Clinical trial NCT06335862: Primary Posterior Tracheopexy Prevents Tracheal Collapse
Official title: Primary pOsterioR TRacheopexy Prevents Collapse of the Trachea in Newborns With Oesophageal AtresIa and Tracheomalacia
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: NA
Conditions: Oesophageal Atresia With Tracheo-Oesophageal Fistula
Tracheomalacia
Oesophageal Atresia
Keywords: Oesophageal atresia
Tracheomalacia
Primary Posterior Tracheopexy
Respiratory Morbidity
Lead sponsor: UMC Utrecht
Sponsor class: OTHER
Collaborators: name: Erasmus Medical Center
name: Karolinska University Hospital
name: Great Ormond Street Hospital for Children NHS Foundation Trust
name: For Wis(h)dom Foundation (funding)
First posted: 2024-03-28
Enrollment: 78
Sex: ALL
Minimum age (years): 34
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients will be randomized 1:1 into either the intervention group (PPT-group) or the wait-and-see group (no-PPT). Since the sutures of the PPT remain in place (in the PPT-group), the participants are allocated to one arm for the duration of the study. After the PPT was or was not performed, the participants will follow the same follow-up schedule.
Primary purpose: TREATMENT

Brief summary: Introduction: Children born with a blind-ending gullet (oesophagus), or Oesophageal Atresia (OA), need to undergo surgical correction in the first week of life. OA is often accompanied by a weakened windpipe (trachea), known as tracheomalacia (TM). TM entails that the windpipe collapses during expiration. Severe TM can cause respiratory symptoms, including frequent respiratory tract infections and blue spells, that can potentially lead to life-threatening events. In some patients, major secondary surgical treatment may be indicated. This surgical procedure involves widening the trachea (using sutures) to prevent collapse, known as secondary posterior tracheopexy (SPT). Prior to performing this SPT, complications and negative consequences of TM may have already occurred. This may be prevented by performing this procedure during the primary OA correction, called a primary posterior tracheopexy (PPT). The aim of this trial is to determine if a PPT can decrease - or prevent - tracheal collapse in newborns with OA and TM, compared to a wait-and-see policy (no-PPT).

Methods: This is an international multicentre double-blind randomised controlled trial. Seventy eight children with OA type C will be included. Patients will be included after written parental informed consent. Half of the patients will be randomly allocated to the PPT-group and half to the no-PPT-group. The degree and location of TM are evaluated through preoperative, intraoperative and two postoperative videoscopic examinations of the trachea (tracheobronchoscopy). Whether TM symptoms occur is assessed during three routine follow-up consultations until the age of 6 months. The primary outcome is the degree of collapse of the tracheal wall during the intraoperative tracheobronchoscopy (after performing the PPT/no-PPT), measured in percentages.

Risks and burden: Since OA correction with PPT (more recently implemented in centres of expertise) and without PPT (wait-and-see policy) are both accepted and safe treatment options, participating in the trial does not pose an increased risk or burden with regards to the treatment. Performing tracheobronchoscopies may pose a potential burden. However, a tracheobronchoscopy is a routine diagnostic procedure commonly used to safely assess the trachea. Complications of a tracheobronchoscopy are rare. Also, many of the tracheobronchoscopies are routinely performed as part of standard care for these patients, regardless of the trial.

Detailed description: Rationale:

A congenital blind-ending gullet (oesophagus), or Oesophageal Atresia (OA), is very often accompanied by a weakened windpipe (trachea). This is known as tracheomalacia (TM) and entails that the windpipe collapses during expiration. Severe TM can cause increased respiratory morbidity, including frequent respiratory tract infections and blue spells, that can potentially progress to respiratory arrest. Respiratory morbidity poses a significant burden on OA patients, both in the short term and over the course of long-term follow-up. When severe TM is identified, surgical intervention may be necessary. This surgical procedure involves widening the trachea (using sutures) to prevent its collapse, known as a posterior tracheopexy (PT). Prior to performing this secondary PT (SPT), complications and sequelae of TM may have already manifested. Additionally, performing this PT as a secondary operation after the OA correction is a complex surgical procedure in newborns, and poses a significant risk of damaging the recently performed OA anastomosis. This separate, SPT requires several hours of surgery, due to the presence of extensive adhesions. As a result, there has been a growing trend to carry out the PT concurrently with the initial correction of OA, known as a primary posterior tracheopexy (PPT). Previous studies have shown a decrease in respiratory tract infections (RTI's) and brief respiratory unexplained events (BRUE's) following the implementation of a PPT, when compared to patients who did not undergo PPT. However, it is important to note that these studies were predominantly conducted at a single medical center and relied mostly on retrospective data analysis. To address several sources of bias, such as center-specific factors, selection-bias and information bias, a double-blind randomized controlled trial should be conducted.

To accurately evaluate the effects of PPT versus no-PPT (i.e. the percentage of tracheal wall collapse) a tracheobronchoscopy needs to be performed, as it is the only objective measure for this purpose. Tracheobronchoscopy allows for a direct visual examination of the trachea, with a minimal effect on normal airway dynamics, ensuring a reliable evaluation of the impact of the PPT on the tracheal diameter.

Objective: The aim of this trial is to evaluate if a PPT can significantly decrease - or possibly prevent - the collapse of the trachea in newborns with OA and TM, compared to a wait-and-see policy (no-PPT). Additionally, the trial aims to determine whether the observed effect of PPT on tracheal stability is sustained over time.

Design and methodology:

Study design: a double-blind randomised controlled trial. Study population: neonates with oesophageal atresia (OA) and a distal trachea-oesophageal fistula (TOF), with tracheomalacia (TM).

Intervention: randomisation between performing a PPT or no-PPT Randomization, blinding and treatment allocation: Seventy eight patients will be included in this trial. Half of the patients will be randomised into the PPT-group and half into the no-PPT-group. We expect that the number of included patients will be approximately equally distributed among the four participating centres. However, the number of included patients per center is dependent on the number of patients treated by each center during the trial.

All participants, parents/caregivers, investigators and treating healthcare personnel, except for the surgical team performing the OA correction, will be blinded to which trial arm the participant is assigned.

Patient timeline:

* When a child with OA is born, the principal investigator (PI) of the trial is notified.
* Parents/caretakers will be contacted by the researcher/PI. An informed consent meeting is planned with the parents/caretakers, to explain the trial and to discuss possible outcomes or complications.
* If informed consent is obtained, the inclusion and exclusion criteria are checked, based on the observations during a preoperative tracheobronchoscopy (if the patient has TM or not). If the patient is included, randomization will take place in the surgical theatre.
* Based on the outcome of the randomisation, the PPT is either performed, or the PPT is not performed.
* Subsequently, the OA correction is carried out.
* During postoperative extubation (within one week after surgery) the first postoperative tracheobronchoscopy is performed, during extubation, through the endotracheal tube, in the neonatal or paediatric intensive care unit (ICU).
* After 2-6 months, the second postoperative tracheobronchoscopy is be performed under general anaesthesia in the surgical theatre.
* Patients will be followed-up at the outpatient clinic at around 2-3 weeks of age, 3 months of age, and at 6 months of age. This is according to the routine follow-up schedule.

We expect a duration of the inclusion period of 2,5 years. Patients will be included in the trial from the surgery until the 6 month follow-up timepoint. The trial is thus expected to be finished within three years. It will take approximately 6 months after the last inclusion to analyse results and write a scientific report of the (most important) findings.

No interim analysis is planned for efficacy or futility. Nevertheless, a Data Safety Monitoring Board will monitor the safety during the trial.

Burden and risks, benefit and group relatedness:

Burden: To determine whether the PPT is superior in preventing or reducing tracheal collapse, and subsequently respiratory morbidity, compared to no-PPT, a randomized double-blind trial is necessary.

This trial will eliminate dependence on other factors specific to individual centres and provide generalisable results. Importantly, since OA correction with PPT (more recently implemented in centres of expertise) and without PPT (wait-and-see policy) are both accepted and safe treatment options, participating in the trial does not pose an increased risk or burden for the participants with regards to the treatment. However, randomization of patients in this trial can be burdensome as it involves assigning them to either the PPT or no-PPT group based on chance. Parents/caretakers may have preferences or expectations regarding treatment, and being randomized to a specific group may not align with those preferences.

Performing intra- and postoperative tracheobronchoscopies may pose a potential burden during the trial. However, a tracheobronchoscopy is a routine diagnostic procedure commonly used to safely assess the condition of the trachea, even in newborns. Complications arising from a tracheobronchoscopy are rare. An intraoperative tracheobronchoscopy through the ventilation tube is always performed in patients with a PPT as routine care. In patients with ventilatory problems, even without PPT, an intraoperative tracheobronchoscopy can also be routinely performed. In this double-blind randomised trial, all patients will undergo the intra-operative flexible tracheobronchoscopy through the ventilation tube. However, considering the controlled circumstances, there is negligible burden and negligible risk.

After the correction of OA, newborns are typically extubated in the neonatal or paediatric ICU within a few days. During this extubation process, the first postoperative tracheobronchoscopy is conducted through the ventilation tube by a paediatric otorhinolaryngologist, with the presence of the ICU specialist and ICU nurse. Therefore, the burden and risk associated with the tracheobronchoscopy procedure are considered negligible, given the controlled and supervised environment. The second postoperative tracheobronchoscopy may present a burden due to the need for readmission and administration of general anaesthesia in the surgical theatre. However, a routine tracheobronchoscopy in the surgical theatre is often performed in all (Karolinska University Hospital and Great Ormond Street Hospital) or half (University Medical Centre Utrecht and Erasmus Medical Centre Rotterdam) of the OA patients. Thus, only in a small percentage of the trial participants, an extra tracheobronchoscopy is needed. Since the majority of these latter patients undergo an oesophagogastroscopy under general anaesthesia for clinical reasons (e.g. dilatation/eosinophilic oesophagitis), the second postoperative tracheobronchoscopy will be performed during this planned oesophagogastroscopy if possible. The general anaesthesia is administered to safely and effectively perform the tracheobronchoscopy in a controlled and supervised environment. The tracheobronchoscopy is the only objective measure to evaluate the degree of collapse in these patients. This second postoperative tracheobronchoscopy will determine if the observed effect of the PPT on tracheal stability is sustained beyond the first 2 months. Also, this burden is justifiable due to the potential deterioration of tracheal collapse that can occur in the first months following the initial OA correction. Conducting a second postoperative tracheobronchoscopy allows for the identification of these patients. The ability to identify such patients may outweigh the associated risks or added burden of the additional procedure in a small percentage of the trial participants. Moreover, if there is no difference between the intra-operative tracheobronchoscopy and the first and second tracheobronchoscopies, this could mean that in the future, we could sustain with only the (less burdensome) intra- (or first post-) operative tracheobronchoscopy. The respiratory complaints will be evaluated to research if the degree of TM corresponds with the severity of the symptoms.

Group relatedness: The advantage of conducting the primary posterior tracheopexy (PPT) earlier in the treatment process will become evident through the results of this randomised controlled trial (RCT). If the PPT demonstrates superior outcomes, it could lead to a reduction in postoperative complications and interventions, including tracheobronchoscopies under general anaesthesia and additional surgeries for SPT. Conversely, if the SPT yields better results, it could mean fewer patients undergoing unnecessary PPT procedures. The trial will provide valuable insights to guide the optimal timing and approach for tracheopexy in improving patient outcomes/symptoms.

Eligibility criteria: Inclusion Criteria:

* Patients with a confirmed diagnosis of OA with a distal TOF
* Tracheomalacia
* Written informed consent by both parents or legal representatives

Exclusion Criteria:

* Patients with OA without a distal TOF
* Premature neonates \<34 weeks
* Endotracheal tube size \< 3.0
* Cormack score 3 or 4 as scored by either the otolaryngologist, anesthesiologist, or neonatal/pediatric intensive care specialist
* Patients with a cyanotic cor vitium

Primary outcomes:
measure: Difference in degree of TM between the PPT-group and no-PPT-group during intraoperative tracheobronchoscopy
timeFrame: Measured by an intraoperative tracheobronchoscopy performed after freeing the trachea and oesophagus (and the PPT) but before the surgical correction of OA, through the ventilation tube
Secondary outcomes:
measure: Key secondary outcome: Difference in degree of TM between the PPT-group and no-PPT-group during postoperative tracheobronchoscopy
timeFrame: Measured by a tracheobronchoscopy performed during extubation (approximately 1 day after surgery) and by a tracheobronchoscopy 2-6 months after surgery.
measure: Difference in symptoms between the PPT-group and no-PPT-group
timeFrame: During follow-up, starting at the first follow-up consultation at 2-3 months, until the last follow-up consultation at 6 months.
measure: Degree of preoperative TM compared to postoperative TM
timeFrame: Comparison between the measurements during the preoperative tracheobronchoscopy and the postoperative tracheobronchoscopy at 2-6 months postoperative.
Other outcomes:
Locations:
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center Rotterdam
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht
city: London
country: United Kingdom
facility: Great Ormond Street Hospital
Study officials:
affiliation: Erasmus Medical Center
name: John Vlot, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Karolinska University Hospital
name: Jan F Svensson, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Great Ormond Street Hospital
name: Colin Butler, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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