Clinical Trial Results:
Clinical efficacy and safety of J022X ST in the prevention of Recurrent Upper-Respiratory Tract Infections (RURTI) in children with a high risk of recurrence
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Summary
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EudraCT number |
2013-001760-31 |
Trial protocol |
IT LT PL RO |
Global end of trial date |
17 Oct 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
02 May 2017
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First version publication date |
02 May 2017
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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 |
J0022XST302
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Pierre Fabre Medicament
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Sponsor organisation address |
45 place Abel Gance, Boulogne, France, 92100
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Public contact |
Elisabeth Carriere Roussel, IRPF
3 avenue Hubert Curien
31100 Toulouse, +33 5 34 50 63 48,
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Scientific contact |
Elisabeth Carriere Roussel, IRPF
3 avenue Hubert Curien
31100 Toulouse, +33 5 34 50 63 48,
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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? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
03 Apr 2017
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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 |
17 Oct 2016
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To assess the clinical efficacy of J022X ST in preventing RURTI in young children at risk.
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Protection of trial subjects |
This study was performed in accordance with the ethical principles stated in the Declaration of Helsinki (1964 and its subsequent amendments). This study was conducted in agreement with International Council on Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines and with applicable national regulations in biomedical research (except in one Romanian centre: see "Recruitment details" caption). The first study protocol version in use , all its amendments, and the patient information sheets, were reviewed by the appropriate independent ethics committees (IECs), including local IECs. This study was placebo-controlled (see rationale in "Evidence for comparator"). In Year 2 of this study, the treatment was proposed only to children having proven recurrent upper respiratory tract infection (RURTI) and for whom it could be beneficial The placebo group received the same medical care as the J00022X group, according to that which would have been provided if they had not participated in this study. If patients showed any early signs of safety concerns or aggravation of symptoms during the study, they were eligible to receive alternative active therapy at any time.
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Background therapy |
There was no systematic concomitant administration of any other product than investigational products. | ||
Evidence for comparator |
This study was placebo-controlled as there is still a medical need for alternative treatments As no other product had formally proven its efficacy in prevention of URTIs and could be considered as a reference product, efficacy was assessed vs. placebo. The use of a placebo control was critical to the study to allow discrimination between patient outcomes caused by J0022XST and outcomes caused by other factors (e.g. the observer or patient expectations, the natural acquisition of immunity, the conditions of study participation). | ||
Actual start date of recruitment |
02 Sep 2013
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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 |
Poland: 197
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Country: Number of subjects enrolled |
Romania: 365
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Country: Number of subjects enrolled |
Italy: 114
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Country: Number of subjects enrolled |
Lithuania: 168
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Country: Number of subjects enrolled |
Russian Federation: 150
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Worldwide total number of subjects |
994
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EEA total number of subjects |
844
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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) |
994
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Adolescents (12-17 years) |
0
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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 |
This phase III study was conducted in two parts: year 1 was an observational phase to select children with RURTI i.e. at least 6 episodes of medically confirmed URTI. year 2: . If eligible, patients were randomised to one of the 2 treatment groups (J022X ST or placebo) | |||||||||
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Pre-assignment
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Screening details |
53 centres located in 5 countries (France, Hungary, Romania, Latvia, Russian Federation) were initiated, 50 centers had at least one patient included and 30 recruited patients. . 1003 Children aged 3-4 year, known for RURTI were screened, 994 were included in year 1 (observational phase), 254 were randomised and analysed | |||||||||
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Pre-assignment period milestones
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Number of subjects started |
994 | |||||||||
Number of subjects completed |
254 | |||||||||
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Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
non premature withdrawal not conitnuing: 467 | |||||||||
Reason: Number of subjects |
premature withdrawal for other reason: 272 | |||||||||
Reason: Number of subjects |
premature withdrawal for safety: 1 | |||||||||
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Period 1
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Period 1 title |
Year 1
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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, Monitor, Data analyst, Carer | |||||||||
Blinding implementation details |
Double-blinding was ensured by identical packaging, labelling and administration of the investigational treatments
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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J0022 X ST | |||||||||
Arm description |
experimental | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
J0022X ST
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Investigational medicinal product code |
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Other name |
Ribomunyl/immucytal/Biomunil
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Pharmaceutical forms |
Granules
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Routes of administration |
Oral use
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Dosage and administration details |
• Active substancea: 0.525 mgb, given as ribosomal RNA content.
Ribosomal fractions (10 parts) including:
- Klebsiella pneumoniae (3.5 parts)
- Streptococcus pneumoniae (3 parts)
- Streptococcus pyogenes group A (3 parts)
- Haemophilus influenzae (0.5 parts)
And membrane fraction (15 parts) including:
- Klebsiella pneumoniae.
In the first month of treatment, the patient took one sachet in the morning on an empty stomach for 4 consecutive days per week, for 3 consecutive weeks.
From the second month of treatment, the patient took one sachet in the morning on an empty stomach for 4 consecutive days per month, at monthly intervals, for 5 consecutive months.
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Arm title
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Placebo | |||||||||
Arm description |
- | |||||||||
Arm type |
Placebo | |||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Granules in sachet
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Routes of administration |
Oral use
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Dosage and administration details |
In the first month of treatment, the patient took one sachet in the morning on an empty stomach for 4 consecutive days per week, for 3 consecutive weeks. From the second month of treatment, the patient took one sachet in the morning on an empty stomach for 4 consecutive days per month, at monthly intervals, for 5 consecutive months.
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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: A total of 740 out of the 994 included patients (73.8%) in year 1 were not randomised in Year 2 due to non premature withdrawal not continuing (467 patients [46.6%]), premature withdrawal for other reason (272 patients [27.1%]) and premature withdrawal for safety reason (one patient [0.1%]). For most patients (609 patients [60.7%]), the categorised reason for non randomisation was because of insufficient URTI épisodes. |
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Period 2
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Period 2 title |
year 2
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Is this the baseline period? |
No | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer | |||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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J0022 X ST | |||||||||
Arm description |
experimental | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
J0022X ST
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Investigational medicinal product code |
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Other name |
Ribomunyl/immucytal/Biomunil
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Pharmaceutical forms |
Granules
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Routes of administration |
Oral use
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Dosage and administration details |
• Active substancea: 0.525 mgb, given as ribosomal RNA content.
Ribosomal fractions (10 parts) including:
- Klebsiella pneumoniae (3.5 parts)
- Streptococcus pneumoniae (3 parts)
- Streptococcus pyogenes group A (3 parts)
- Haemophilus influenzae (0.5 parts)
And membrane fraction (15 parts) including:
- Klebsiella pneumoniae.
In the first month of treatment, the patient took one sachet in the morning on an empty stomach for 4 consecutive days per week, for 3 consecutive weeks.
From the second month of treatment, the patient took one sachet in the morning on an empty stomach for 4 consecutive days per month, at monthly intervals, for 5 consecutive months.
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Arm title
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Placebo | |||||||||
Arm description |
Control arm | |||||||||
Arm type |
Placebo | |||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Granules in sachet
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Routes of administration |
Oral use
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Dosage and administration details |
In the first month of treatment, the patient took one sachet in the morning on an empty stomach for 4 consecutive days per week, for 3 consecutive weeks. From the second month of treatment, the patient took one sachet in the morning on an empty stomach for 4 consecutive days per month, at monthly intervals, for 5 consecutive months.
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Baseline characteristics reporting groups
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Reporting group title |
J0022 X ST
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Reporting group description |
experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Full analysis set
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Full Analysis Set (FAS), composed of all patients randomised in Year 2, having received at least one dose of the study treatment. This set was used to perform analyses for efficacy and safety.
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End points reporting groups
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Reporting group title |
J0022 X ST
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Reporting group description |
experimental | ||
Reporting group title |
Placebo
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Reporting group description |
- | ||
Reporting group title |
J0022 X ST
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Reporting group description |
experimental | ||
Reporting group title |
Placebo
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Reporting group description |
Control arm | ||
Subject analysis set title |
Full analysis set
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Full Analysis Set (FAS), composed of all patients randomised in Year 2, having received at least one dose of the study treatment. This set was used to perform analyses for efficacy and safety.
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End point title |
Difference in the number of URTI between J0022XST and placebo at year 2 | |||||||||
End point description |
Treatment effect on the number of URTI episodes medically assessed by the Investigator over the 12 months of Year 2 was tested using an analysis of covariance (ANCOVA) model. This model included age at randomisation in Year 2, sex and year of randomisation as covariates, and country as stratum factor. The primary analysis was performed on the FAS and repeated on the PP Set as a supportive analysis.
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End point type |
Primary
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End point timeframe |
The main statistical objective was to show a difference in the number of URTIs in Year 2 between J022X ST and placebo on the FAS.
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Statistical analysis title |
Primary analysis | |||||||||
Statistical analysis description |
Treatment effect on the number of URTI episodes medically assessed by the Investigator over the 12 months of Year 2 was tested using an analysis of covariance (ANCOVA) model. This model included age at randomisation in Year 2, sex and year of randomisation as covariates, and country as stratum factor. The primary analysis was performed on the FAS and repeated on the PP Set as a supportive analysis.
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Comparison groups |
J0022 X ST v Placebo
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Number of subjects included in analysis |
254
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | |||||||||
P-value |
= 0.21 | |||||||||
Method |
ANCOVA | |||||||||
Parameter type |
Median difference (net) | |||||||||
Point estimate |
-0.31
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-0.8 | |||||||||
upper limit |
-0.18 | |||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.25
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| Notes [1] - The main statistical objective was to show a difference in the number of URTIs in Year 2 between J022X ST and placebo on the FAS with the following null hypothesis H0a: there was no difference between treatments in the number of URTIs in Year 2 vs. H1a: there was a difference between treatments. |
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Adverse events information
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Timeframe for reporting adverse events |
From randomisation to End of Study Visit (expected to be V10/D50 or V9/D43 the End of Treatment Visit if the patient did not enter the follow-up)
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Adverse event reporting additional description |
AEs and AEs other than URTIs, reported in Year 2 : i.e. defined as any AEs started after the Randomisation visit of Year 2 or ongoing at the Randomisation visit of Year 2
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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 |
18.0
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Reporting groups
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Reporting group title |
J0022 X ST
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Reporting group description |
experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
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| Frequency threshold for reporting non-serious adverse events: 2.5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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27 Mar 2014 |
Addition of the CROs involved in the study
Update of the planned study period according to the approval from AIFA
Precision on inclusion and non-inclusion criteria (e.g. other diseases and relating to treatments)
Precision on premature withdrawal visits of Year 1 and Year 2
Correction of flow-chart
Addition of the Interactive Web Response System (IWRS) procedure
Addition of information due to the modification of the safety document reference (Italian Summary of Product Characteristics→Safety section of the Investigator’s Brochure as requested by Russian Authorities
Addition of requests made by the Russian Ministry of Health
Change of Clinical Study Manager and modification of the Corporate Safety Officer’s contact details
Removal of information on the Head of Therapeutic Area
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17 Jul 2014 |
Addition of paracetamol and NSAIDs for URTI as authorised treatments
Clarification that ibuprofen had to be prescribed at more than 30 mg/kg/day in the definition of a severe URTI
Clarification that anti-histamines could be prescribed during the study
Addition of information on test product quantity
Removal of the IWRS and update of the treatment number allocation procedure
Replacement of the Medical Study Manager by the Clinical Program Director
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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 | |||
