Clinical Trial Results:
Evaluation of the Therapeutic Efficacy of APD-209 Eye Drops in Treatment of Acute Phase Adenoviral-Induced Epidemic Keratoconjunctivitis (EKC). A Randomised, Double-Masked, Placebo-Controlled, Multi-Centre Proof-of-Concept Study
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Summary
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EudraCT number |
2012-005694-31 |
Trial protocol |
SE DE PL |
Global end of trial date |
12 Apr 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
02 Nov 2017
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First version publication date |
02 Nov 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 |
2012/ADE002
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01977443 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Adenovir Pharma AB
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Sponsor organisation address |
Kullagatan 8, Helsingborg, Sweden, 25220
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Public contact |
CEO, Adenovir Pharma AB, +46 4238 74 28, bjorn.dellgren@adenovir.com
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Scientific contact |
CEO, Adenovir Pharma AB, +46 4238 74 28, bjorn.dellgren@adenovir.com
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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 |
02 Nov 2016
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
31 Mar 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
12 Apr 2016
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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 assess the adenoviral load in epidemic keratokonjunctivitis (EKC) infected eyes following topical treatment with APD-209 Eye drops given 8 times daily for 14 days compared to placebo.Exploratory analyses investigated if there were indications of effects not obvious due to of the small no. of randomized pts in statistical testing.Pts included had symptoms for different lengths;therefore the analysis was adjusted for onset of symptoms.Onset-adjusted analysis of the limited no. of pts that met incl/excl criteria showed a difference in reduction in viral load in favour of APD-209 of 74% (absolute scale) and 12% (log scale) compared with Placebo.Clinical assessments as blurred vision, redness and foreign body sensation showed reductions in symptom scores following treatment with APD-209. Similarly,cumulative proportion analysis of the risk of second eye infection and the risk of opacities showed reductions in favour of APD-209. The differences observed were not statistically significant.
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Protection of trial subjects |
A standard physical exmination, vital signs and laboratory safety assessments were performed at study visit 1, 5 and 6.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
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: 3
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Country: Number of subjects enrolled |
Sweden: 7
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Country: Number of subjects enrolled |
Germany: 37
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Worldwide total number of subjects |
47
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EEA total number of subjects |
47
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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) |
44
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From 65 to 84 years |
3
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85 years and over |
0
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Recruitment
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Recruitment details |
The initial plan estimated a recruitment of 80-130 subjects, with the exact number to be determined at an interim analysis at 60 recruited subjects. The study was conducted at 10 centers in Germany, Poland and Sweden. Due to slow enrolment the recruitment stopped on March 22 2016. | |||||||||
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Pre-assignment
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Screening details |
The inclusion and exclusion criteria of the study allowed for inclusion of subjects with EKC infection in either one or both eyes. In total there were 53 subjects screened in the study, out of which 6 were screen failures. | |||||||||
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Period 1
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Period 1 title |
Treatment
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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 | |||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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ADP-209 Eye drops | |||||||||
Arm description |
25 enrolled. 3 lost to follow up, 3 lost due to withdrawal of inform consent. 19 patients completed the period. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
APD-209
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Investigational medicinal product code |
APD-209
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Other name |
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Pharmaceutical forms |
Eye drops
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Routes of administration |
Topical use
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Dosage and administration details |
The active ingredient of APD-209 Eye drops is APD-209. Each dose of 45 µl of APD-209 Eye drops 0.125 mg/ml corresponded to 5.6 µg APD-209. The colourless to bluish, slightly turbid drug product was provided in 10 ml amber glass bottles with a pump, which was especially developed for preservative-free multi-dose eye drops. The pump delivers a dose of 45 µl. The mode of administration was topical administration. The first administration of IMP was done at the clinic at Visit 1 after the subjects had received the corresponding instructions by trained site staff. The IMP was then administered by the subjects at home according to the given instructions.
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Arm title
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APD-209 Placebo Eye drops | |||||||||
Arm description |
22 enrolled. 1 lost due to prohibited concomittant medication, 1 lost due to diagnosis of other disease than EKC in anterior chamber, 2 lost due to follow-up, 2 lost due to consent withdrawn by subject. 16 completed the period. | |||||||||
Arm type |
Placebo | |||||||||
Investigational medicinal product name |
APD-209 Placebo eye drops
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Investigational medicinal product code |
APD-209 placebo eye drops
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Other name |
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Pharmaceutical forms |
Eye drops
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Routes of administration |
Topical use
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Dosage and administration details |
APD-209 Placebo Eye drops is a glycerol solution provided in 10 mL amber glass bottles with a pump, which was especially developed for preservative-free multi-dose eye drops. The pump delivered a dose of 45 μL. Each glass bottle was filled with 8 mL (= 8.0 g) and two bottles were to be used per subject during the study. The mode of administration was topical administration. The first administration of IMP placebo was done at the clinic at Visit 1 after the subjects had received the corresponding instructions by trained site staff. The IMP placebo was then administered by the subjects at home according to the given instructions.
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Period 2
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Period 2 title |
Enrollment
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Is this the baseline period? |
Yes [1] | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst | |||||||||
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Arms
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Arm title
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Subjects enrolled | |||||||||
Arm description |
- | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
APD-209
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Investigational medicinal product code |
APD-209
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Other name |
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Pharmaceutical forms |
Eye drops
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Routes of administration |
Topical use
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Dosage and administration details |
The active ingredient of APD-209 Eye drops is APD-209. Each dose of 45 µl of APD-209 Eye drops 0.125 mg/ml corresponded to 5.6 µg APD-209. The colourless to bluish, slightly turbid drug product was provided in 10 ml amber glass bottles with a pump, which was especially developed for preservative-free multi-dose eye drops. The pump delivers a dose of 45 µl. The mode of administration was topical administration. The first administration of IMP was done at the clinic at Visit 1 after the subjects had received the corresponding instructions by trained site staff. The IMP was then administered by the subjects at home according to the given instructions.
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| Notes [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period. Justification: Due to manual error treatment period was entered before baseline period. |
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Baseline characteristics reporting groups
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Reporting group title |
Subjects enrolled
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
ADP-209 Eye drops
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Reporting group description |
25 enrolled. 3 lost to follow up, 3 lost due to withdrawal of inform consent. 19 patients completed the period. | ||
Reporting group title |
APD-209 Placebo Eye drops
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Reporting group description |
22 enrolled. 1 lost due to prohibited concomittant medication, 1 lost due to diagnosis of other disease than EKC in anterior chamber, 2 lost due to follow-up, 2 lost due to consent withdrawn by subject. 16 completed the period. | ||
Reporting group title |
Subjects enrolled
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Reporting group description |
- | ||
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End point title |
viral load in tear liquid from EKC infected eyes, as measured by the AUC at 3-14 days from start of treatment. | ||||||||||||
End point description |
Statistical analysis (MMRM*) comparing Viral load in tear liquid, mean AUC at 3-14 days. (Modified Intent-to-treat population)
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End point type |
Primary
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End point timeframe |
Day 3-14
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Statistical analysis title |
Comparison vs. Placebo | ||||||||||||
Comparison groups |
ADP-209 Eye drops v APD-209 Placebo Eye drops
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Number of subjects included in analysis |
15
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.3785 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Parameter type |
LSmean | ||||||||||||
Point estimate |
0.7398
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-1.076 | ||||||||||||
upper limit |
2.556 | ||||||||||||
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End point title |
Viral load in tear liquid from EKC infected eyes, as measured by the AUC at 0-14 days from start of treatment | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Day 0-14
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| No statistical analyses for this end point | |||||||||||||
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End point title |
The time point of viral eradication in tear liquid from EKC infected eyes, defined as the time point when viral load=0 or below the lower limit of quantification (LLOQ). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The time point of viral eradication in tear liquid from EKC infected eyes, defined as the time point when viral load=0 or below the lower limit of quantification (LLOQ). The days where plotted into a Kaplan Meier curve, log-rank test). The Kaplan Meier curves for APD-209 and APD-209 placebo were compared with a log rank test statistics of 0.6809 with a p-value of 0.4093.
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End point type |
Secondary
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End point timeframe |
Visit day 0 to 16
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Resolution of acute ocular symptoms at each time of assessment, as measured by objective (Investigator-based) assessment of conjunctival discharge. | ||||||||||||||||||||||||||||||
End point description |
Statistical analysis (Wilcoxons rank sum test) of difference in resolution of Conjunctival discharge symptoms (investigators assessment) at visit 1-6 (mITT)
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End point type |
Secondary
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End point timeframe |
Visit 1 to 6
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Resolution of acute ocular symptoms at each time of assessment, as measured by objective (Investigator-based) assessment of redness. | ||||||||||||||||||||||||||||||
End point description |
Statistical analysis (Wilcoxons rank sum test) of difference in resolution of redness symptoms (investigator assessement) at visit 1-6 (mITT)
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End point type |
Secondary
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End point timeframe |
Visit 1 to 6
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Resolution of ocular symptoms as measured by subject worksheet assessment of irritation symptoms | ||||||||||||||||||||||||||||||
End point description |
Resolution of ocular symptoms at each time of assessment, as measured by subjective (Subject Worksheet) assessment of irritation symptoms.
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End point type |
Secondary
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End point timeframe |
Visit 1 to 6
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Resolution of ocular symptoms as measured by subject worksheet assessment of foreign body sensation | ||||||||||||||||||||||||||||||
End point description |
Resolution of ocular symptoms at each time of assessment, as measured by subjective (Subject Worksheet) assessment foreign body sensation.
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End point type |
Secondary
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End point timeframe |
Visit 1 to 6
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Resolution of ocular symptoms at each time os assessment as measured by subjective assessment of tearing. | ||||||||||||||||||||||||||||||
End point description |
Resolution of ocular symptoms at each time os assessment, as measured by subjective (Subject Worksheet) assessment of tearing.
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End point type |
Secondary
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End point timeframe |
Visit 1-6
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Resolution of ocular symptoms at each time of assessment measured by subjective assessment of pain. | ||||||||||||||||||||||||||||||
End point description |
Resolution of ocular symptoms at each time of assessment, as measured by subjective (Subject Worksheet) assessment of pain.
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End point type |
Secondary
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End point timeframe |
Visit 1-6
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Resolution of ocular symptoms at each time of assessment measured by subjective assessment of blurred vision. | ||||||||||||||||||||||||||||||
End point description |
Resolution of ocular symptoms at each time of assessment, as measured by subjective (Subject Worksheet) assessment of blurred vision.
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End point type |
Secondary
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End point timeframe |
Visit 1-6
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Location of opacities at each time of assessment measured by slit lamp examination. | ||||||||||||||||||||||||||||||
End point description |
Location of opacities at each time of assessment, as measured by slit lamp examination. Statistical analysis (Wilcoxons rank sum test) of difference in quantity of opacities (slit lamp) at visit 1-6 (MiTT)
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End point type |
Secondary
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End point timeframe |
Visit 1-6
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Presence of opacities at each time of assessment, as measured by slit lamp examination. | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Visit 1-6
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Visual acuity at each time of assessment by use of the logarithm of the Minimum Angle of Resolution (LogMAR) chart. | ||||||||||||||||||||||||||||||
End point description |
The LogMAR score was to be calculated from the data entered into the eCRF as: LogMAR score = LogMAR line value + (0.02 x number of incorrect letters)
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End point type |
Secondary
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End point timeframe |
Visit 1-6
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Occurence of second eye infection | |||||||||||||||||||||||||||||||||||||||||||||
End point description |
Presence of clinical symptoms of EKC infection in the second eye. Statistical analysis (Fisher´s) exact test) of difference in presence of second eye infection at visit 1-6. (MiTT)
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End point type |
Secondary
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End point timeframe |
Visit 1-6
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
To evaluate the safety of the APD-209 treatment, AEs were reported in the eCRF at the study visits (1-6)
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Adverse event reporting additional description |
Safety analyses were performed in the safety population, defined as all subjects who received at least 1 dose of study treatment during the study, which included 25 APD-209 subjects and 22 placebo subjects. Most AE’s were considered mild in severity and not related to study treatment. APD-209 Eye Drops was found to be safe and well tolerated.
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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 |
16.0
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Reporting groups
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Reporting group title |
Subjects enrolled
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Reporting group description |
All safety analyses were performed in the safety population, defined as all subjects who received at least one dose of study treatment during the study. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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09 Apr 2014 |
• Prolongation of the maximum allowed time between first eye symptom and inclusion from 48 to 72 hours
• Recording of start of onset of first eye symptom
• Addition of exploratory analysis investigating effect of time between first eye symptom and inclusion
• Removal of the Ad quick test (AdenoPlus) from the screening visit
• Clarification of exclusion criterion 8 (concomitant medication)
• Clarification of review of Subject Dosing Cards and return of investigational medicinal product (IMP) at Visit 5 or at Visit 6, depending on which day Visit 5 is performed
• Clarification of the LogMAR chart for assessment of visual acuity
• Clarification of non-compliance in relation to definition of the per protocol set
• Increase of number of study centres in Germany to up to 5 centres
• Prolongation of the total study period
• Change of project leader at TFS and address of the Danish TFS office
• Change of biostatistician |
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23 Apr 2015 |
• Prolongation of the maximum allowed time between first eye symptom and inclusion of the subject in the study from 72 hours to 7 days
• Additions to the exploratory analyses investigating effect of time between first eye symptom and inclusion of the subject in the study
• Change in inclusion criterion 2 to remove the upper age limit
• Clarification of exclusion criterion 4 (diagnosis of bacterial or fungal ocular infections) to state that it refers to diagnoses made by the study Investigator only (and not to diagnoses made by other physicians seen by the subject prior to the study)
• Clarification of exclusion criterion 5 (use of antibiotics or corticosteroids) to allow ocular antibiotics until 2 hours before first dose
• Clarification that tear supplements or saline may be administered in the untreated eye
• Increase of number of study centres in Germany to up to 7 centres
• Prolongation of the total study period |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | |||||||
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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. | |||||||
| Out of 47 randomised subjects, only 15 were included in the mITT analysis set used to assess the primary efficacy variable. 31 out of the 47 randomised subjects were shown not to have adenovirus of the right type plus one more subject excluded. | |||||||
