Clinical Trial Results:
Optimising effectiveness and minimising toxicity of intravenous salbutamol in children with acute asthma
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Summary
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EudraCT number |
2014-002996-27 |
Trial protocol |
GB |
Global end of trial date |
30 Jun 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
13 Oct 2018
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First version publication date |
13 Oct 2018
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Other versions |
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Summary report(s) |
13CC34 Final Study Report and Results |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
13CC34
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Additional study identifiers
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ISRCTN number |
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US NCT number |
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WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
Great Ormond Street Hospital for Children NHS Foundation Trust
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Sponsor organisation address |
30 Guilford Street , London, United Kingdom, WC1N 1EH
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Public contact |
Avani Shukla, Great Ormond Street Hospital and Great Ormond Institute of Child Health R&D Office, +44 (0) 2079052863, avani.shukla@gosh.nhs.uk
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Scientific contact |
Dr Padmanabhan Ramnarayan, Great Ormond Street Hospital for Children NHS Trust, +44 (0) 2074305850, p.ramnarayan@gosh.nhs.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
19 Jun 2018
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
30 Jun 2017
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The objective was to determine the best way to use a crucial drug called salbutamol in children with life-threatening asthma. We wish to analyse how the dose of salbutamol relates to its blood concentration level; and how the blood concentration level relates to effectiveness and toxicity. This study will allow us develop a population pharmacokinetic-pharmacodynamics (PKPD) model of salbutamol in children. This will enable to determine the optimal dose of salbutamol; to maximise its effectiveness but minimise harmful side effects.
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Protection of trial subjects |
The study was conducted under appropriate UK ethics and regulatory approvals. The study was sponsored and monitored by Great Ormond Street Hospital.Annual progress report and Development Safety Update Reports were submitted to ethics committee and MHRA each year during the whole study enrolment duration. The study involved no active interventions except of taking blood samples for pharmacokinetic analysis. All patients were treated according to local policy for the management of acute severe asthma. All treatments were recorded but no modifications were made for the purposes of the study. To alleviate burden on participants the blood patients with an indwelling catheter had bloods taken at specific time points, as this does not require venesection. The blood sample was limited to 1ml/kg/day according to Medicines for Children Research Network (MCRN) guidelines.
since Intravenous Salbutamol (IVS) was considered an urgent treatment that could not be delayed while obtaining written informed consent from parents/guardians, written consent was usually obtained 24-48 hours after recruitment to the study by site research nurses for continuation in the study and for ongoing data collection This process was approved by ethics committee. Age-specific patient information leaflets were provided to each participant.
The patient details were processed according to data protection act confidentially during the course of the trial and all patients were assigned a unique trial number. Only the patient direct care team and those approved on consent (i.e. monitors and regulators) had access to data when required. The study data will be stored and archived according to GOSH local practice, data protection act 1998 and applicable research regulations.
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Background therapy |
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Evidence for comparator |
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Actual start date of recruitment |
02 Mar 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 54
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Worldwide total number of subjects |
54
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EEA total number of subjects |
54
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
17
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Children (2-11 years) |
29
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Adolescents (12-17 years) |
8
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Between September 2014 and May 2017, 576 patients were screened. Of the 91 eligible patients, 8 refused or were unable to consent, one was previously recruited and 19 were missed. Of the 63 patients subsequently recruited, 4 were withdrawn due to insufficient samples, 3 patients IVS was not started and 2 were withdrawn as found to be underage. | ||||||
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Pre-assignment
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Screening details |
Participants were identified by the treating clinical teams, and recruited by site research nurses or the clinical teams. Patients were eligible for inclusion if they were aged 1-15 years (inclusive); admitted to hospital for acute severe asthma, as defined by the British Thoracic So. guidelines; and about to receive or receiving IV Salbutamol. | ||||||
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Period 1
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Period 1 title |
Baseline & Recruitment (overall period)
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Is this the baseline period? |
Yes | ||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||
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Arms
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Arm title
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NO ARM - PKPD Study | ||||||
Arm description |
The study is a PKPD model and does not have any interventional arms | ||||||
Arm type |
No Arms | ||||||
Investigational medicinal product name |
Ventolin Injection
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Investigational medicinal product code |
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Other name |
Salbutamol
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Pharmaceutical forms |
Injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Dosage schedule is as per local policy, expected to be in keeping with the BTS guidelines of acute severe asthma, incorporated into the BNF for children.
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Baseline characteristics reporting groups
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Reporting group title |
Baseline & Recruitment
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Reporting group description |
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End points reporting groups
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Reporting group title |
NO ARM - PKPD Study
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Reporting group description |
The study is a PKPD model and does not have any interventional arms | ||
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End point title |
Effectiveness measure [1] | ||||||||||||
End point description |
Population PD modelling was also successfully performed. 111 effectiveness measurements were obtained within the ED cohort, and an Emax concentration-efficacy relationship gave the best model fit. The EC50 values for PASS and the individual variables were estimated to be between 0.2 ng/mL and 0.5 ng/mL, with Emax from 6.67 to 7.77. No covariants were found to be statistically significant, although a 5.3-fold difference between patients with heterozygous and with homozygous rs1042713 in β-2 adrenoceptor is demonstrated. Examining the baseline salbutamol concentration levels, we can see that many patients are saturated from an effectiveness perspective early in the course of their IVS treatment using current dosage regimens.
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End point type |
Primary
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End point timeframe |
Between September 2014 and May 2017
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Sequential population pharmacokinetic/pharmacodynamic (PKPD) modelling was performed with NONMEM® (version 7.3) where a PK model was firstly developed and individual PK parameters were combined with a PD model to describe the time course of PD observations. PASS scores were treated as categorical data and modelled with ordered logistic regression where the bronchodilation effect was linked with the probability of achieving PASS scores. A chart is attached to this endpoint. |
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Attachments |
CSR Effectiveness Measures |
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End point title |
Toxicity Variable [2] | ||||||||||||||||||||||||
End point description |
Toxic effects increased immediately with the increase of plasma concentrations, the opposite for pH and base excess measures; these findings were consistent with physiological observations. Parameter values for each toxicity measurement are outlined in Table 5 in the attached report. Heart rate and base excess were found to be the most sensitive to a change in IVS, with EC50 values of 6.23 ng/mL and 27.9ng/mL respectively.
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End point type |
Primary
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End point timeframe |
Between September 2014 to March 2017
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The following continuous markers of toxicity were modelled: lactate, pH, base excess, blood glucose, heart rate, systolic and diastolic blood pressure. Toxicity effects were driven from an effect compartment with first-order equilibration with the plasma compartment, in order to examine whether delayed onset occurred for each toxicity measure after IVS. A sigmoidal Emax model was used to link effect compartment concentration with toxicity effects. A chart is attached to this endpoint. |
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Attachments |
CSR Toxicity Variables |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Salbutamol concentration levels [3] | ||||||||||||
End point description |
As anticipated from the current dosage schedule, salbutamol infusion doses ranged from 0-2 μg/kg/min in the ED cohort, and 0-4 μg/kg/min in the CATS cohort. Median duration of IVS treatment was 5 hours in the ED cohort (range 0.5 – 19.1), and 3.5 hours (range 0.2-196.2) in the CATS cohort. More information can be found in attached table.
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End point type |
Primary
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End point timeframe |
Between September 2014 to March 2017
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: One- and two-compartment PK models were tested to describe the time course of salbutamol plasma concentration for individual patients, with baseline plasma concentration estimated due to uncertain and lengthy dosing history of nebulised salbutamol prior to enrolment. Allometric size scaling with body weight on clearance and volume of distribution was added a priori, and a sigmoidal maturation function describing the change of clearance over age was tested. |
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Attachments |
CSR Salbutamol Concentrations |
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information [1]
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Timeframe for reporting adverse events |
The time frame for reporting adverse events was from consent till patient discharge.
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Adverse event reporting additional description |
As the safety profile of Salbutamol is very well known and documented in the Salbutamol (Ventolin) Summary of product characteristics, we did not record all non-serious adverse events outside of those recorded as signs of toxicity as per study protocol.
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Assessment type |
Systematic | ||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
Not applicable | ||||||||||
Dictionary version |
0
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Reporting groups
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Reporting group title |
NO ARM - PKPD Study
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Reporting group description |
The study is a PKPD model and does not have any interventional arms | ||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||
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| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: As the safety profile of salbutamol is very well known and documented in the Salbutamol (Ventolin) SmPC, we did not record all non-serious AEs outside of those recorded as signs of toxicity as per study protocol. |
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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29 Jul 2016 |
1. To allow minimum of 2 salbutamol levels, 2 toxicity measures +/- 3 efficacy measures
2. Patients with only 2 salbutamol levels will require five effectiveness scores (PASS) to be included in the study.
3. Inclusion of Royal London Hospital PICU department (Please note Royal London is already an approved site) to maximise recruitment and allow modelling within the full clinical spectrum of acute severe asthma treatment.
4. To remove chronic asthma score from secondary objective as there is no sufficient evidence for the use of Chronic Asthma Score in these patients.
5. Administrative changes: Change of Sponsor Representative Contact on CTA application form |
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10 Feb 2017 |
Amendment for change in the chief investigator of the trial. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| Recruitment numbers were less than anticipated from our audit data. We decided to end the study early however effectiveness measurements were only available in the self-ventilating ED cohort. | |||
