (> 7 cm)  Previous esophageal or gastric surgery (except for gastric perforation)  Not capable to fill out questionnaires (f.e. due to language barrier)  Not available for follow-up  Esophageal diverticula in the distal oesophagus

2.3. Stratification

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A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

2.3.1. Patients will be stratified according to age (< or > 40 years) 2.3.2. Patients will be stratified per center

3. Treatments 3.1. Pneumatic dilation 

Clear liquid diet for at least one day before the procedure. If the esophagus still contains solid material, the esophagus should be cleaned by lavage.



Conscious i.v. sedation. The choice of the sedatives used is free, but should be recorded in the CRF.



The balloon (Rigiflex) is positioned fluoroscopically along the diaphragm. At inflation of the balloon with 1-3 PSI, correct positioning of the balloon with indentation in the middle of the balloon. The position can be checked by fluoroscopy or endoscopy.



Dilation with 5 PSI during 1 min, followed by 8 PSI during 1 min



After the procedure, the patients will be monitored at least 2 hr. Before leaving the hospital, they will be asked to drink some water.



In case of clinical suspicion of esophageal perforation (pain during drinking of water), an esophagram with water-soluble contrast will be made. A perforation is defined as the extramural extravasation of contrast at the esophagram. Treatment can be either nothing by mouth and antibiotics i.v. or surgery. In case of perforation, the patient will remain in the study for further follow-up.

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A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia



In case of hematemesis or melena, the haemoglobin level will be determined to assess the severity of the GI bleeding. The treating physician will decide whether re-endoscopy is required based on clinical judgement.



Aspiration will be recorded as complication if aspiration if evident during the procedure or if a pneumonia develops within one week.



Standard treatment consists of 2 dilations. The 1st dilation is performed with a 30 mm balloon, followed by a 35 mm balloon within 2 weeks. If necessary, due to for instance travel distances, the 2nd dilation may be performed the day after the 1st dilation.



If the drop in Eckardt score is less than 2 points and/or the total score is still greater than 3 after 4 weeks (compared to the Eckardt score at visit 1), a 3rd dilation with a 40 mm balloon will be performed.



After this standardized protocol, re-dilation for recurrent symptoms will be done with a 35 mm balloon, followed by a 40 mm balloon if Eckardt score is still above 3 (assessed 4 weeks after the first dilation). A third and last series of dilations is only allowed two years later. If symptoms recur within 2 years after the second series of dilations, the patient is considered a failure but will remain in follow-up.

3.2. Laparoscopic Heller myotomy + Dor fundoplication 

It is important that the operation is performed by a surgeon with experience in this laparoscopic procedure (at least 30 laparoscopic GE junction operations of which 5 myotomies). If the local surgeon is not experienced enough, an

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A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

experienced surgeon should be present during the operation. The procedure will be recorded on video to make evaluation afterwards possible. 

Before the procedure a nasogastric tube is inserted and remnants of food are removed. Crash intubation is advised to avoid aspiration.



For the laparoscopic Heller myotomy a five trocar technique is used with the patient in the French position as used for laparoscopic anti-reflux procedures. A 12 to 15 mm Hg pneumoperitoneum is established. A left paramedian trocar is used for the camera (for optimal visualisation a 30 degree optical system is advised) and two lateral trocars for elevating the liver and retraction of the stomach and two trocars for dissection and suturing. It is allowed to use robotic surgery devices.



The phrenoesophageal ligament is divided starting on the right by opening the lesser sac and the distal esophagus is mobilized on the lateral and anterior side. The anterior vagal nerve is identified and spared. The myotomy is performed by dividing both muscle-layers extending at least 6 cm above the gastroesophageal junction and at least 1-1.5 cm inferiorly over the stomach. The extent downwards is performed after dividing the well vascularized epiphrenic fat pad overlying the cardia. The length of the myotomy is measured.



Peroperative endoscopy and manometry are not performed but a check for perforation may be performed by the modality used as the local standard.



An anterior fundoplication according to Dor is routinely performed. Only if necessary the fundus of the stomach is mobilized by dividing the short gastric

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A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

vessels. The fundus is sutured to both cut edges of the myotomy. using nonresorbable material (3-0 ethibond). 

Conversion to open technique is sometimes necessary. If so, the patient will remain in the study thereafter.



A nasogastric tube can be removed within 24 hours. A gastrografin swallow the day after to confirm esophageal emptying without leakage is only performed in case of clinical suspicion for perforation. Thereafter patient is allowed to eat food and may be discharged. No postoperative medication is given routinely.



Depending on the trial center: resection of muscle for histological studies will be obtained.

If symptoms recur after surgery with an Eckardt score > 3, the patient is considered as failure and pneumatic dilation with a 35 mm Rigiflex balloon will be offered. Failures will remain in follow-up.

4. Methods 4.1. Manometry In order to assure adequate recording of LES pressure, especially during swallowing, the manometry should be performed using a sleeve assembly. The basal LES pressure and the swallow-induced LES relaxation will be monitored and measured at the end of expiration. After introduction and equilibration, basal pressure is monitored during at least 5 minutes. Swallow-induced relaxation of the sphincter is assessed by 5 ml wet swallows, at least 30 s apart. Achalasia is

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A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

diagnosed if at least 1. Aperistalsis is present, and 2. The nadir pressure of the LES > 10 mm Hg.

4.2. Esophageal emptying According to de Oliveria et al. (Am J Rontgenol, 1997), patients will ingest low density barium sulphate over 30-45 s. The patients will be instructed to drink the amount of barium they can tolerate without regurgitation or aspiration (200 ml). With the patient upright in a slight left posterior position, a radiograph is taken at time = 0, and after 1, 2 and 5 min. The distance from the tapered distal esophagus to the top of the barium column and the maximal diameter are measured. The five min barium height is used as measure of esophageal emptying. The height is measured relative to the height of the vertebrae (level of the diaphragm).

4.3. Symptom score (Eckardt) According to Eckardt et al. (Gastroenterology, 1992), weight loss, dysphagia, chest pain and regurgitation will be scored on a scale from 0 to 3. See below. Score

Weight loss (kg)

Dysphagia

Chest pain

Regurgitation

0

None

None

None

None

1

10

Each meal

Several times a day

Each meal

4.4. Gastroesophageal reflux symptom questionnaire

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A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

The HRQL questionnaire, specifically assessing reflux complaints, will be filled out at fixed time points (see enclosed schedule).

4.5. Quality of life Both a general (SF-36) and a disease-specific quality of life questionnaire (EORTC QLQ-OES24) will be filled out at multiple time points (see enclosed schedule).

4.6. Endoscopy + Lugol staining (optional; The Netherlands only) In order to evaluate prospectively the risk to develop dysplasia and/or esophageal carcinoma, endoscopy combined with lugol staining (biopsy) will be performed every 3 year.

4.7 Sample prelevation (optional; The Netherlands) During laparoscopic myotomy resection material will be obtained for histological studies to determine whether auto-immune responses play a role in the inflammation within the esophageal myenteric plexus as seen in patients with achalasia. Blood samples will be obtained and the sera will be analyzed to determine the presence of myenteric neuronal antibodies and to evaluate which antigens are recognized by these antibodies. All samples will be marked with a unique code number and stored at the central site, maintaining confidentiality. Only the investigator at the study site can identify the patient. The patient will continue to be the owner of the sample and retains the

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A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

right to have the sample material destroyed at any time by contacting the investigator. The tissue samples and sera may be stored for up to 20 years to research scientific questions related to achalasia.

4.8 – DNA isolation (optional; The Netherlands)

As approximately 200 patients will be included in this study, enough blood samples for DNA analyses can be obtained to evaluate a possible genetic background of achalasia. Therefore, an extra blood sample will be taken for DNA analysis. All samples will be marked with a unique code number and stored at the central site, maintaining confidentiality. Only the investigator at the study site can identify the patient. The patient will continue to be the owner of the DNA sample and retains the right to have the sample material destroyed at any time by contacting the investigator. The DNA samples may be stored for up to 20 years to research scientific questions related to achalasia.

5. Trial design Before

1 month

6 months

1 year

Every yr

Demographics

×

Symptom score

×

×

×

×

×

QoL

×

×

×

×

×

Manometry

×

×

×

×

24h pH metry Esoph. emptying

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× ×

×

×

Every 3 yr

× ×

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A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

Endoscopy

×

Laboratory

×

EUS or CT *

×

×

×

* Only if pseudo-achalasia is clinically suspected.

6. Registration and randomization of patients Patients will be registered in a trial center file at each center. In order to guarantee the privacy of the included patients, a numeric code will be used such that only the investigator at the study site can identify the patient. Data will be collected in a hard copy of the CRF; one copy will be sent to the central site (Amsterdam) whereas one copy will be stored at the study site. The data will be entered in a specific-designed database at the central site (Amsterdam). Stratification of patients should be stratified in each center according to: 1. age (> or < 40 years of age) The investigator will contact the central site where randomization will take place using a randomization program.

7. Sample size According to Altman (Practical Statistics for Medical Research, p. 456), the sample size can be calculated as follows: P1 = expected success rate method 1 P2 = expected success rate method 2 (20 % difference considered as clinically relevant) PM = mean of P1 and P2

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A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

The standardized difference is P1 – P2/ root of PM (1-PM). Via a nomogram, the sample size can be determined, according to the predetermined significance level and power. Assuming that the success rate of endoscopic treatment is 70%, and of surgery is 90 % (difference of 20 % considered as clinically relevant), then the sample size with P=0.05 and power=0.9 should be 160. To compensate for drop-outs, the sample size will be increased to 200.

8. Forms and data handling Data will be entered in a hard copy of the CRF. A copy of this CRF will be transferred to Amsterdam for central data handling.

9. Plans for statistical analysis The development of a database and the statistical analysis will be done in collaboration with the department of Biostatistics and Epidemiology. Statistical analysis after one year: The primary outcome (success rate) will be compared between the two treatment groups using the chi-square test. The symptom score after one year will be compared using the Mann_Whitney test. Statistical analysis after several years of follow-up: The time to failure will be analysed using Kaplan-Meier curves and log rank test Repeatedly measured symptom scores will be analysed using mixed-model ANOVA.

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A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

Interim analysis: No interim analysis will be performed during the study.

Section 10 – References

1.

Spiess AE, Kahrilas PJ. Treating achalasia: from whalebone to laparoscope. JAMA 1998; 280: 638-42.

2.

Howard PJ, Maher L, Cameron EWJ, Heading RC. Five year prospective study of the incidence, clinical features, and diagnosis of achalasia in Edinburgh. Gut 1992; 33: 1011-1015.

3.

Podas T, Eaden J, Mayberry M, Mayberry J. Achalasia: a critical review of epidemiological studies. Am J Gastroenterol 1998; 93: 2345-7.

4.

Hirano I, Tatum RP, Shi G, et al. Manometric heterogeneity in patients with idiopathic achalasia. Gastroenterology 2001; 120: 789-98.

5.

Mearin F, Mourelle M, Guarner F et al. Patients with achalasia lack nitric oxide synthase in the gastro-eosophageal junction. Eur J Clin Invest 1993; 23: 724-8.

6.

Saur D, Paehge H, Schusdziarra, Allescher HD. Distinct expression of splice Variants of neuronal nitric oxide synthase in the human gastrointestinal tract. Gastroenterology 2000; 118: 849-58.

7.

Verhagen MAMT, Gooszen HG, Smout AJPM. Pathofysiologie en behandeling van achalasie. Ned Tijdschr Geneeskd 1996; 140: 2442-7.

8.

Pasricha PJ, Ravich WJ, Hendrix TR et al. Intrasphincteric botulinum toxin for the treatment of achalasia. N Engl J Med 1995; 322: 774-8.

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A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia 9.

Vantrappen G, Hellemans J. Treatment of achalasia and related motor disorders. Gastroenterology 1980; 79: 144-54.

10. Wevers AC, Bartelsman JFWM, Tytgat GNJ. Pneumodilatatie als behandeling van

oesophagusachalasie. Ned Tijdschr Geneeskd 1985; 129: 2015-8. 11. Csendes A, Braghetto I, Henríquez, Cortes C. Late results of a prospective randomised

study comparing forceful dilation and oesophagomyotomy in patients with achalasia. Gut 1989; 30: 299-304. 12. Eckardt VF, Aignherr C, Bernhard G. Predictors of outcome in patients with achalasia

treated by pneumatic dilation. Gastroenterology 1992; 103: 1732-8. 13. Vantrappen G, Hellemans J, Deloof P, et al. Treatment of achalasia with pneumatic

dilations. Gut 1971; 12: 268-75. 14. Parkman HP, Reynolds JC, Ouyang A, et al. Pneumatic dilation or esophagomyotomy

treatment for idiopathic achalasia: clinical outcomes and cost analysis. Dig Dis Sci 1993; 38: 75-85. 15. Katz PO, Gilbert J, Castell DO. Pneumatic dilation is effective long-term treatment for

achalasia. Dig Dis Sci 1998; 43: 1973-7. 16. Torbey CF, Achkar E, Rice TW et al. Long-term outcome of achalasia treatment: the

need for closer follow-up. J Clin Gastroenterol 1999; 28 (2): 125-130. 17. Vaezi MF, Baker ME, Richter JE. Assessment of esophageal emptying post-pneumatic

dilation: use of the timed barium esophagram. Am J Gastroenterol 1999; 94: 1802-7. 18. Anselmino M, Perdikis G, Hinder RA, et al. Heller myotomy is superior to dilation for

the treatment of early achalasia. Arch surg 1997; 132: 233-40.

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A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia 19. Mäkelä J, Kiviniemi H, Laitinen S. Heller’s cardiomyotomy compared with pneumatic

dilation for treatment of oesophageal achalasia. Eur J Surg 1991; 157: 411-414. 20. Abid S, Champion G, Richter JE, et al. Treatment of achalasia: the best of both worlds.

Am J Gastroenterol 1994; 89: 979-85. 21. Patti MG, Pellegrini CA, Horgan S, et al. Minimally invasive surgery for achalasia: an

8-year experience with 168 patients. Ann Surg 1999; 230: 587-94. 22. Hunter JG, Trus TL, Branum GD, Waring JP. Laparoscopic Heller myotomy and

fundoplication for achalasia. Ann Surg 1997; 225: 655-65. 23. Just-Viera JO, Haight C. Achalasia and carcinoma of the esophagus. Surg Gynecol

Obstet 1969; 128: 1081-95. 24. Streitz JM, Ellis FH, Gibb SP, Heatley GM. Achalasia and squamous cell carcinoma of

the esophagus: analysis of 241 patients. Ann Thoracic Surg 1995; 59: 1604-9. 25. Meijssen MAC, Tilanus HW, van Blankenstein M et al. Achalasia complicated by

oesophageal squamous cell carcinoma: a prospective study in 195 patients. Gut 1992; 33: 155-8. 26. Porschen R, Molsberger G, Kühl A et al. Achalasia-associated squamous cell

carcinoma

of

the

esophagus:

flow-cytometric

and

histological

evaluation.

Gastroenterology 1995; 108: 545-9. 27. Freczko PJ, Ma CK, Halpert RD, Batra SK. Barrett’s metaplasia and dysplasia in

postmyotomy achalasia patients. Am J Gastroenterol 1983; 78: 265-8. 28. Ellis FH, Gibb SP, Balogh K, Schwaber JR. Esophageal achalasia and adenocarcinoma

in Barrett’s esophagus: a report of two cases and a review of the literature. Dis Esophagus 1997; 10: 55-60.

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A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia 29. Goodman P, Scott LD, Verani RR, Berggreen CC. Esophageal adenocarcinoma in a

patient with surgically treated achalasia. Dig Dis Sci 1990; 35: 1549-52

Section 11 – Publication of data Section 11.1 – Principles

The department of Gastroenterology of the AMC (Amsterdam, The Netherlands) will manage the publication of study results in partnership with the participating coinvestigators. The principal author (dr. G.E.E. Boeckxstaens) will take a leading role in this process. The principal author will propose a suitable journal and/or meeting and timelines for publication, in consultation with the co-authors.

Section 11.2 – Authorship The AMC adopts the principal criteria for authorship eligibility which are detailed in the Uniform Requirements for Submission of Manuscripts to Biomedical Journals (ICMJE, 5th Edition, 1997): ‘All persons designated as authors should qualify for authorship. Each author should have participated sufficiently in the work to take public responsibility for the content. Authorship credit should be based on substantial contributions to 1) conception and design, or analysis and interpretation of data; and to 2) drafting the article or revising it critically for important intellectual content; and 3) on final approval of the version to be published. Conditions 1, 2 and 3 must all be met’

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A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

These criteria apply equally to the co-investigators and to the AMC employees and any specific requirements of the selected journal will also be respected. The lead author for the main (primary) publication(s) from this study will be a major contributor to the study who is prepared to take public responsibility for the overall study design, data interpretation, and conclusions. The principal author, in conjunction with the lead author will be responsible for determining the number and sequence of co-authors. The full authorship will be agreed with the contributors based on such criteria as contribution to the design and the conduct of the study. Other contributing investigators who are not authors will be acknowledged within the manuscript.

Section 11.3 – Secondary publications The principal author will co-ordinate the timing and authorship of derived publications or reviews referring to data from this study to ensure that secondary publications do not jeopardise the primary publications from this study.

.

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A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

AMENDMENT 1

Central site Academic Medical Center Meibergdreef 9 1105 AZ Amsterdam The Netherlands Phone : +31 20 566 91 11 Fax : +31 20 691 07 33 E-mail : [email protected] Central site team Principal Investigators: Guy E.E. Boeckxstaens, MD, PhD (Dept. of Gastroenterology) Olivier R.C. Busch, MD, PhD (Dept. of Surgery) Trial nurse : Aaltje Lei (Dept. of Gastroenterology) Research technician : Cynthia B. Verkleij (Dept. of Gastroenterology)

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A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

1.

Rationale for amendment

Sample prelevation and DNA isolation The Ethics committee of one of the Dutch centers has requested a precise description of the procedures concerning sample prelevation.

Storage of samples The Ethics committee of one of the Dutch centers has requested more information about the storage of the blood, tissue and DNA samples.

2.

Supplements to the protocol

Section 4.7 – DNA isolation Sample prelevation (optional; The Netherlands)

During laparoscopic myotomy resection material will be obtained for histological studies to determine whether auto-immune responses play a role in the inflammation within the esophageal myenteric plexus as seen in patients with achalasia. Blood samples will be obtained and the sera will be analyzed to determine the presence of myenteric neuronal antibodies and to evaluate which antigens are recognized by these antibodies. All samples will be marked with a unique code number and stored at the central site, maintaining confidentiality. Only the investigator at the study site can identify the

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A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

patient. The patient will continue to be the owner of the sample and retains the right to have the sample material destroyed at any time by contacting the investigator. The tissue samples and sera may be stored for up to 20 years to research scientific questions related to achalasia.

Section 4.8 – DNA isolation (optional; The Netherlands)

As approximately 200 patients will be included in this study, enough blood samples for DNA analyses can be obtained to evaluate a possible genetic background of achalasia. Therefore, an extra blood sample will be taken for DNA analysis. All samples will be marked with a unique code number and stored at the central site, maintaining confidentiality. Only the investigator at the study site can identify the patient. The patient will continue to be the owner of the DNA sample and retains the right to have the sample material destroyed at any time by contacting the investigator. The DNA samples may be stored for up to 20 years to research scientific questions related to achalasia.

3.

Institutional Review Board/Independent Ethics Committee Approval

The IRB/IEC must receive a copy of this amendment.

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A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

AMENDMENT 2

Central site Academic Medical Center Meibergdreef 9 1105 AZ Amsterdam The Netherlands Phone : +31 20 566 91 11 Fax : +31 20 691 07 33 E-mail : [email protected] Central site team Principal Investigators: Guy E.E. Boeckxstaens, MD, PhD (Dept. of Gastroenterology) Olivier R.C. Busch, MD, PhD (Dept. of Surgery) Trial nurse : Aaltje Lei (Dept. of Gastroenterology) Research technician : Cynthia B. Verkleij (Dept. of Gastroenterology) January 2003

A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

1.

Rationale for amendment

This amendment concerns supplementary information only. No changes were made to the protocol.

Statistical plans The Ethics committee in France has requested an a priori justified and detailed plan for statistical analysis of the results. To complete the study protocol, a short description of the plan for the statistical analysis of the primary study objectives has been written in collaboration with the department of Biostatistics and Epidemiology.

References The Ethics committee in France has requested to add a list of references to the study protocol.

2.

Supplements to the protocol

Section 9 - Plans for statistical analysis The development of a database and the statistical analysis will be done in collaboration with the department of Biostatistics and Epidemiology.

Statistical analysis after one year: -

The primary outcome (success rate) will be compared between the two treatment groups using the chi-square test.

January 2003

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A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

-

The symptom score after one year will be compared using the Mann_Whitney test.

Statistical analysis after several years of follow-up: -

The time to failure will be analysed using Kaplan-Meier curves and log rank test

-

Repeatedly measured symptom scores will be analysed using mixed-model ANOVA.

Interim analysis: -

No interim analysis will be performed during the study.

Section 10 – References

1.

Spiess AE, Kahrilas PJ. Treating achalasia: from whalebone to laparoscope. JAMA 1998; 280: 638-42.

2.

Howard PJ, Maher L, Cameron EWJ, Heading RC. Five year prospective study of the incidence, clinical features, and diagnosis of achalasia in Edinburgh. Gut 1992; 33: 10111015.

3.

Podas T, Eaden J, Mayberry M, Mayberry J. Achalasia: a critical review of epidemiological studies. Am J Gastroenterol 1998; 93: 2345-7.

4.

Hirano I, Tatum RP, Shi G, et al. Manometric heterogeneity in patients with idiopathic achalasia. Gastroenterology 2001; 120: 789-98.

5.

Mearin F, Mourelle M, Guarner F et al. Patients with achalasia lack nitric oxide synthase in the gastro-eosophageal junction. Eur J Clin Invest 1993; 23: 724-8.

January 2003

3

A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

6.

Saur D, Paehge H, Schusdziarra, Allescher HD. Distinct expression of splice Variants of neuronal nitric oxide synthase in the human gastrointestinal tract. Gastroenterology 2000; 118: 849-58.

7.

Verhagen MAMT, Gooszen HG, Smout AJPM. Pathofysiologie en behandeling van achalasie. Ned Tijdschr Geneeskd 1996; 140: 2442-7.

8.

Pasricha PJ, Ravich WJ, Hendrix TR et al. Intrasphincteric botulinum toxin for the treatment of achalasia. N Engl J Med 1995; 322: 774-8.

9.

Vantrappen G, Hellemans J. Treatment of achalasia and related motor disorders. Gastroenterology 1980; 79: 144-54.

10. Wevers AC, Bartelsman JFWM, Tytgat GNJ. Pneumodilatatie als behandeling van

oesophagusachalasie. Ned Tijdschr Geneeskd 1985; 129: 2015-8. 11. Csendes A, Braghetto I, Henríquez, Cortes C. Late results of a prospective randomised

study comparing forceful dilation and oesophagomyotomy in patients with achalasia. Gut 1989; 30: 299-304. 12. Eckardt VF, Aignherr C, Bernhard G. Predictors of outcome in patients with achalasia

treated by pneumatic dilation. Gastroenterology 1992; 103: 1732-8. 13. Vantrappen G, Hellemans J, Deloof P, et al. Treatment of achalasia with pneumatic

dilations. Gut 1971; 12: 268-75. 14. Parkman HP, Reynolds JC, Ouyang A, et al. Pneumatic dilation or esophagomyotomy

treatment for idiopathic achalasia: clinical outcomes and cost analysis. Dig Dis Sci 1993; 38: 75-85. 15. Katz PO, Gilbert J, Castell DO. Pneumatic dilation is effective long-term treatment for

January 2003

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A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

achalasia. Dig Dis Sci 1998; 43: 1973-7. 16. Torbey CF, Achkar E, Rice TW et al. Long-term outcome of achalasia treatment: the

need for closer follow-up. J Clin Gastroenterol 1999; 28 (2): 125-130. 17. Vaezi MF, Baker ME, Richter JE. Assessment of esophageal emptying post-pneumatic

dilation: use of the timed barium esophagram. Am J Gastroenterol 1999; 94: 1802-7. 18. Anselmino M, Perdikis G, Hinder RA, et al. Heller myotomy is superior to dilation for

the treatment of early achalasia. Arch surg 1997; 132: 233-40. 19. Mäkelä J, Kiviniemi H, Laitinen S. Heller’s cardiomyotomy compared with pneumatic

dilation for treatment of oesophageal achalasia. Eur J Surg 1991; 157: 411-414. 20. Abid S, Champion G, Richter JE, et al. Treatment of achalasia: the best of both worlds.

Am J Gastroenterol 1994; 89: 979-85. 21. Patti MG, Pellegrini CA, Horgan S, et al. Minimally invasive surgery for achalasia: an 8-

year experience with 168 patients. Ann Surg 1999; 230: 587-94. 22. Hunter JG, Trus TL, Branum GD, Waring JP. Laparoscopic Heller myotomy and

fundoplication for achalasia. Ann Surg 1997; 225: 655-65. 23. Just-Viera JO, Haight C. Achalasia and carcinoma of the esophagus. Surg Gynecol

Obstet 1969; 128: 1081-95. 24. Streitz JM, Ellis FH, Gibb SP, Heatley GM. Achalasia and squamous cell carcinoma of

the esophagus: analysis of 241 patients. Ann Thoracic Surg 1995; 59: 1604-9. 25. Meijssen MAC, Tilanus HW, van Blankenstein M et al. Achalasia complicated by

oesophageal squamous cell carcinoma: a prospective study in 195 patients. Gut 1992; 33: 155-8.

January 2003

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A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

26. Porschen R, Molsberger G, Kühl A et al. Achalasia-associated squamous cell carcinoma

of the esophagus: flow-cytometric and histological evaluation. Gastroenterology 1995; 108: 545-9. 27. Freczko PJ, Ma CK, Halpert RD, Batra SK. Barrett’s metaplasia and dysplasia in

postmyotomy achalasia patients. Am J Gastroenterol 1983; 78: 265-8. 28. Ellis FH, Gibb SP, Balogh K, Schwaber JR. Esophageal achalasia and adenocarcinoma in

Barrett’s esophagus: a report of two cases and a review of the literature. Dis Esophagus 1997; 10: 55-60. 29. Goodman P, Scott LD, Verani RR, Berggreen CC. Esophageal adenocarcinoma in a

patient with surgically treated achalasia. Dig Dis Sci 1990; 35: 1549-52

3.

Institutional Review Board/Independent Ethics Committee Approval

The IRB/IEC must receive a copy of this amendment.

January 2003

6

Academic Medical Center Amsterdam The Netherlands

A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

AMENDMENT 3

Central site Academic Medical Center Meibergdreef 9 1105 AZ Amsterdam The Netherlands Phone : +31 20 566 91 11 Fax : +31 20 691 70 33 E-mail : [email protected] Central site team Principal Investigators: Guy E.E. Boeckxstaens, MD, PhD (Dept. of Gastroenterology) Olivier R.C. Busch, MD, PhD (Dept. of Surgery) Trial nurse : Aaltje Lei (Dept. of Gastroenterology) Research technician : Cynthia B. Verkleij (Dept. of Gastroenterology) September 2003

A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

1.

Rationale for amendment

This amendment concerns important changes to the protocol.

Pneumodilation So far, 13 pneumodilations with a 35 mm balloon have been performed. Four pneumodilations were complicated by a perforation. This complication rate of more than 30 % was not expected and is unacceptably high. Therefore, a Stearing Committee was appointed by the Principal Investigators to discuss whether changes should be made to the protocol. The Stearing Committee consisted of the following investigators: Boeckxstaens (NL), Zaninotto (I), Tack (B), Pera (E) and Bruley des Varannes (F). Based on the available statistics regarding the complication rate in centers 001 (AMC, The Netherlands) and 006 (Leuven, Belgium), the Stearing Committee has decided that the protocol should be adapted in accordance with the dilation protocol normally used in these centers.

2.

Changes to the protocol

Section 3.1 – Pneumatic dilation  …..  Standard treatment consists of 2 dilations 1 dilation session with a 35 mm balloon. The 1st dilation is performed with a 30 mm balloon, followed by a 35 mm balloon within 2 weeks. If necessary, due to for instance travel distances, the 2nd dilation may be performed the day after the 1st dilation. September 2003

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A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

 If Eckardt score >3 after 4 weeks, a 2nd dilatation with 40 mm balloon will be performed. If the drop in Eckardt score is less than 2 points and/or the total score is still greater than 3 after 4 weeks (compared to the Eckardt score at visit 1), a 3rd dilation with a 40 mm balloon will be performed.  ……

The redilation protocol remains unchanged (1st dilation with a 35 mm balloon, followed by a 2nd dilation with a 40 mm balloon if symptoms have improved insufficiently).

3.

Institutional Review Board/Independent Ethics Committee Approval

This amendment was submitted for approval to the IEC of the Central site (AMC Amsterdam, The Netherlands) at the 1st of October. Every participating center must submit a copy of this amendment to their local IRB/IEC for approval.

September 2003

3

Academic Medical Center Amsterdam The Netherlands

A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

AMENDMENT 4

Central site Academic Medical Center Meibergdreef 9 1105 AZ Amsterdam The Netherlands Phone : +31 20 566 91 11 Fax : +31 20 691 70 33 E-mail : [email protected] Central site team Principal Investigators: Guy E.E. Boeckxstaens, MD, PhD (Dept. of Gastroenterology) Olivier R.C. Busch, MD, PhD (Dept. of Surgery) Trial nurse : Aaltje Lei (Dept. of Gastroenterology) Research technician : Cynthia B. Verkleij (Dept. of Gastroenterology) September 2003

A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

1.

Rationale for amendment

This amendment concerns important changes to the protocol.

Pneumodilation complicated by perforation According to the current protocol, subjects will be excluded from the study in case treatment with pneumodilation is complicated by esophageal perforation. During the Initiation visit in Paris, France, the question rose why these subjects should be excluded from the study, since subjects treated with laparoscopic myotomy will remain in the study in case of an esophageal perforation. According to the opinion of the participating French centers, subjects should not be excluded from the study after an esophageal perforation, regardless of the allocated treatment modality. During the 19th International Symposium on Neurogastroenterology and Motility in Barcelona, Spain, this topic was further discussed with several particpating investigators. It was decided that the protocol will be adapted. As of today, all subjects remain in the study after an esophageal perforation. Subjects who have already been excluded from the study due to a perforation, will be approached and invited to resume their participation.

2.

Changes to the protocol

Section 3.1 – Pneumatic dilation  …..  In case of clinical suspicion of esophageal perforation (pain during drinking of water), an

October 2003

2

A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

esophagram with water-soluble contrast will be made. A perforation is defined as the extramural extravasation of contrast at the esophagram. Treatment can be either nothing by mouth and antibiotics i.v. or surgery. In case of perforation, the patient will remain in the study for further follow-up..  …..

3.

Institutional Review Board/Independent Ethics Committee Approval

This amendment was submitted for approval to the IEC of the Central site (AMC Amsterdam, The Netherlands) at the 29th of October. Every participating center must submit a copy of this amendment to their local IRB/IEC for approval.

October 2003

3

Deleted: will be excluded from the study

Academic Medical Center Amsterdam The Netherlands

A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

AMENDMENT 5

Central site Academic Medical Center Meibergdreef 9 1105 AZ Amsterdam The Netherlands Phone : +31 20 566 91 11 Fax : +31 20 691 70 33 E-mail : [email protected] Central site team Principal Investigators: Guy E.E. Boeckxstaens, MD, PhD (Dept. of Gastroenterology) Olivier R.C. Busch, MD, PhD (Dept. of Surgery) Trial nurse : Aaltje Lei (Dept. of Gastroenterology) Research technician : Cynthia B. Verkleij (Dept. of Gastroenterology) August 2004

A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

1.

Rationale for amendment

This amendment concerns supplementary information only. No changes were made to the existing protocol.

The Ethics committee of one of the Dutch centers has requested to add a publication policy to the study protocol.

2.

Supplement to the protocol

Section 11 – Publication of data Section 11.1 – Principles The department of Gastroenterology of the AMC (Amsterdam, The Netherlands) will manage the publication of study results in partnership with the participating co-investigators. The principal author (dr. G.E.E. Boeckxstaens) will take a leading role in this process. The principal author will propose a suitable journal and/or meeting and timelines for publication, in consultation with the co-authors.

Section 11.2 – Authorship The AMC adopts the principal criteria for authorship eligibility which are detailed in the Uniform Requirements for Submission of Manuscripts to Biomedical Journals (ICMJE, 5th Edition, 1997): ‘All persons designated as authors should qualify for authorship. Each author should have

August 2004

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A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

participated sufficiently in the work to take public responsibility for the content. Authorship credit should be based on substantial contributions to 1) conception and design, or analysis and interpretation of data; and to 2) drafting the article or revising it critically for important intellectual content; and 3) on final approval of the version to be published. Conditions 1, 2 and 3 must all be met’

These criteria apply equally to the co-investigators and to the AMC employees and any specific requirements of the selected journal will also be respected.

The lead author for the main (primary) publication(s) from this study will be a major contributor to the study who is prepared to take public responsibility for the overall study design, data interpretation, and conclusions.

The principal author, in conjunction with the lead author will be responsible for determining the number and sequence of co-authors. The full authorship will be agreed with the contributors based on such criteria as contribution to the design and the conduct of the study. Other contributing investigators who are not authors will be acknowledged within the manuscript.

August 2004

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A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

Section 11.3 – Secondary publications The principal author will co-ordinate the timing and authorship of derived publications or reviews referring to data from this study to ensure that secondary publications do not jeopardise the primary publications from this study.

3.

Institutional Review Board/Independent Ethics Committee Approval

This amendment was submitted for approval to the IEC of the Central site (AMC Amsterdam, The Netherlands) in August 2004. Every participating center must submit a copy of this amendment to their local IRB/IEC for approval.

August 2004

4

Academic Medical Center Amsterdam The Netherlands

A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

AMENDMENT 6

Central site Academic Medical Center Meibergdreef 9 1105 AZ Amsterdam The Netherlands Phone : +31 20 566 91 11 Fax : +31 20 691 70 33 E-mail : [email protected] Central site team Principal Investigators: Guy E.E. Boeckxstaens, MD, PhD (Dept. of Gastroenterology) Olivier R.C. Busch, MD, PhD (Dept. of Surgery) Trial nurse : Aaltje Lei (Dept. of Gastroenterology) Research technician : Cynthia B. Verkleij (Dept. of Gastroenterology) August 2004

A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

1.

Rationale for amendment

This amendment concerns important changes to the protocol.

Failures According to the current protocol, subjects will be excluded from the study in case treatment with either pneumodilation or myotomy failed. Several failures have been reported so far. Excluding these subjects from follow-up would lead to a considerable loss of potentially valuable data. Therefore, failures will remain in follow-up as of today.

All centers will receive a new Study Termination page as soon as possible to record data regarding the secondary/additional alternative treatment modality used for re-treatment of subjects in which the allocated treatment modality failed. The current Study Termination page in the CRF should be replaced with this new page. The follow-up visits should be scheduled as planned and can be filled out at the CRF-pages of the follow-up visits currently in the CRF.

2.

Changes to the protocol

Section 1.1.3 – Follow-up of failures If treatment fails (pneumatic dilation or myotomy), other treatment options are to be considered. The investigator/attending physician will judge (in consultation with the subject) which treatment modality should be used in case of re-treatment. There are no obligatory retreatment modalities.

August 2004

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A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

Follow-up visits will be scheduled as planned. Thus, all follow-up visits (visit 3 and further) should be planned x months or years after initial treatment. When the patient is treated by pneumatic dilation at visit 2, the follow-up visits should be planned x months or years after the last dilation of treatment session 1.

Section 3.1 - Pneumatic dilation  …..  ….. If symptoms recur within 2 years after the second series of dilations, the patient is considered a failure. Failures will remain in follow-up.

Section 3.2 – Laparoscopic Heller myotomy + Dor fundoplication  …..  ….. Failures will be excluded from the study. Failures will remain in follow-up.

3.

Institutional Review Board/Independent Ethics Committee Approval

This amendment was submitted for approval to the IEC of the Central site (AMC Amsterdam, The Netherlands) in August 2004. Every participating center must submit a copy of this amendment to their local IRB/IEC for approval.

August 2004

3

Academic Medical Center Amsterdam The Netherlands

A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

AMENDMENT 7

Central site Academic Medical Center Meibergdreef 9 1105 AZ Amsterdam The Netherlands Phone : +31 20 566 91 11 Fax : +31 20 691 70 33 E-mail : [email protected] Central site team Principal Investigators: Guy E.E. Boeckxstaens, MD, PhD (Dept. of Gastroenterology) Olivier R.C. Busch, MD, PhD (Dept. of Surgery) Trial nurse : Aaltje Lei (Dept. of Gastroenterology) Research technician : Cynthia B. Verkleij (Dept. of Gastroenterology) September 2005

A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

1.

Rationale for amendment

This amendment concerns important changes to the protocol.

Failures According

to

the

current

protocol,

failures

will

remain

in

follow-up.

The

secondary/additional alternative treatment modality used for re-treatment of subjects in which the allocated treatment modality failed, is recorded on the Study Termination Page. Follow-up visits are scheduled as planned and are filled out at the CRF-pages currently in the CRF. Planning the follow-up with regard to initial treatment would lead to a considerable loss of potentially valuable data, since there will be no uniformity in follow-up visits between patients. Therefore, whenever treatment fails, follow-up visits should be planned with regard to the date of alternative treatment as of today. All follow-up visits should be performed, starting with visit 3 (1 month after alternative treatment).

2.

Changes to the protocol

Section 1.1.3 – Follow-up of failures If treatment fails (pneumatic dilation or myotomy), other treatment options are to be considered. The investigator/attending physician will judge (in consultation with the subject) which treatment modality should be used in case of re-treatment. There are no obligatory retreatment modalities.

September 2005

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A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

Follow-up visits will be scheduled as planned. Thus, all follow-up visits (visit 3 and further) should be planned x months or years after initial treatment. When the patient is treated by pneumatic dilation at visit 2, the follow-up visits should be planned x months or years after the last dilation of treatment session 1.

For all failures the follow-up visits should be scheduled with regard to the date of alternative treatment instead of to the date of initial treatment, starting with visit 3 (1 month after alternative treatment). All data should be filled out in a new, blanc CRF.

3.

Institutional Review Board/Independent Ethics Committee Approval

This amendment was submitted for approval to the IEC of the Central site (AMC Amsterdam, The Netherlands) in September 2005. Every participating center must submit a copy of this amendment to their local IRB/IEC for approval.

September 2005

3

A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

Statistical Analysis Plan

Principal Investigators: Statistician:

Guy E.E. Boeckxstaens, MD, PhD (Dept. of Gastroenterology) Olivier R.C. Busch, MD, PhD (Dept. of Surgery) A.H. Zwinderman, PhD (Dept. of Biostatistics and Epidemiology)

Statistical analysis plan

A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

Table of contents

1.

Study objective

2.

Primary outcome

3.

Secondary outcome

4.

Power calculation

5.

Intention to treat

6.

Per protocol

7.

Statistical analysis

8.

Subgroup analysis

Statistical analysis plan

A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

1.

Study Objective

Achalasia is a rare esophageal motor disorder clinically characterized by dysphagia, chest pain and regurgitation of undigested food. Treatment is aimed at reducing the resistance to flow at the level of the esophagogastric junction, by pneumatic dilation or by laparoscopic Heller myotomy according to Dor. The aim of this multi-center study is to compare the clinical success rates of the two treatments for idiopathic achalasia in a randomized prospective trial.

2.

Primary outcome

The time till failure is the primary outcome parameter. The time is measured from date of pneumatic dilation or laparoscopic myotomy to date of failure. Symptoms will be evaluated using the Eckardt scoring system (Table 1.). Therapeutic success is defined as a drop in Eckardt score to ≤ 3 after treatment and symptom control at yearly follow-up which is also defined as an Eckardt score of ≤ 3. If symptoms recur within patients randomized for pneumatic dilation, retreatment with pneumatic dilation is allowed according to the protocol. If retreatment does not result in reduction of the symptom score below 4, the patient will be considered as a treatment failure.

3.

Secondary outcomes

The secondary outcome parameters were assessed according to the trial design (Table 2.). 

Complication rate: Complications (perforation, bleeding, etc) occurring during or immediately following the procedure are recorded by the attending phycisian. In addition, gastroesophageal reflux is measured using 24h pHmetry after 1 year. The number of patients with pathological acid exposure (>4.5% of time a pH 3. Symptom scores are assessed after one month, six months and than yearly.



Lower esophageal sphincter pressure Esophageal manometry is used to measure lower esophageal sphincter pressure (in mmHg). Manometry is performed after one month and yearly.



Height of the timed barium esophagogram A timed barium esophagogram is performed to measure the stasis of the barium column after 1, 2 and 5 minutes. For analysis the centimetres of stasis after 5 minutes will be used. An esophagogram is made after one month and yearly.



Quality of life (QLQ-SF36, QLQ-OES24) The quality of life is determined using a general QoL questionnaire, namely the SF36 questionnaire. In addition, a more disease specific questionnaire, i.e. the EORTC QLQ-OES24 questionnaire, is filled out. These questionnaires have scored the QoL at fixed time points during follow-up (1 month, 6 months and yearly).

Statistical analysis plan

A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

4.

Power Calculation

Assuming that the success rate of endoscopic treatment is 70%, and of surgery is 90 % (difference of 20 % considered as clinically relevant), then the sample size with P=0.05 and power =0.9 should be 160. To compensate for drop-outs, the sample size will be increased to 200.

5.

Intention to treat

All patients will be analyzed in their randomized group in the intention to treat analysis. The distension protocol was amended after the first 13 patients randomized for pneumodilation. By consequence, these 13 patients will be excluded from the primary analysis and the trial is focussed on comparing the revised distension protocol with laparoscopic myotomy. When patients are randomized for pneumodilation and have recurrent symptoms (Eckardt ≥4) after first treatment, a new treatment session is allowed according to the protocol. However, when patients refuse additional pneumodilation, for instance because of pain during earlier treatment, patients will be regarded as treatment failures in intention to treat analysis.

6.

Per protocol analysis

All patients that were treated according to the protocol are included in the per protocol analysis.

7.

Statistical Analysis

The primary outcome will be analysed using Kaplan-Meier curves and log rank test. Success rates of the two treatment groups will also be compared at one and two years of follow up using the chi-square test.

Statistical analysis plan

A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

Secondary outcomes will be compared by chi-square or Fisher’s exact test in case of categorical parameters. Continuous variables will be compared using the Student’s t-test. Data are presented as mean (95%CI) or median (IQR) when appropriate. No interim analysis is performed during the study. Risk factor analysis will be performed using Cox regression analysis. The time till failure and the time till first redilation will be related to age, sex, basal LES pressure, chest pain, height of barium swallow, and maximum esophageal width.

8.

Subgroup analysis

Subgroup analyses for risk factors of treatment failure will be performed with specified variables for all patients, both treatment groups and for patients that need retreatment in the pneumatic dilation group. Variables with evidence of influencing outcome in literature include age ≤ 40 versus > 40 years, sex, basal LES pressure after treatment of ≤ 10 versus > 10 to ≤ 20 versus >20 mmHg, daily chest pain versus no or less than daily chest pain, height of barium swallow after 5 min after treatment ≤ 5 versus > 5 to ≤ 10 versus > 10 cm and maximum esophageal width prior to treatment of ≤ 4 versus > 4 cm.

Statistical analysis plan

A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

Table 1. According to Eckardt et al. (Gastroenterology, 1992), weight loss, dysphagia, chest pain and regurgitation will be scored on a scale from 0 to 3. Score

Weight loss (kg)

Dysphagia

Chest pain

Regurgitation

0

None

None

None

None

1

10

Each meal

Several times a day

Each meal

Statistical analysis plan

A prospective randomized multi-center study comparing endoscopic pneumodilation and laparoscopic myotomy as treatment of idiopathic achalasia

Table 2. Trial design Before

1 month

6 months

1 year

Every yr

Demographics

×

Symptom score

×

×

×

×

×

QoL

×

×

×

×

×

Manometry

×

×

×

×

24h pH metry

×

Esoph. emptying

×

Endoscopy

×

Laboratory

×

EUS or CT *

×

×

× ×

Statistical analysis plan

Every 3 yr

× × ×