Clinical Trial Results:
Randomized, blinded phase III clinical trial on the use of inhaled tobramycin compared to placebo in mechanically ventilated patients colonized by Gram-negative bacteria to test its efficacy in reducing mechanical ventilation time.
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Summary
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EudraCT number |
2015-001109-15 |
Trial protocol |
ES |
Global end of trial date |
18 Feb 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
04 Feb 2022
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First version publication date |
04 Feb 2022
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Other versions |
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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 |
BIOTOB
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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 |
Instituto de Investigaión Sanitaria La Fe de Valencia
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Sponsor organisation address |
Avenida Fernando Abril Martorell, Torre 106 A 7 planta , Valencia, Spain, 46026
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Public contact |
Jose María Millan Salvador, Instituo de Investigación Sanitaria La Fe, Instituto de Investigación Sanitaria La Fe (IIS La Fe), 34 961246611, investigacion_clinica@iislafe.es
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Scientific contact |
Jose María Millan Salvador, Instituo de Investigación Sanitaria La Fe, Instituto de Investigación Sanitaria La Fe (IIS La Fe), 34 961246611, investigacion_clinica@iislafe.es
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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 |
11 Aug 2021
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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 |
18 Feb 2020
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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 |
To reduce by 10% the duration of mechanical ventilation in patients treated with inhaled tobramycin compared to patients treated with placebo.
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Protection of trial subjects |
The reference study was conducted in Spain under the legal framework of Royal Decree 1090/2015. It has been performed in accordance with the Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects, adopted by the General Assembly of the World Medical Association (1996). In addition, the study has been conducted in accordance with the protocol, good clinical practice (GCP) in accordance with the guidelines of the international conference on harmonization (ICH) and regulatory requirements for participating institutions.
An appropriately performed informed consent has been used, in compliance with GCP according to ICH guidelines and approved by the CEIm of the Hospital Universitario y Politécnico La Fe. Prior to inclusion of subjects in the study, a copy of the CEIm-approved informed consent has been reviewed with the prospective participant, signed and dated. The investigator has provided a copy of each subject's signed informed consent form and has retained a copy in the subject's study file.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
11 Oct 2017
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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 |
Spain: 93
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Worldwide total number of subjects |
93
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EEA total number of subjects |
93
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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) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
93
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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 |
Patients over 18 years of age, admitted to the ICU, subjected to mechanical ventilation and carriers of artificial airway (endotracheal tube or tracheostomy) for at least 7 days, with persistent respiratory colonization of the airway by Gram-negative bacteria, presenting abundant and purulent bronchorrhea. | |||||||||||||||
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Pre-assignment
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Screening details |
Scales APACHE II & SOFA, systemic antibiotherapy, use invasive devices, development nosocomial infections. Complete blood analysis, determination of C-reactive protein & procalcitonin. Arterial blood gas analysis. Chest X-ray. Mini-bronchoalveolar lavage (miniBAL) and bronchoaspirate (BAS) for quantitative microbiological culture. | |||||||||||||||
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Pre-assignment period milestones
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Number of subjects started |
93 | |||||||||||||||
Number of subjects completed |
5 | |||||||||||||||
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Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Physician decision: 88 | |||||||||||||||
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Period 1
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Period 1 title |
Treatment assignment (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||
Roles blinded |
Subject, Investigator | |||||||||||||||
Blinding implementation details |
Patients are randomly assigned to receive one of the two treatments, in a 1:1 ratio. The randomization list is generated by a computer program equipped with a random number generator. The randomization codes are inserted into consecutively numbered envelopes which are kept sealed until the time of allocation. If, due to the occurrence of a serious adverse event or accidentally, the code is broken, the incident is noted in the data collection notebook and the sponsor is notified immediately.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Experimental treatment | |||||||||||||||
Arm description |
Tobramycin 300 mg/5 ml inhaled every 12h. | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
Tobramycin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation solution
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Routes of administration |
Inhalation use
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Dosage and administration details |
300 mg/5 ml inhaled every 12h.
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Arm title
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Control treatment | |||||||||||||||
Arm description |
Physiological saline 0.9% 5 ml inhaled every 12h | |||||||||||||||
Arm type |
Active comparator | |||||||||||||||
Investigational medicinal product name |
Physiological saline
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation solution
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Routes of administration |
Inhalation use
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Dosage and administration details |
0.9% 5 ml inhaled every 12h.
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| Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: Of the 93 patients selected, 88 were selection failures and only 5 were recruited. Of the 5 recruited, only 1 completed the study, the rest (4) were withdrawn. |
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Baseline characteristics reporting groups
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Reporting group title |
Treatment assignment
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
FULL ANALYSIS
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Subject analysis set type |
Full analysis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Of the 93 patients selected, 88 were selection failures and only 5 were recruited.
Of the 5 recruited: only 1 completed the study, the rest (4) were withdrawn.
With the sample size of only one patient, it was not possible to perform the statistical analyses reflected in the protocol. Therefore, it was not possible to determine a subgroup of patients who meet the study hypotheses.
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End points reporting groups
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Reporting group title |
Experimental treatment
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Reporting group description |
Tobramycin 300 mg/5 ml inhaled every 12h. | ||
Reporting group title |
Control treatment
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Reporting group description |
Physiological saline 0.9% 5 ml inhaled every 12h | ||
Subject analysis set title |
FULL ANALYSIS
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Of the 93 patients selected, 88 were selection failures and only 5 were recruited.
Of the 5 recruited: only 1 completed the study, the rest (4) were withdrawn.
With the sample size of only one patient, it was not possible to perform the statistical analyses reflected in the protocol. Therefore, it was not possible to determine a subgroup of patients who meet the study hypotheses.
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End point title |
10% reduction in mechanical ventilation time in patients treated with inhaled tobramycin compared to patients treated with placebo [1] | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Treatment ends on day 8 or at the time of withdrawal of mechanical ventilation (if earlier).
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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: With the sample size finally collected of only one patient, it was not possible to perform the statistical analyses reflected in the protocol. Therefore, it was not possible to determine in any way a subgroup of patients who meet the study hypotheses. |
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| Notes [2] - Only one patient completed the study so no data were obtained. [3] - Only one patient completed the study so no data were obtained. [4] - Only one patient completed the study so no data were obtained. |
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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 |
Serious adverse events are reported to the sponsor within 24 hours of becoming aware of the event.
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Adverse event reporting additional description |
The investigator follows up on the serious adverse event and notifies the sponsor when the severity/delay or causality changes. A safety assessment form is used to report serious adverse events.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||
Dictionary version |
24.1
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Reporting groups
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Reporting group title |
Experimental treatment
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Reporting group description |
Patients treated with Tobramycin | ||||||||||||||||||||||||||||||
Reporting group title |
Control treatment
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Reporting group description |
- | ||||||||||||||||||||||||||||||
| 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: Only one person completed the study procedures, so no non-serious adverse events have been reported. |
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||
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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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14 Mar 2018 |
Changes are made to the CRD and the HIP, eliminating an exclusion criterion and adding a secondary objective. The following text is included in the protocol:
"Diagnosis and main inclusion and exclusion criteria: patients over 18 years of age, admitted to the ICU, subjected to mechanical ventilation and carriers of artificial airway (endotracheal tube or tracheostomy) for at least 7 days, with persistent respiratory colonization of the airway by large negative bacteria (regardless of the pattern of antimicrobial resistance), presenting abundant and purulent bronchorrhea that may interfere with the patient's respiratory process, without criteria of respiratory infection associated with mechanical ventilation, will be included in the study. Patients with allergy to aminoglycosides, renal insufficiency or use of renal replacement therapy, pregnant or breastfeeding women, and patients with bronchiectasis or cystic fibrosis will be excluded.
The secondary objective is added: To evaluate the effect of inhaled tobramycin on the eradication of gram-negative bacteria that at the time of inclusion in the study are resistant to tobramycin."
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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. | |||
| None reported | |||
