1.1. Synopsis

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1.2. Schema

1.3. Schedule of Activities (SoA)

The following schedule of activities are to be completed for each participant.

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2.1. Study rationale – The need for a trial

Acute asthma exacerbations are a leading cause of pediatric emergency department (ED) visits and hospitalizations [1,2]. Despite receiving optimal initial treatment with inhaled salbutamol, ipratropium and systemic corticosteroids (CS), 50% of the children with severe acute asthma experience ongoing moderate-to-severe respiratory distress [3]. In this refractory population, which accounts for 84% of asthma hospitalizations, guidelines recommend intravenous magnesium (IVMg) [4–9]. However, IVMg therapy is resource-intensive as it demands close monitoring by specialized pediatric ED nurses, requires IV insertion, and can cause hypotension [10]. To minimize these concerns, we evaluated the benefits of nebulized Magnesium (Mg) in a 7-centre Canadian CIHR-funded Randomized Controlled Trial (RCT) (MAGNUM) in this population [3]. MAGNUM identified no benefits of inhaled Mg compared to placebo (Appendix A in S1 File) [3].

There is highly limited and disparate evidence of benefit for IVMg in children, requiring further evidence to justify its continued use [11,12]. Early evidence from 2 small single-center placebo-controlled pediatric RCTs (total N = 61) suggested hospitalization benefit [13,14], while a third study reported no benefit (N = 54) [15]. The most-recent Cochrane review based on these 3 studies expressed lack of confidence in the evidence prompted by a more appropriate re-analysis which yielded lack of IVMg effect on hospitalizations [16]. Similar conclusion was reached by another review [17]. Recent large observational studies found that IVMg was not associated with improved outcomes [11,18]. A U.S-wide PHIS study of 91,000 children with acute asthma showed no association of IVMg with shorter hospital stay, duration of airway support or use of IV salbutamol [19]. In a prospective study of pediatric moderate-severe refractory asthma with a propensity score-covariate adjustment, IVMg was associated with a 2-hour worsening of the Acute Asthma Intensity Research Score, a 6-fold higher odds of hospitalization and no difference in time to every 4 hours salbutamol, an accepted parameter for discharge home, compared to no IVMg [11].

These conflicting results may be due to differences in the timing of IVMg administration, confounding, and the choice and the timing of the primary outcome: 1) the early RCTs only measured an immediate IVMg effect on respiratory status [13,14,20–22]; there is no evidence of its incremental benefit on outcomes measured at the peak effect of routine key co-interventions with CS and bronchodilators, when hospitalization is usually considered (approximately 4 hours after CS); 2) past RCTs did not employ validated asthma scores; 3) IVMg is usually given after ≥4 hours of unsuccessful ED treatment when most clinicians have already decided to admit, even if there is significant clinical improvement [19]; 4) children given IVMg have 6–10 times higher odds of hospitalization, in part due to confounding by indication, possible lack of Mg efficacy and physician discomfort with discharge after Mg due to concerns about rebound effects [11,23]. In a secondary analysis of MAGNUM where some children required IVMg, we demonstrated that the decision to admit is independent of the presenting asthma severity and clinical response to IVMg [23], suggesting that some hospitalizations may be driven by physician discomfort about discharge after Mg rather than by true clinical Mg efficacy. Therefore, hospitalization does not represent an appropriate primary outcome to assess IVMg efficacy. In contrast, alleviation of respiratory distress is a highly suitable primary outcome, as it is the main reason for IVMg therapy [24].

We propose an RCT [MAGnesIum Trial in ACute Asthma In Emergency DepArtmeNt: MAGICIAN trial] to conclusively determine if IVMg alters the asthma exacerbation course: it must be given early, with the improvement in respiratory distress measured at the peak effect of key co- interventions using a valid, discriminative, reproducible and responsive-to-change instrument, the Pediatric Respiratory Assessment Measure (Appendix B: Pram Score in S1 File)) [25].

Trial results will impact care regardless of whether an association is found. If IVMg is found to decrease respiratory distress, we will use knowledge translation (KT) to implement routine and early IVMg therapy for refractory asthma. A negative result will be followed by de-implementation strategies to cease the use of IVMg for refractory asthma which may also lead to cost savings: IVMg therapy is personnel- intensive, requires an IV which may not be necessary in moderate-severe asthma, may cause hypotension [10], and as such greatly augments the odds of hospitalization [11,23].

2.2. Background

Pediatric asthma guidelines recommend inhaled ß2 agonists, anticholinergics and systemic CS for acute attacks [4–6,8,9,26]. However, 50% asthmatics are resistant to ß2 agonists [3] and a response to CS may take well above 4 hours [27]. In MAGNUM, 49% of screened children remained in moderate-severe distress after initial therapy and 45% were hospitalized [3]. These non-responders represent the majority of asthma hospitalizations [25], with high treatment costs [28,29]. IVMg sulfate could relieve airway obstruction by multiple mechanisms [30–33]. Of the 8 RCTs evaluating IVMg in children, only 3 used a placebo-controlled design (N 31,30,54) assessing lung function/asthma score and hospitalization [13–15], with disparate conclusions. Two positive RCTs excluded preschoolers who constitute the majority of pediatric asthma ED visits [34] and failed to use ipratropium for initial therapy [13,14], and the negative study did not limit enrolment to refractory asthma [15]. The table below summarizes the pediatric RCTs of IVMg: 3 used non-placebo comparators, 1 did not measure hospitalization [21] and 1 had no control group: only 3 small trials were placebo-controlled (shaded lines).

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A review of 61,854 pediatric Emergency Department (ED) asthma visits from the U.S.PECARN registry found that only 26% of children hospitalized for asthma got IVMg in the ED [10], and that IVMg is generally given late (median 154 min) [19]. In our secondary MAGNUM analysis, IVMg was associated with a 10-fold increase in hospitalizations when adjusted for presenting and post Mg asthma severity [23], suggesting either confounding by indication, lack of Mg efficacy or concern about discharge after Mg due to potential rebound effect (Appendix C in S1 File)). The short IVMg half-life (2–2.7 hrs) [35,36] has not been linked to the duration of clinical effect of IVMg [17]. Only 1.8% children discharged post IVMg return to the ED vs 3.6% without [10].

Equipoise exists for IVMg benefit in refractory pediatric asthma [16]. The latest 2016 Cochrane review highlights the limitations of the evidence, especially the small number of participants and disparate results [16]. While the fixed-effect analysis of the 3 studies [13–15] suggests a large reduction in hospitalizations, a re-analysis with a more appropriate random-effect method yielded lack of significant difference [OR 0.18 (0.02-1.59)] and while the point estimate is low, so was the authors’ confidence in the evidence [16].

While IVMg itself is inexpensive, its administration is resource-intensive because of the need for nurses skilled in pediatric ED care and IVMg infusion protocols [37,38], as well as for blood pressure monitoring due to the potential for hypotension [39]. Given challenges with IV access in some young children [40–44], ED physicians tend to delay IVMg therapy to avoid the “poke” [39]. Clarification of IVMg benefit would provide a much-needed justification for related human and interventional resource use.

In preparation for this study, we conducted a Pediatric Emergency Research Canada (PERC) survey showing that a) alleviation of respiratory distress represents the main reason for IVMg use, b) most ED physicians routinely hospitalize after IVMg, irrespective of asthma severity or Mg response, in part due to lack of solid evidence of improved outcomes after IVMg (Appendix D: PERN Survey in S1 File)) [24].

2.3. Risk/Benefit assessment – Participant safety

Mg has a theoretical potential for hypotension, hypopnea and heart block [45], but only hypotension has been reported with any frequency. The IVMg RCT of 1109 adults reported 8% hypotension [46] but nobody had Mg stopped for hypotension. Pediatric IVMg trials with Mg doses 75 and 100 mg/kg did not report any hypotension (N = 101) [15,20]. While a review of the PECARN Registry found a median dose 50 mg/kg had a hypotension rate of 6.8% [10], the mean decrease in the systolic pressure was 5 mm Hg, with uncertain clinical significance. No hypotension was observed in 3 pediatric pharmacologic ICU studies of 75 mg/kg IV Mg in children ≤30 kg and 50 mg/kg in those >30 kg followed by 40 mg/kg/hour for 4 hours [47–49]. Two of our participating sites routinely use 75 mg/kg IVMg. A literature review of pediatric status asthmaticus confirms lack of IVMg toxicity [50]. Nonetheless, blood pressure will be measured at 10, 20, 30 and 60 minutes and hourly to 180 minutes. If the systolic pressure drops below the 5^th percentile-for-age [51], necessary treatment such as IV fluids will be given. Because the children with unstable airway will be excluded and further inhaled salbutamol/other asthma therapies will be given if needed, lack of Mg in the placebo group will not endanger these participants. All study patients will be monitored for 180 minutes post-intervention prior to discharge, to ensure safety. Only 13/723(1.8%) children discharged post IVMg return to the ED vs 1383/38,623(3.6%) without; IVMg is not associated with re-visits [10].

4.1. Overall design and the scientific rationale for study design

As mentioned above, previous RCTs of IV Mg in children are small and have methodologic limitations. The most recent systematic review (Griffiths, 2016) concludes there is equipoise about IV Mg benefit. More recent large IVMg studies cast doubt on Mg benefit but these have non-RCT designs. Therefore, we propose a 6-centre randomized, double-blind, placebo-controlled trial. Two groups will be compared: IVMg sulfate and IV0.9% saline placebo. After initial therapy with the systemic CSs routinely used for acute asthma management at a given site, 3 treatments with inhaled salbutamol and ipratropium (indications for ipratropium vary by site) [52], eligible patients with PRAM ≥5 (Appendix B: PRAM Score in S1 File)) will receive a 30-minute IV infusion of 75 mg/kg of Mg sulfate (maximum 2.5 g) [experimental group] or an identical volume of 0.9% saline [control group]. Outcomes will be measured during the 180-minute observational period in the ED and at 72 hours post ED discharge. Primary outcome will be the PRAM score at 120 minutes after start of experimental therapy.

PRAM: PRAM is a validated 12-point asthma severity score [53] which exhibits the most comprehensive measurement properties of all asthma scores [54] and has been successfully used as an outcome in major trials [3,55]. It is the only score with demonstrated criterion validity, using respiratory resistance as the gold standard [25,53]. PRAM has been validated in both preschool and school-aged children in the ED with asthma and has strong association with admission [25]. PRAM has inter-rater reliability above 70% [25] and is adopted in all pediatric EDs in Canada. Most children treated for acute asthma are preschoolers [56] who lack coordination to perform pulmonary function tests reliably. To maximize the accuracy of the PRAM measurement, all study nurses will complete online PRAM training module [57] at https://enseignement.chusj.org/PRAM-En. We will use an eligibility cut-off of PRAM ≥ 5 post initial therapy as this is associated with clinically concerning respiratory distress requiring further intervention. PRAM ≥ 5 after one hour of initial care has high accuracy (AUC: 0.88) to predict hospitalization [58]. Of the 215 children given IVMg in MAGNUM, 118 had PRAM 5, 41 PRAM 6, 35 PRAM 7 and 21 PRAM ≥8 prior to IV Mg [3].

4.2. End of study definition

A participant is considered to have completed the study if he or she has completed all phases of the study including the last scheduled procedure shown in Section 1.3(SoA).

A participant who is discharged home at the index ED visit will have relevant outcome measures completed by the study nurse up to 180 minutes. These participants will also complete a follow-up questionnaire at approximately 72 hours, at which point their study will be complete.

A participant who is admitted to the hospital (e.g., transferred from ED to an in-patient unit) will have the study nurse complete any study measures up to 180 minutes. After that, the participant is considered complete. No follow-up will occur 72 hours later.

5.1. Inclusion criteria

1. 1) Age 2.00–17.99 years (prior to 18^th birthday),
2. 2) Diagnosis of asthma, defined as an asthma or probable asthma diagnosis/asthma-like phenotype made by a physician (this includes ED physician) in a patient who in the opinion of the treating ED physician requires therapy for acute asthma in the ED (GINA asthma guidelines, 2024) [59].
3. 3) Moderate-severe asthma after initial therapy with 3 treatments of inhaled salbutamol and ipratropium, defined as an eligibility PRAM ≥5, indicating a strong association with hospitalization [25].

5.2. Exclusion criteria

1. 1) Receipt of IVMg within 24 hours prior to ED arrival.
2. 2) Need for airway support on arrival. (Airway support on arrival meeting exclusion criteria will include immediate need for high flow nasal cannula therapy for suspected respiratory failure, non-invasive CPAP/bi-PAP ventilation or invasive ventilation with endotracheal intubation, as decided by the attending Emergency Department (ED) physician. Supplemental oxygen therapy by any route will not represent an exclusion criterion.)
3. 3) Known renal, chronic pulmonary, neurologic, cardiac or systemic disease: these may influence outcomes after Mg.
4. 4) Known hypersensitivity to Mg sulfate.
5. 5) Previous enrollment in this study.
6. 6) Poor mastery of English and/or French language precluding informed consent understanding.
7. 7) No phone/email; unavailable for follow-up

5.3. Strategies for recruitment and retention

We expect 6 Canadian Hospitals to participate in this study. The anticipated study duration is approximately 38 months. We anticipate an 8-month pre-enrollment period, patient recruitment will occur for approximately 26 months, and an estimated 4-month post-enrollment period.

The target sample size is 192 participants. We anticipate an accrual rate of 7–8 participants a month in Emergency Departments (ED) across all sites.

Children presenting to the collaborating EDs who meet eligibility criteria will be approached for enrollment when the research nurses are on duty/on call (days and evenings). Participating sites have research assistants in the ED who will pre-screen potentially eligible patients and ensure the miss rate is kept to a minimum.

As per our previous MAGNUM trial with a similar design, we estimate that only 15% of screened patients will participate: 75% will be ineligible and 50% of the remaining will decline consent or not join for other reasons [3]. We shall adopt the MAGNUM enrollment schedule, with coverage by on-call research nurses, to enroll 192 patients with full data across 6 sites in approximately 26 months. This is achievable given that MAGNUM used the same eligibility criteria and entry asthma severity and randomized 729 children with full data at 7 centers in 5 years (21 patients/year/site). Thus, we anticipate annual enrollment of 109 eligible consenting children with full data based on annual asthma ED presentations (Appendix F in S1 File)) and a conservative estimate of 30% weekly hours coverage, 25% eligibility, 50% of those eligible not participating for refusals/other reasons, 5% non-compliance with intervention (crossover) and 1% loss to follow up.

6.1. Study intervention description

The Research Ethics Board of the Hospital for Sick Children approved this study. A written informed consent will be obtained from all participants.

Previously healthy children 2.00-17.99 years of age with acute asthma will have PRAM routinely measured in triage, as per usual practice. Children presenting with a PRAM ≥ 5 will be considered potentially eligible and will receive oral dexamethasone, predniso(lo)ne or IV CS in triage/shortly thereafter. They will also receive three salbutamol inhalations with or without inhaled ipratropium (depending on site practice) [60] via Metered Dose Inhaler/valved holding chamber approximately 20 minutes apart, with medication doses and ipratropium indications depending on local practice. If the PRAM is ≥ 5 after the first bronchodilator treatment and the child has no co-morbidities [61], a consent to approach for research will be obtained. At the conclusion of the 3 baseline inhalations, the research nurse will confirm eligibility, confirm the eligibility PRAM score, and obtain informed consent. A topical anesthetic may be used at the IV if that is the practice at a given site and IV line will be inserted. Participants may also receive an IV fluid bolus, as per site ED practice, prior to the experimental therapy, to improve hydration and prevent hypotension.

Thereafter, the trained and intervention-blinded study nurse will enter the patient eligibility data into the database, obtain the next study kit assigned to the appropriate age group (<6^th birthday vs age 6 years and older) from the study fridge and enter the study kit number in the database. Master lists will be provided to all participating research pharmacies which will permit the preparation of the study kits according to the randomization schedule. Prior to the start of the experimental therapy, the study nurse will measure the patient’s Baseline PRAM, respiratory rate, heart rate, blood pressure and oxygen saturation.

6.2. Study procedures (Dosing and administration)

The study nurse will administer the assigned experimental therapy (IV Mg sulfate or normal saline placebo) over a 30-minute period. The patients, study nurses, ED physicians and investigators will be blinded to treatment assignment; the pharmacy will be unblinded. [The SickKids research pharmacist will provide a manual with instructions on how each pharmacy will prepare blinded numbered kits with Mg or 0.9% saline placebo, according to routine IVMg sulfate infusion protocols (Section 6.4.3 Logistics of Blinding and Kit Making). Each site will receive requirements for drug accountability and handling].

Mg dose: The chosen Mg sulfate dose of 75 mg/kg is at the upper end of the recommended dose range [62,63] and is needed to minimize the probability that a subtherapeutic dose led to lack of observed treatment effect. Children weighing ≤30 kg require larger IVMg dose/kg than their heavier counterparts [47,48]. Therefore, we shall administer IVMg 75 mg/kg (up to 2.5 g) to patients weighing ≤33 kg and 2.5 g to those >33 kg. This regime has a reassuring safety record: two pediatric studies of IVMg have employed doses of 75-100mg/kg without adverse effects [15,20]. In three pediatric studies of 75 mg/kg IVMg bolus followed by 40 mg/kg/hour for 4 hours, no child developed hypotension [47,48]. Two participating sites (Ste Justine’s, McMaster) routinely use 75 mg/kg IVMg.

6.3. Study procedures (after administration of study intervention)

Following the 30-minute experimental infusion, participants will continue to receive inhaled salbutamol, supplemental oxygen and other asthma medications as clinically warranted. To prevent contamination, the use of open-label IVMg will be strongly discouraged until after primary outcome determination at 120 minutes. In the highly exceptional event of respiratory failure after the intervention, immediate open-label IVMg will be permitted with locally used Mg doses (Section 6.6 Emergency Unblinding Procedure), but unblinding will not be needed because a 2^nd Mg infusion is safe for normotensive patients [47–49,51,64]. Because children with unstable airway will be excluded and other routine asthma co-therapies will be given if needed, we do not anticipate open-label IVMg use prior to this time. IV in the placebo group is both clinically reasonable and ethically defensible: as the eligible children have refractory asthma, their ongoing respiratory distress will justify an IV to provide the often inadequate hydration and a potentially beneficial therapy to alleviate respiratory distress. Many of these children will need to be hospitalized which is often accompanied by IVMg therapy, other IV bronchodilators, and hydration. Topical anesthesia may be used if that is the practice at a given site.

Disposition will be determined by intervention-blinded ED physicians. While there is no known association between Mg serum levels and the duration of Mg bronchodilator effect, all study patients will be observed for 3 hours, to ensure safety. As per guidelines, discharged patients will be prescribed inhaled salbutamol, oral CS and inhaled CS, using locally employed regimes and doses. Further care will be sought if salbutamol is given more often than every 4 hours or if respiratory status interferes with the usual activity. There will also be a standardized electronic/telephone follow up to ascertain outcomes at 72 hours post ED discharge home.

6.4. Preparation/Handling/Storage/Accountability

6.4.3. Logistics of Blinding and Kit Making.

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Each site will prepare consecutively numbered randomization kits, numbered according to the site’s Master Randomization table.

Each kit will contain:

• Magnesium Sulfate Injection 500 mg/mL OR 0.9% sodium chloride injection
  • Active Kits will contain Magnesium Sulfate injection
    • Injection to be administered by intravenous administration
    • Unblinded site pharmacy will repackage small batches of Canadian commercial magnesium sulfate injection (5.5mL) into 10mL empty sterile vials in a laminar air flow hood according to a detailed worksheet procedure in the Pharmacy Manual of Operations.
  • Placebo Kits will contain 0.9% sodium chloride injection
    • Unblinded site pharmacy will prepare small batches of Normal Saline (0.9%) injection (5.5mL) into 10mL empty sterile vials in a Laminar Air Flow hood according to a detailed worksheet procedure in the Pharmacy Manual of Operations.
  • The repackaged Magnesium Sulfate and compounded placebo vials will be given an up-to 3-month expiry date, depending on site kit repackaging conditions.
  • During Kit assembly by the site pharmacy, identical labels will be placed on the blinded vials to ensure the integrity of the blind.
  • Blinded Numbered Randomization Kits will be assembled by the unblinded site pharmacy and made available to the Emerg Study RNs for storage in the ED for use once a subject is eligible to be randomized.

In this Investigator initiated study, the numbered kits will be assembled and labeled in the local Research Pharmacy according to detailed kit making Standard Operating Procedures provided by the Coordinating Pharmacy at SickKids. All kits/products will have appropriate Clinical Trial labeling according to Canadian regulations.

6.5. Measures to minimize bias: Randomization and blinding

Treatment allocation: The leading site pharmacy will use the randomize.net tool to produce the study Master Randomization tables, stratified by site and age group (< 6years old, i.e., prior to 6^th birthday vs ≥ 6 years old as pre-schoolers may respond differently to asthma therapies) [52], employing permuted randomization of varying block sizes in a 1:1 ratio of Mg sulfate to placebo. The study nurse will transcribe the assigned study kit numbers into the secure Health Canada-validated REDCap database.

Master lists will be provided to all participating research pharmacies which will permit the preparation of the study kits according to the randomization schedule.

The patients, outcome assessors (study nurses, ED physicians) and investigators will be blinded to treatment assignment; the pharmacy will be unblinded. The SickKids research pharmacist will provide a manual with instructions on how each pharmacy will prepare blinded numbered kits with Mg or 0.9% saline placebo, according to routine IVMg sulfate infusion protocols (Section 6.4.3 Logistics of Blinding and Kit Making). Each site will receive requirements for drug accountability and handling. Unblinding is unlikely and did not occur in MAGNUM. The active Mg and saline placebo are identical in volume, color, odor, and appearance. Further, children with unstable airway will be excluded and only 6% experience a mean BP drop 5mmHg after IVMg with fewer requiring intervention [10].

Administration of open-label IV-Mg would highly increase the probability of study contamination and will be strongly discouraged until after 120 minutes after the start of the experimental therapy. Children not responding to/worsening after the experimental therapy will be given back-to-back administration of inhaled salbutamol, other required medications and supplemental oxygen if necessary. In the highly exceptional event of impending respiratory failure after the intervention (children with unstable airway on arrival will be excluded), immediate open-label IVMg will be permitted with locally used Mg doses, but unblinding will not be needed because a 2^nd Mg infusion is safe for normotensive patients [47–49,51,64]. (Section 6.6 Emergency Unblinding).

6.6. Emergency unblinding procedures

Unblinding should only be requested when the clinical treatment of the patient will be different by knowing which arm of the study the patient was previously on. This may occur in a highly exceptional scenario of a suspected respiratory failure accompanied by clinically significant hypotension requiring treatment during the experimental therapy (presumed to have occurred during experimental Mg), and continuation of the experimental therapy would be undesirable. Hypotension will be defined as systolic blood pressure <70 mm Hg +(age in years x2) in children 2–10 years old and as <90 mm Hg in those >10 years old. The study PI/local PI and the study nurses will remain blinded.

Hypotension occurring after the experimental therapy will be treated as needed but does not require unblinding.

The following Emergency Unblinding procedure will be followed:

1. Treating Physician or RN should contact the local QI of the study for consultation to unblind. In the event they cannot be reached immediately go to the next step.
2. Contact the SickKids hospital pharmacy by phone. The Research Pharmacy is available Mon – Fri from 08:00–16:00 EST at 416-813-6705 ext. 1 and ask to speak to a Research Pharmacist. At all other times or on statutory holidays call 416-813-6699 and ask to speak to a Pharmacist about an unblinding.
3. Provide the patient’s study randomization number, reason for unblinding, your site and your name to the SickKids pharmacist who will then provide the unblinded study arm.
4. Note that all patients whose therapy is unblinded must stop receiving the experimental therapy The ED physician will prescribe additional treatment as clinically appropriate.
5. The requesting physician should initiate Email communication within 24 hours detailing the request for Emergency unblinding and why. The email must inform the local PI and SickKids Research Pharmacist and Study Principal Investigator (suzanne.schuh@sickkids.ca)
6. The DSMC and REB will be advised of emergency unblinding within 48 hours of Sponsor becoming aware of the incident.

6.7. Concomitant therapy

We are collecting medications given prior to arrival in the ED. This is to compare groups at baseline. Following the 30-minute experimental infusion, participants will continue to receive inhaled salbutamol, supplemental oxygen and other asthma medications as clinically warranted, except IVMg (can only be given after 120 minutes).These medications will be collected as outlined in section 1.3 (SoA) in the case report form.

7.1. Discontinuation of study intervention

In the exceptional event the patient develops hypotension requiring therapy, apnea, or another adverse event reasonably attributable to Mg and the ED physician feels that the experimental therapy cannot be safely continued, the experimental treatment will be stopped and appropriate treatment given. Hypotension will be defined as systolic blood pressure <70 mm Hg +(age in years x2) in children 2–10 years old and as <90 mm Hg in those >10 years old.

Lack of clinical improvement/deterioration after experimental therapy will be treated with administration of supplemental oxygen (if needed) and further inhaled salbutamol ± ipratropium treatments. Hypotension after experimental therapy will be treated with supplemental IV fluids/other measures, as per usual clinical practice. Neither of these scenarios apply to discontinuation of the study and if the participant would like to continue participation, the study assessments and survey should proceed.

7.2. Withdrawal from the study

Participants are free to withdraw from participation of this study at any time upon request. An Investigator may discontinue or withdraw a participant from this study for the following reasons:

• Withdrawal of informed consent (participant or parent/guardian withdraw for any reason)
• If the participant’s blood pressure drops below the 5^th percentile during the experimental infusion (this needs to be confirmed with manual BP measurement) and the treating physician feels that treatment is required, experimental infusion will be stopped but the child will remain in the study and study allocation will remain blinded. Participants who develop hypotension or receive open-label IVMg during the 180-minute observational period will also remain in the study without unblinding. Participants whose treatment assignment has been unblinded will also remain in the study.

7.3. Lost to follow-up

We anticipate virtually no loss to follow-up for the primary outcome because the primary endpoint will happen in the ED. Participants discharged home from the ED will be contacted via email or phone (as per the preference of the family) 72 hours after discharged for a follow-up survey. The site will make every effort to contact the participant daily up to 7-days after discharge.

If the participant is unable to be reached via phone or email (their preferred method of contact) within 7 days after discharge, we will consider them lost to follow-up for this secondary outcome. They will not be withdrawn from the study, we will record in the study database that we were unable to contact participant for the final study time point.

8.1. Assessments

The schedule of activities is provided in section 1.3 (SoA).

All relevant data will be captured on paper or electronic case report forms (eCRFs) in accordance with the eCRF completion guidelines.

9.1. Sample size

Sample size is based on the assessment of the PRAM change in the IVMg vs the control group and we conservatively aim for an inter-group PRAM difference in change of ≥1.0 point (SD 2.5), based on the following evidence. Children 1–17 years old with a baseline PRAM ≥4 points had a median PRAM change of 3 points if discharged vs.1 point if admitted [25]. In a PRAM validation study of children with moderate dyspnea anchored against expert physician-perceived clinical improvement a PRAM change of 1.5 (SD 2.3) was seen for children judged clinically improved vs. 0.0 (SD 2.2) for those unchanged [65]. When compared to a change in respiratory rate percentile, a PRAM change of 1.1 (SD 2.7) was seen in the improved patients vs.0.3 (SD 2.2) in those unimproved [65]. Based on this evidence, the investigators agree that a minimally clinically significant difference in PRAM changes between groups is 1 point. Although the study non-compliance and loss to follow-up rates in MAGNUM were both 0%, we conservatively assume that the non-compliance (crossover) with allocated therapy and the follow up loss may be as high as 5% and 1%, respectively. Based on these parameters, a study sample of 192 children (96 per group) provides 80% power with a two-sided significance level 0.05. Accounting for the randomization factors of site and age, a sample of 192 children obtained by recruiting in 12 strata (2 ages x 6 sites) with a similar number of children per strata, a significance level of 0.05 and an intracluster correlation coefficient of 0.05, achieves 80% power to detect PRAM difference in change of 1.0 (SD 2.3) based on a mixed-model analysis.

9.2. The primary outcome measure

The primary outcome measure will be the PRAM score [25,53], measured at 30, 60, 120 and 180 minutes post intervention, with the 120 minute measurement as the primary end-point. PRAM is the best tool to ascertain clinical response in this trial. It is routinely used in pediatric EDs across Canada and abroad to guide asthma therapy and will: a) help identify eligible candidates, b) measure the incremental benefit of IVMg across sites, c) promote acceptance of trial results by the end-users, d) provide greater sensitivity to change than spirometry, and e) facilitate implementation of findings in Canada and beyond.

Two ED studies (N = 200) of children with moderate-severe acute asthma confirmed that the PRAM score at 3 hours post initial management accurately predicted hospitalization/long ED stay (AUC 0.85 to 0.88, OR 2.0) as well as clinical improvement (our primary end-point) [58,66]. This time point also corresponds to 4 hours post initial CS therapy when CS is expected to act and hospitalization decisions are usually made. PRAM is a 12-point instrument validated in children 1–17 years old with acute asthma in the ED exhibiting the most comprehensive measurement properties of all pediatric acute asthma scores [54], which was successfully used as an outcome in major trials [3,55]. PRAM is the only pediatric acute asthma score developed for pre-schoolers by criterion (oscillometry) and construct (physician severity appraisal) validity [25,53]. PRAM also demonstrates good discrimination and responsiveness to change: a construct-validation (hospitalization) in 800 children aged 1–17 years (oscillometry and physician appraisal) showed good internal consistency (Cronbach α 0.7), responsiveness (Guyatt responsiveness index 0.7), and inter-rater reliability across ages [25,53]. PRAM is one of two scores that performed best in validation, responsiveness, and reliability in the two systematic reviews [54,67]. Two prospective validation studies compared the psychometric properties of the highest-rated clinical scores in 50 children [65,68]. One found PRAM as one of two most valid (construct and content-wise) scores of 36 dyspnea scores. The inter-rater reliability was modest, because of no rating of the auscultation and palpation criteria, which represented 3 of 5 items [65]. The second study rated PRAM as second-best for predicting hospitalization (AUC 0.89) [68]. Because the raters were not PRAM-trained, the inter-rater reliability was lower than in the primary studies (weighted kappa 0.50): this will be remedied by a mandatory participation in an online training module [57] by all research nurses. While PRAM detected significant and meaningful changes in ED treatment from baseline to 4 hours in school-aged children, spirometry did not, suggesting a higher PRAM sensitivity to change [69]. Unlike spirometry, PRAM will allow inclusion of preschoolers who represent 60% of asthma visits to pediatric EDs and 40% of the school-aged children unable to perform spirometry [56].

We considered but rejected using hospitalization as the primary outcome as it would likely artificially attenuate inter-group difference and mask a true difference in clinical improvement. Hospitalization is a subjective decision influenced by asthma severity, hospital policy and provider risk-tolerance. Further, major confounding by indication is likely [11,23]. Finally, a meaningful PRAM effect size would provide a compelling reason for routine early use of IVMg, regardless of hospitalization, while hospitalization is irrelevant with a null or negative result.

The 120-minute time point includes the initial asthma therapy (one hour), subsequent period involving eligibility confirmation, informed consent, IV placement and pre-hydration (approximately one hour) and the two-hour period after the start of experimental therapy. Because corticosteroids are typically given at the start of the initial therapy, the 120-minute point will occur approximately 4 hours post corticosteroids when most of the improvement after corticosteroids occurs (Alnaji et al, Acad Emerg Med 2014).

9.3. Secondary outcome measures

The two study groups will also be compared with respect to:

1. a. Hospitalization for asthma at the index ED visit.
2. b. Changes in PRAM, respiratory rate, heart rate, oxygen saturation and blood pressure from baseline (pre- intervention) to 30, 60, 120, and 180 min and also in blood pressure to 10 and 20 min post-intervention
3. c. Area under the receiver operating characteristic curve for the PRAM score changes at 30, 60, and 120 minutes.
4. d. PRAM denoting mild asthma (≤ 3 points is a widely accepted discharge criterion [25]) at 120 minutes
5. e. Hospitalization for asthma at any medical facility within 72 hours post- ED discharge.
6. f. Unscheduled asthma-related visits to any health care provider within 72 hours post- ED discharge.
7. g. Hospital length of stay.
8. h. Open label IVMg administration after the 120-minute measurement of the primary outcome.

9.4. Other rare outcomes

While the study cannot be powered for their meaningful analysis, we will collect

a) ICU admissions, b) safety outcome of actionable hypotension (systolic blood pressure <5th percentile for age [51] treated with IV fluids/other therapy) (Section 10 Adverse and Serious Adverse Events). While many physicians claim to use IVMg to decrease ICU admissions, only 5% (19/372) of hospitalized children received ICU care in MAGNUM [3].

9.5. Analyses: Primary efficacy analysis

We will adopt an intention-to-treat (ITT) approach and a sensitivity analysis using a per-protocol (PP) approach. Variables will be reported using frequencies and proportions; and continuous variables will be expressed as means and standard deviations or medians and interquartile ranges in case of non-normal distribution. Baseline variables will be compared between the IVMg vs placebo using standardized differences (SD) with an absolute SD < 0.10 being considered balanced.

9.6. Primary outcome

For the primary outcome of the change in PRAM at 120 minutes, the study groups will be compared using the Student’s t-test. A comparison based on a multiple regression analysis will be conducted adjusting for the randomization stratification factors site and age.

9.7. Secondary outcomes

For the continuous outcomes changes in the PRAM, respiratory rate, heart rate and oxygen saturation from pre-intervention to 30, 60, 120, and 180 min, a mixed model repeated measures will be conducted with treatment group as the between factor (IVMg vs placebo) and the within factor time 0,60,120,180 min. The analysis will be repeated with the randomization stratification factors site and age. Similarly, blood pressure will be analyzed with the additional time measures at 10, 20 and 30 minutes. For overall hospital stay, the study groups will be compared using the Wilcoxon ranked-sum test. For binary outcomes (hospitalization, PRAM indicating mild asthma, unscheduled asthma-related re-visits), groups will be compared using the chi-square test. For the analysis of the area under the ROC curve for PRAM scores, a mixed model repeated measures ANOVA will be conducted with the between factor study group (intervention vs placebo) and within factor time (30, 60, 120 minutes). In addition to the omnibus test for the group and time factors, an orthogonal polynomial analysis will be conducted to compare trends over time between the study groups.

A comparison based on a logistic regression analysis will be conducted adjusting for the randomization stratification factors site and age. As the secondary analyses are exploratory, overall significance for them will be set at 0.05 (2-sided).

9.8. Measurement of outcomes at follow up

Trained and intervention-blinded research nurses will measure PRAM, respiratory rate, oxygen saturation and blood pressure pre-randomization and at the above intervals, up to 180 minutes post starting the intervention, ascertain disposition and other pharmacotherapy given in the ED and determine other outcomes via automatic REDCap e- mails/study team e-mail/telephone at 72 hours post-ED discharge. If there has been no response, there will be daily reminders until day 7.

9.9. Safety outcomes

Each adverse event will be described as per good clinical practice guidelines. Descriptive statistics will be used to report frequencies of adverse events and SAEs in the groups. If appropriate, differences between the groups will be compared using a two-sample t-test or Wilcoxon rank sum test. These analyses will be reviewed by Data and Safety Monitoring Committee (DSMC) every 6 months.

Missing Data: Missing data will be imputed using multiple imputation. Analysis will be done using SAS™ software.

9.10. Interim analysis

Given the long study timeline, one interim analysis is planned after we recruit 50% of our sample. We will follow the O’Brien-Fleming group sequential method with a level of significance of 0.0054 at the interim analysis and 0.0492 for the final analysis. This analysis will be conducted by the statistician assigned to the DSMC (not otherwise involved in the trial) and evaluated by the DSMC.

9.11. Subgroup analyses

A priori we identified the following subgroups for subgroup analyses: age ≤ 5 vs ≥ 6 years [53,70], sex [71], post-randomization PRAM score, personal atopy, non-rhinovirus viral nasal pathogen, and “acute viral induced wheeze” phenotype (age ≤ 5 years without atopy or cough between respiratory infections) [72,73]. For subgroup analyses, we will use generalized linear mixed modelling with treatment group-subgroup interaction factor, controlling for site and age randomization factors. Sex subgroup analysis – while we are unable to stratify randomization by sex due to feasibility, sex will be considered in a pre-identified key subgroup analysis.

9.12. Economic analysis

We will assess the cost-effectiveness of IVMg to alleviate respiratory distress. We will use cost-utility analysis (CUA) to assess the incremental cost-effectiveness of IVMg vs placebo in terms of cost per quality-adjusted life year and cost-effectiveness analysis to assess cost per alleviating respiratory distress (PRAM ≤3). Using a decision tree, analyses will be undertaken from the perspective of the Canadian healthcare system over a 72-hour horizon which will conform to Canadian guidelines for economic evaluation [74].

Comparative effectiveness of IVMg versus placebo will be derived from the MAGICIAN data, including PRAM ≤3 points at 3 hours (secondary outcome c); patient disposition (i.e., discharge or hospitalization during the index ED visit; secondary outcome a), resource use (secondary outcomes d–f), and adverse events. Costs will include drug acquisition and administration, healthcare resource use, and adverse event management. For the CUA, utilities will be sourced from the literature. Scenario analyses will include adopting a societal perspective. Further information can be found in Appendix E: Economic Analysis in S1 File).

9.13. Adherence

This is unlikely to be a problem since intervention delivery will be given in the ED. The experimental period is short and IV administration guarantees medication delivery. Conservatively, we assume a 5% crossover between groups; the sample size has been adjusted accordingly.

9.14. Follow up loss

Due to the short follow-up period, we expect the loss to follow-up to be zero. In MAGNUM with the same follow-up interval, follow-up loss was 1/818. Studies of asthma and bronchiolitis from SickKids had follow up rates at 28 days approaching 100% [75–77]. Conservatively, we anticipate the rate of the loss to follow up at 1%, although it will likely be lower.

10.1. Definition of adverse events (AE)

An Adverse Event (AE) is any untoward medical occurrence associated with the use of an intervention in a study participant, which does not necessarily have a causal relationship with the intervention. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of the intervention, whether or not considered related to the investigational intervention. Stable chronic conditions which are present prior to entry in the study and do not worsen are not considered AE. These pre-existing conditions will be documented in the participant’s medical history.

A qualified physician, who is part of the study team, will be responsible for determining whether an AE is expected or unexpected, and the relationship to the study intervention will be described as unrelated, unlikely to be related, possibly related, probably related, or related, based on the temporal relationship to the administration of the study intervention and the study physician’s clinical judgment.

An AE will be considered unexpected if the nature, severity, or frequency of the event is not consistent with the risk information previously described in section 2.3 (Risk/Benefit Assessment - Participant Safety) and Product Monograph for magnesium.

Adverse events will be collected using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

10.2. Definition of Serious Adverse Events (SAE)

A Serious Adverse Event is any AE that is:

• fatal
• life-threatening
• requires or prolongs inpatient hospital stay
• results in persistent or significant disability or incapacity
• a congenital anomaly or birth defect
• an important medical event

The term “life-threatening” in the definition of “serious” refers to an AE in which the participant was at risk of death at the time of the event. It does not refer to an AE that hypothetically might have caused death if it were more severe.

Important medical events are those that may not be immediately life threatening but are clearly of major clinical significance. They may jeopardize the participant and may require intervention to prevent one of the other serious outcomes noted above. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse

Serious Adverse Event (SAE) will be documented. The following are highlighted as they are considered more likely to occur:

1. 1) hypotension below the 5^th percentile for age requiring medical intervention within 180 minutes of the start of the experimental therapy, or
2. 2) admission to intensive care unit (ICU) at the index ED visit.
3. 3) admission to intensive care unit (ICU) for asthma within 72 hours after being discharged from ED.

These will be reported to the PI, SickKids REB, local REB and the DSMC.

Since hypotension is the only side-effect of IVMg occurring with appreciable frequency, all enrolled patients will be on precautionary frequent blood pressure monitoring as per the study protocol. If the systolic blood pressure drops below 5^th percentile for age, treatment will be given as necessary and DSMC will be notified.

10.3. Classification of an adverse event

11.1. Confidentiality and privacy

Participant confidentiality and privacy is strictly held in trust by the participating Investigators, their staff, and the Sponsor(s). This confidentiality is extended to cover the clinical information relating to participants. Therefore, the study protocol, documentation, data, and all other information generated will be held in strict confidence.

Any research information obtained about the patient in this study will be kept confidential. A patient will not be identified by name, only by unique study ID number. The patient’s name or any identifying information will not appear in any reports published as a result of this study. All identifying information will be kept behind 2 security measures or as per equivalent institutional policy, under the supervision of the study/site PI and will not be transferred outside of the hospital.

The study monitor, auditor and other authorized representatives of the Sponsor, representatives of the Research Ethics Board (REB), Governors of the University of Alberta, as represented by the Women & Children’s Health Research Institute, and regulatory agencies may inspect all documents and records required to be maintained by the Investigator, including but not limited to, medical records and pharmacy records for the participants in this study. The clinical study site will permit access to such records.

Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be transmitted to and stored at the Governors of the University of Alberta, as represented by the Women & Children’s Health Research Institute. This will not include the participant’s contact or identifying information. Rather, individual participants and their research data will be identified by a unique study identification number. The study data entry and study management systems used by clinical sites and by Governors of the University of Alberta, as represented by the Women & Children’s Health Research Institute research staff will be secured and password protected. At the end of the study, all study databases will be de-identified and archived at the The Hospital for Sick Children.

11.2. Safety oversight - Data safety and monitoring committee (DSMC)

Safety oversight will be under the direction of the Data Safety and Monitoring Committee (DSMC). The DSMC members will be listed in the DSMC charter.. The members of this committee will not be collaborators of this trial. They will be notified of all serious adverse events and provide feedback to the Trial Steering Committee to determine if the study should be stopped early, continued or terminated. A DSMC charter will be developed in conjunction with the DSMC members to guide the committee process. The DSMC will meet every 6 months or ad hoc if necessary.

11.3. Participant safety

Magnesium has a theoretical potential for hypotension, hypopnea and heart block [45], but only hypotension has been reported in previous studies. The IVMg RCT of 1109 adults reported 8% hypotension [46] but nobody had Mg stopped for hypotension. Pediatric IVMg trials with Mg doses 75 and 100 mg/kg did not report any hypotension (N = 101) [15,20]. While a review of the PECARN Registry found a median dose 50 mg/kg had a hypotension rate of 6.8% [10], the mean decrease in the systolic pressure was 5 mm Hg, with uncertain clinical significance. No hypotension was observed in 3 pediatric pharmacologic ICU studies of 75 mg/kg IV Mg in children ≤30 kg and 50 mg/kg in those >30 kg followed by 40 mg/kg/hour for 4 hours [47–49]. Two of our participating sites routinely use 75 mg/kg IVMg. A literature review of pediatric status asthmaticus confirms lack of IVMg toxicity [50]. Nonetheless, blood pressure will be measured at 30 and 60 minutes and hourly to 180 minutes. If the systolic pressure drops below the 5^th percentile-for-age [51], necessary treatment such as IV fluids will be given. If the hypotension occurs at either the 10 minute or 20 minute measurement, further experimental infusion will be stopped and blood pressure will be treated according to local practices. Hypotension will be defined as systolic blood pressure <70 mm Hg +(age in years x2) in children 2–10 years old and as <90 mm Hg in those >10 years old. Because the children with unstable airway will be excluded and further inhaled salbutamol will be given if needed, lack of Mg in the placebo group will not endanger these participants. All study patients will be monitored for 180 minutes post-intervention prior to discharge, to ensure safety. Only13/723(1.8%) children discharged post IVMg return to the ED vs 1383/38,623(3.6%) without; IVMg is not associated with re-visits [10].

11.4. Study monitoring

Monitoring of the trial will be performed to verify that:

• The rights and well-being of participants are protected;
• The reported trial data are accurate, complete, and verifiable from source documents; and
• The conduct of the trial is in compliance with the currently approved protocol/amendment(s), ICH GCP, and local regulations and requirements.

The Sponsor will be responsible for all monitoring activities. Any trial-related duty or function transferred to and assumed by a third party, including monitoring and auditing, will be specified in a clinical trial agreement and oversight provided by the Sponsor.

The monitoring plan for the trial will be documented prior to the activation of the study and include the following;

• Follow risk-based practices,
• Document the rationale for the chosen monitoring strategy,
• Reference the Sponsor’s process that will be followed to address situations of non-compliance,
• Describe the monitoring responsibilities of all the parties involved, and
• Outline the data and processes to be monitored.

The site Investigator(s)/delegate(s) will allow direct access to source data/documents for the purposes of monitoring by the Sponsor, and inspection by regulatory authorities, both domestic and foreign (if applicable). It is important that the Sponsor, site Investigator and site personnel are available during monitoring visits and inspections, and that sufficient time is devoted to the process.

Monitoring procedures will be implemented beginning with the data entry system and data checks that will be run on the database will be generated. Any missing data or data anomalies will be communicated to the site(s) for clarification/resolution.

Monitoring reports will be issued after each monitoring visit for review and follow up by the Sponsor, site Investigator, and appropriate management and personnel responsible for trial and site oversight.

11.5. Quality assurance and quality Control

Each site should have SOPs for quality management that describe:

• The documents to be reviewed (e.g., CRFs, clinic notes, product accountability records, etc), who is responsible, and the frequency for reviews.
• Who will be responsible for addressing QA issues (e.g., correcting procedures that are not in compliance with protocol) and QC issues (e.g., correcting errors in data entry).
• Staff training methods and how such training will be tracked.

Regular monitoring and an independent audit, if conducted, must be performed according to ICH GCP. See also Section 11.4 (Study Monitoring).

Each clinical site will perform internal quality management of study conduct, data, documentation and completion.

Auditing of the trial will be performed independently from monitoring to evaluate trial conduct and compliance with the protocol/amendment(s), SOP, ICH GCP and local regulations and requirements.

The Sponsor will be responsible for all auditing activities. Any trial-related duty or function transferred to and assumed by a third party, including auditing, will be specified in a clinical trial agreement and oversight provided by the Sponsor.

11.6. Data handling and record keeping

11.7. Protocol deviations

A protocol deviation is any noncompliance with the clinical trial protocol or Manual of Operations (MOO) requirements, if applicable. The Principal Investigator will assure that both the Sponsor and the REB will be notified of protocol deviations in accordance with Sponsor and local REB requirements. The noncompliance may be either on the part of the participant, the Investigator, or the study site staff. Depending on the type of protocol deviations, sites may be required to develop and implement corrective and preventative actions. All protocol deviations will be documented using a protocol deviation log; the Principal Investigator will assess each protocol deviation to determine the impact to the patient’s rights, safety or welfare, study efficacy and data integrity. If there is any uncertainty regarding the impact of the protocol deviation, the Principal Investigator will consult with Dr. Suzanne Schuh.

11.8. Publication and dissemination of results

The results of this study will be submitted for presentation at a scientific conference and the manuscript will be submitted for publication in a peer-reviewed scientific journal.

This study will comply with the CIHR Open Access Policy. The study has been registered at ClinicalTrials.gov (NCT06785272), and results information from this study will be submitted to ClinicalTrials.gov. Conduct, reporting, editing, and publication of resultant scholarly work will be guided by the International Committee of Journal Medical Editors (ICJME)’s published recommendations. The identity of participants will not be revealed in any published data or in presentation of the information obtained for this study.