Efficacy and safety of dexmedetomidine for prevention of withdrawal syndrome in the pediatric intensive care unit: protocol for an adaptive, multicenter, randomized, double-blind, placebo-controlled, non-profit clinical trial

Background Prolonged treatment with analgesic and sedative drugs in the pediatric intensive care unit (PICU) may lead to undesirable effects such as dependence and tolerance. Moreover, during analgosedation weaning, patients may develop clinical signs of withdrawal, known as withdrawal syndrome (WS). Some studies indicate that dexmedetomidine, a selective α2-adrenoceptor agonist, may be useful to prevent WS, but no clear evidence supports these data. The aims of the present study are to evaluate the efficacy of dexmedetomidine in reducing the occurrence of WS during analgosedation weaning, and to clearly assess its safety. Methods We will perform an adaptive, multicenter, randomized, double-blind, placebo-controlled trial. Patients aged < 18 years receiving continuous intravenous analgosedation treatment for at least 5 days and presenting with clinical conditions that allow analgosedation weaning will be randomly assigned to treatment A (dexmedetomidine) or treatment B (placebo). The treatment will be started 24 h before the analgosedation weaning at 0.4 μg/kg/h, increased by 0.2 μg/kg/h per hour up to 0.8 μg/kg/h (neonate: 0.2 μg/kg/h, increased by 0.1 μg/kg/h per hour up to 0.4 μg/kg/h) and continued throughout the whole weaning time. The primary endpoint is the efficacy of the treatment, defined by the reduction in the WS rate among patients treated with dexmedetomidine compared with patients treated with placebo. Safety will be assessed by collecting any potentially related adverse event. The sample size assuring a power of 90% is 77 patients for each group (total N = 154 patients). The study was approved by the Ethics Committee of the University-Hospital S.Orsola-Malpighi of Bologna on 22 March 2017. Discussion The present trial will allow us to clearly assess the efficacy of dexmedetomidine in reducing the occurrence of WS during weaning from analgosedation drugs. In addition, the study will provide a unique insight into the safety profile of dexmedetomidine. Trial registration ClinicalTrials.gov, NCT03645603. Registered on 24 August 2018. EudraCT, 2015–002114-80. Retrospectively registered on 2 January 2019.

Background Analgesia and sedation are essential treatments required by the majority of children admitted to the Pediatric Intensive Care Unit (PICU). In addition to their favorable effects, a prolonged exposure to analgosedation drugs may lead to undesirable effects, such as dependence, tolerance and withdrawal syndrome (WS) [1][2][3]. WS is a clinical syndrome occurring after discontinuation or during the weaning of opioids or benzodiazepines, with an incidence ranging from 17 to 57%, up to 64.6% among patients undergoing 5 or more days of treatment [4]. The syndrome is characterized by central nervous system excitement, gastrointestinal disturbance and sympathetic system activation. Typical symptoms are tremors, agitation, sleeplessness, inconsolable crying, sweating, yawning, sneezing and diarrhoea or vomiting for opioid drugs [1][2][3]. The presence of WS causes intense suffering and increases morbidities and the length of PICU-stay [3]. For this reason, several studies in the last decades have been designed to identify WS risk factors and an intense effort has been made to find any possible prevention strategy to avoid the onset of WS [7]. Despite that, no clear strategy has been identified so far and the prevention of WS still remain a challenge for the pediatric intensivists.
Finckel et colleagues first described the successful use of dexmedetomidine to allow a rapid weaning from conventional analgosedation in 2 children after cardiac transplantation [11]. Baddigam et al, in the same year, reported the successful use of dexmedetomidine for the treatment of WS in 3 patients after cardiac surgery [12]. Also, Tobias and colleagues described the use of intravenous or subcutaneous dexmedetomidine for the prevention of WS in 7 children in PICU, with satisfying results [13,14]. However, up to now, no high-level evidence studies have supported the dexmedetomidine role in WS prevention.
We conceived a prospective randomized controlled trial with the aim to evaluate the efficacy of dexmedetomidine in reducing the occurrence of WS during the weaning of conventional analgesic and sedative drugs.

Methods
The present study is an adaptive, multicenter, randomised, double blind, placebocontrolled, non-profit, superiority clinical trial with two-parallel groups. The study will be conducted in adherence to the principles of the World Medical Association's Declaration of Helsinki. An internal Data and Safety Monitoring Board (DSMB) has been nominated to monitor data and safety and it will decide on the continuation, modification or termination  The study was authorized by the Italian Medicines Agency (AIFA, ID TIP-15-01) and registered in the National Monitoring Center for Clinical Trial (OsSC) and successively in the Eudra CT Register (Identification Number 2015-002114-80). In addition, the study was prospectively registered on the ClinicalTrial.gov Registry (registration date 24 August 2018) with the Identification Number NCT03645603. The protocol has been designed following the SPIRIT international guidelines: the Figure 1 shows the SPIRIT-schedule of enrolment, interventions and assessments, and a populated SPIRIT Checklist is attached as Additional File 1.

Setting
The study will involve three PICUs belonging to three tertiary-care pediatric academic consists of 11 items, determined by the following components: a review of the patient's record for the past 12 hours, a direct observation of the patient for 2 minutes, a patient assessment using a progressive stimulus and an assessment of post-stimulus recovery [5].
The score ranges from 0 to 12 and a score ≥3 indicates the presence of signs or symptoms of WS. The severity of WS is higher as the score increases, as defined by the WAT-1 official definition [5].

Recruitment and Consent
Comprehensive information will be provided by each Center Principal Investigator to parents of children potentially involved. A detailed information sheet has been designed to support the oral communication. A written informed consent will be obtained from both parents for each involved child. Even when appropriate for age, a child's consent will be not needed because of the sedation status. A guarantee of optimal children's care will be assured independently of the study involvement. If present, a consent refusal will be recorded.

Randomization
Each patient will be randomly assigned to one of the 2 treatment groups: treatment-A group (receiving dexmedetomidine) or treatment-B group (receiving placebo). An identification code will be individually assigned to each patient. The Investigational Drug Service of the Coordinating Center has generate a block randomisation scheme on 11 June 2017 using the Web site Randomization.com (available online http://radomization.com).
This confidential document will be available only to the non-blinded staff, who will carry out the preparation of the treatments. Thus, the allocation sequence and the treatment administration will be unknown for the blinded researchers, including the study Principal Investigator. During the study, two sealed copies of the randomisation list that clearly show the treatment attributed to the patient will be available for emergencies. A sealed list will be kept in the archive of the Investigational Drug Service of the Coordinating Center and the others in the archive of each Principal Investigator. If an opening is needed, the Investigator will be asked to report the reason, the date/time of the opening and to immediately notify the Project Principal Investigator.

Interventions
Twenty-four hours before the start of the analgosedation weaning, an intravenous infusion of dexmedetomidine or placebo (i.e. normal saline) will be started according to the following schedule ( Figure 2). The starting dose will be 0.4 mcg/kg/h. No loading dose will be administered. If the infusion will be well-tolerated (i.e. without the occurrence of adverse effects), the dose will be increased of 0.2 mcg/kg/h per hour up to 0.8 mcg/kg/h.
Given the pharmacological peculiarities of the neonatal period [15], newborns will receive a starting dose of 0.2 mcg/kg/h, which will be increased of 0.1mcg/Kg/h up to 0.4mcg/Kg/h. At 24 hours of dexmedetomidine infusion, the analgosedation weaning process will be started, consisting in a 10% reduction of one of the drugs every 12 hours.
If requested, a switch from opioid and/or benzodiazepine to an equipotent drug of the same pharmacological class but longer half-life will be allowed (including enteral methadone, morphine, lorazepam). The switch should aim to facilitate the patient's management. In the same way as iv drugs, enteral drugs will be weaned with 10% reduction every 12 hours.
The WAT-1 scale will be administered every 12 hours of treatment infusion. If WS will be diagnosed, the clinician will administer a rescue dose of the using opioid and/or benzodiazepine, repeatable until resolution of the crisis, and will increase the dexmedetomidine/placebo dose by 0.2 mcg/kg/h (0.1 mcg/Kg/h in neonates). If the following WAT-1 score shows a decrease by at least 1 point compared with the previous one, the weaning program will be restarted (by 10% of reduction) and the current dexmedetomidine/placebo dosage will be maintained. If the WS symptoms persist, dexmedetomidine/placebo will be increased by 0.2 mcg/kg/h (0.1 mcg/Kg/h in neonates) according to the WS score, up to a maximum of 1.6 mcg/Kg/h (0.8 mcg/kg/h in neonates).
Once the analgosedation weaning will be completed, dexmedetomidine will be weaned or discontinued. A gradual reduction of the dexmedetomidine dose is strongly recommended to prevent the risk of dexmedetomidine withdrawal [16,17], but it is not mandatory. Since the analysis of dexmedetomidine weaning is not a specific aim of the present study, no specific protocol will be recommended. Time and modality of dexmedetomidine weaning will be recorded.
A follow-up visit will be performed at five days after PICU discharge, with the aim to collect the following data: (1) actual duration of the analgosedation weaning when longer than 5 days, (2) values of WAT-1 scores collected every 12 hours up to 72 hours after the analgosedation discontinuation, (3) length of dexmedetomidine weaning (hours), (4) occurrence of signs and symptoms of dexmedetomidine withdrawal.

Primary outcome measure
The primary outcome measure of our study is the efficacy of the treatment efficacy in the prevention of WS, i.e. the reduction of the WS rate in the DEX arm comparing with the placebo arm.

Treatment safety
The safety of the treatment will be assessed: (1) with a strict monitoring of hemodynamic parameters (heart rate, systolic and diastolic blood pressure) which are considered altered if their values differ more than 20% comparing with the patient's baseline values, (2) collecting every Adverse Reactions (ARs), Adverse Events (AEs), Serious AEs and Suspected Unexpected Serious Adverse Reactions (SUSARs). Every AR, AE or SUSAR potentially-related to dexmedetomidine will be summarized separately.

Secondary outcome measures related to Efficacy
Secondary outcome measures evaluated to confirm the efficacy of the treatment will be: (1) trend of WAT-1 score; (2) number of rescue doses required for WS symptoms; (3) number of temporary discontinuations of the analgosedation weaning due to the presence of WS, (4) duration of analgosedation weaning (days); (5) length of mechanical ventilation (days); (6) PICU length of stay (days).

Data collection and management
The blinded investigators will collect data by means of a standardized paper case-report form (CRF). Paper CRFs will be stored in accordance with national regulations. Paper CRFs will have an identifiable patient code in order to allow a clinical follow-up and a data monitoring by national coordinators or regulatory committees. Investigators will transcribe patient's data into an electronic CRF using the identification code. No patients' identifiable data will be directly accessible from the electronic CRF. Data recorded on each CRF will be entered in a dedicated database, checked and subsequently processed.

Sample size
The sample size has been calculated in respect with our primary outcome measure, that is the reduction of the WS rate. A recent multicenter national study reported a WS incidence of 64.6% among PICU patients receiving more than 5 days of analgosedation with opioids and/or benzodiazepines [4]. Given the small level of available evidence, to have a clearer picture of the potential reduction of WS, we decided to apply a classical prior elicitation process in four separate stages [18, 19]: (i) selecting the experts and identifying the aspects of the problem to elicit; (ii) proceeding with the elicitation process, that is, interaction with the experts; (iii) fitting the probability distributions to the expert's summaries; and (iv) including the information from the elicitation process in the evaluation of the sample size requirements.

Prior elicitation process
Twenty-eight pediatric intensivists and nurses expert in the field of analgesia and sedation were asked via an email survey about: (i) if they believe that DEX has some efficacy in reducing WS prevalence and (ii) if yes, what is the expected reduction in WS prevalence via DEX compared to standard care (placebo in the terms of this trial). All of the experts replied to the survey, and 25 (92%) of them declared to expect DEX to have an effect in WS prevalence: 23 of them declared that DEX is able to reduce the WS prevalence, 2 of them declared that DEX is not able to prevent WS and the last 3 were not able to provide an certain answer. Among those who replied affirmatively (n=23), 18 provided an estimated percentage of WS reduction in DEX arm vs. placebo. The median expected reduction in WS prevalence was 47.5% (I quartile 33.75% and III quartile 51.25%).

Adaptive design
We assumed that the WS prevalence, according to literature [4], amounts at about π Placebo = 64.6% and this value was used for sample size calculation. According to the prior elicitation process, we conservatively adopted the most pessimistic evaluation provided by the experts, assuming a reduction in WS prevalence of 33.75 points in the DEX group compared to Placebo. The sample size has been computed using an adaptive approach based on a two-stage Group Sequential Design with an interim Sample Size Reassessment in order to compensate for discrepancies between expected and observed incidence of the primary endpoint at the first stage [20].
The following assumptions were considered: Two-sided superiority Z test without continuity correction for rejecting the null hypothesis H 0 : π Placeboπ DEX = 0; α = 0.05; Power 0.90;

Efficacy bounds are derived using an O'Brien-Fleming boundary;
No futility bounds; An incidence rate of π Placebo = 0.646 in Placebo arm and π DEX = 0.375 in DEX arm (corresponding to a 33.75% reduction out of the 64.6%); An allocation rate of 1:1; Based on the above assumptions, this yields to 138 patients overall. To account for a possible R=5% dropout rate, the sample size n has been increased [21] to total patients. Thus, the trial has been designed as 20 + 20 = 40 patients at first stage and 154 overall (Supplemental Table 1).

Sample Size Reassessment
A promising zone design has been considered. Following steps have been provided at the first interim analysis step: b) Otherwise, the study will continue until the second stage; c) If the CP is critically lower than 0.3, then the internal DSMB will be consulted to discuss a termination of the trial for futility reasons.
A simulation has been performed to evaluate the extent of a sample size reassessment assuming that the null hypothesis will not be rejected at the first interim analysis, and assuming that the interim conditional power is in the promising zone.
To this purpose, reductions in the expected difference in the primary endpoint at interim, are investigated. A range of interim event rates say p interim /placebo , from 0.5 to 0.75 following a pace of 0.01, has been hypothesized in the Placebo arm. The event rate at interim in DEX arm is supposed equal to p interim to/DEX = 0.6625 * p interim /placebo , where 0.6625 corresponds to the most pessimistic reduction hypothesized above.
For each scenario, the number of patients to add to the sample size at the second stage (n add ), given the interim results, is computed to achieve a conditional statistical power of at least 0.8 (Supplemental Table 2).
Sample size estimation has been performed using the gsDesign [22] and the R-System [23].

Statistical analysis
The primary endpoint will be analyzed for the Intent-to-Treat (ITT) population in terms of WS rate (placebo vs. dexmedetomidine). If the interim conditional power will be not in the promising zone, no modifications to the design will be performed.
The final efficacy of the treatment will be evaluated using a Z test statistics; after having reached the sample size foreseen for each of the stages, an evaluation using a 95% repeated confidence interval will be performed.
Demographics (age, sex, and race) and other baseline characteristics will be summarized using descriptive statistics. As for secondary outcome measures, no formal testing procedure will be adopted, to avoid the inflation of type-I error. Differences in distributions will be evaluated on a clinical reasoning basis.
An analytical detailed list of patients who will discontinue the study for AR, AE or SUSARs will be collected. All analyses will be performed using the R-system [23].

Trial status
The

Discussion
At the best of our knowledge, this is the first randomized prospective controlled trial addressing the important issue of WS prevention using dexmedetomidine, a highly selective alfa-2 agonist with unique pharmacological properties.
WS represents one of the most important cause of morbidity in patients receiving prolonged-sedation in PICU [3], and several studies have been conducted so far to identify the main risk factors and the most successful prevention strategy. The cumulative dose of the analgosedation drug and the duration of treatment have been described as main factors associated with the onset of WS, as well as the rapid dosage reduction and the abrupt discontinuation of the treatment. [7]. Therefore, WS prevention strategies have been addressed both to restriction of drug exposure and to tapering of the infusion. A strategy of drug-switch has been also proposed, replacing the using drug with another equipotent drug with longer half-life. Although no drug seems more effective than others, methadone is the most commonly prescribed [8]. However, the efficacy of these strategies in preventing the WS is still unclear.
In the past decades, dexmedetomidine has been suggested as a useful strategy to prevent WS [9][10][11][12][13][14]. Binding the α2-receptor, dexmedetomidine is able to block the release of noradrenaline in the locus coeruleus mediating a sedative and anxiolytic effect [1] and to block the substance-P release in the dorsal horns of the spinal cord mediating a mild analgesic effect [25][26][27][28]. The sympathetic inhibition is also responsible for the most common AEs, such as hypotension and bradycardia, usually easily reversible with dose reduction [29,30]. The concept that dexmedetomidine could have a potentiality in WSmanagement originated from the knowledge of other α2-receptor agonists, i.e. clonidine and lofexidine, used in the adult population [9,31]. In fact, the ability of α2-agonists to interact with the sympathetic system represents the pharmacological rationale for their use as adjuvant-drug for the management of WS, which is characterized by sympathetic activation [31]. The interaction between dexmedetomidine and opioids has been first described in murine models treated with morphine prolonged-infusions and inducted to present WS [32]. The authors described that dexmedetomidine and opioids seem to have a reciprocal adjuvant effect to induce both analgesia and hypnosis. During opioid-WS, dexmedetomidine maintains its hypnotic effect even if its analgesic effect and the morphine-reciprocal effect decrease [32]. Other than these pre-clinical results, studies on dexmedetomidine for prevention of withdrawal syndrome have been limited to case series [9][10][11][12][13][14], and its clinical use in pediatrics has been limited by its off-label status.
The present trial will aim to systematically analyse the efficacy of dexmedetomidine for prevention of WS in pediatric patients receiving a prolonged analgosedation treatment. Its multicenter randomized controlled design will allow to clearly assess this research question with a high level of evidence. The systematic evaluation of WS by means of a standardized score validated for pediatric age, i.e. the Withdrawal Assessment Tool version 1 (WAT-1) [5] will assure precision in the WS registration and increase the validity of the study, as well as its reproducibility. Moreover, the feasibility of the present trial will be guarantee by the fact that dexmedetomidine is easily available in most of the tertiarycare pediatric centers in Europe, as well as the other resources requested for the implementation of the study. In case the efficacy of dexmedetomidine will be proven, the dexmedetomidine-arm of the present trial could be translated in a successful WSprevention protocol, offering a real opportunity to adequately approach one of the biggest challenges on prolonged sedation in PICU. In addition, the present study will measure if the use of dexmedetomidine could reduce the duration of conventional analgosedation, mechanical ventilation and PICU-stay with a possible impact in the PICU-resources management. Finally, the trial will systematically evaluate any kind of dexmedetomidinerelated adverse events, particularly the hemodynamic ones, providing a unique insight into its safety profile.
Our study is also subject of limitations. In fact, patient selection, protocols for conventional analgesia and sedation and for WS treatment were not standardized, and are therefore subject to practice variability. The randomization is not balanced among centers, precluding the control of a possible center-effect. The most severe patients could be difficult to be enrolled due to the complexity of maintaining the commitment to the protocol. Finally, the follow-up could be subject to missing data if the discharge includes a transfer to another center or institution. Despite these limits, we believed that this trail could represent an important step in the definition of a new strategy for the prevention of WS in critically-ill children.

Ethics and consent to participate
The Study Protocol Final Version 2.0 (registered on 18 September 2016) was approved by the Ethics Committee of University-Hospital S.Orsola-Malpighi of Bologna on 22 March 2017. All centers approved the protocol. The study was also authorized by the Italian Medicines Agency National Authority. Written informed consent will be obtained from both parents of each involved child.

Consent for publication
Not applicable.

Availability of data and materials
The Principal investigator (MCM) and the authors will have full access to the final dataset data during the analysis. The datasets used and analysed during the current study are available from the corresponding author on reasonable request.

Competing interests
Orion Pharma assured the liability insurance of the study (total amount of € 10.758). The supporter had no role in study design, decision to publish and preparation of the manuscript and will have no access or role in data collection and analysis. The authors have not received any personal funding or compensation for the research. Therefore, the authors did not have any personal interest to declare.

Funding
The study did not receive any institutional founding, nor external, internal or individual funding.