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    Clinical Trial Results:
    A Phase II Randomized Study to Compare Anti-VEGF Agents in the Treatment of Diabetic Macular Edema (CADME)

    Summary
    EudraCT number
    		 2012-005486-13
    Trial protocol
    		 GB  
    Global end of trial date
    15 Jul 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Jul 2016
    First version publication date
    28 Jul 2016
    Other versions
    Summary report(s)
    		 CADME Study Final Results

    Trial information

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    Trial identification
    Sponsor protocol code
    12-EI-0134
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01610557
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    National Eye Institute
    Sponsor organisation address
    NIH , Bethesda, United States,
    Public contact
    Henry Wiley, National Eye Institute, wileyhe@nei.nih.gov
    Scientific contact
    Henry Wiley, National Eye Institute, wileyhe@nei.nih.gov
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    09 Apr 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main study objective was to compare the treatment efficacy of ranibizumab versus bevacizumab in eyes with diabetic macular edema (DME).
    Protection of trial subjects
    Institutional review board/independent ethics committee approval was obtained at both sites and all participants gave written informed consent. The study was conducted in accordance with the tenets of the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 May 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 41
    Country: Number of subjects enrolled
    United States: 15
    Worldwide total number of subjects
    56
    EEA total number of subjects
    41
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    33
    From 65 to 84 years
    21
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Eligible participants had type 1 or type 2 diabetes mellitus, were at least 18 years old, and could enter one or both eligible eyes in the study.

    Pre-assignment
    Screening details
    		 56 participants enrolled: 50 participants had one eye randomly assigned (unilateral participants) and 6 participants had two eyes enrolled (bilateral participants) for a total of 62 eyes analyzed at baseline. Bilateral participants had the right eye randomly assigned and the left eye assigned to the group with the schedule inverse to the right eye.

    Period 1
    Period 1 title
    36-Week Randomized Crossover Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    Participants were assigned to one of the four treatment sequences using a randomization list generated by the Data and Statistical Coordinating Center prior to study initiation, with balance following every 12 enrollments. The list was provided to unmasked pharmacists at each site who confirmed a valid participant identification code prior to dispensing study treatment. Both clinical sites utilized the same randomized list, but selected treatment assignments from opposite ends.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1 - Ranibizumab-Ranibizumab-Bevacizumab Injection Series
    Arm description
    		 Group 1 eyes were assigned to the Ranibizumab-Ranibizumab-Bevacizumab (RRB) treatment sequence and received intravitreal injections of ranibizumab at baseline, Weeks 4, and 8 (period 1), and Weeks 12, 16 and 20 (period 2), then crossed over to receive intravitreal injections of bevacizumab at Weeks 24, 28 and 32 (period 3). Participants for whom one eye was enrolled (unilateral participants) in the study had this eye randomly assigned to one of four groups. Participants for whom both eyes were enrolled (bilateral participants) had the right eye randomly assigned; the left eye was assigned to the group with the schedule inverse to that for the right eye. Participants randomly assigned to Group 1: 14 unilateral and 2 bilateral (left eye assigned to Group 3) Participants' eyes assigned to Group 1: 17
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ranibizumab
    Investigational medicinal product code
    Other name
    Lucentis
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Series of three intravitreous injections of ranibizumab [0.3 milligrams (mg)]* or bevacizumab (1.25 mg) administered every 4 weeks for three 12-week periods. Following this crossover phase, eyes received ranibizumab or bevacizumab to which they were originally assigned and treated on an as-needed basis until study completion. *Eleven doses of ranibizumab 0.5 mg were given to participants at the start of the study; after the United States (US) Food and Drug Administration (FDA) approval of the 0.3 mg dose for diabetic macular edema (DME), the protocol was amended and 0.3 mg was used for the remainder of the study (98% of all injections).

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Series of three intravitreous injections of ranibizumab [0.3 milligrams (mg)]* or bevacizumab (1.25 mg) administered every 4 weeks for three 12-week periods. Following this crossover phase, eyes received ranibizumab or bevacizumab to which they were originally assigned and treated on an as-needed basis until study completion. *Eleven doses of ranibizumab 0.5 mg were given to participants at the start of the study; after the United States (US) Food and Drug Administration (FDA) approval of the 0.3 mg dose for diabetic macular edema (DME), the protocol was amended and 0.3 mg was used for the remainder of the study (98% of all injections).

    Arm title
    		 Group 2 - Ranibizumab-Bevacizumab-Bevacizumab Injection Series
    Arm description
    		 Group 2 eyes were assigned to the Ranibizumab-Bevacizumab-Bevacizumab (RBB) treatment sequence and received intravitreal injections of ranibizumab at baseline and Weeks 4 and 8 (period 1), then crossed over to receive intravitreal injections of bevacizumab at Weeks 12, 16, 20, 24, 28 and 32 (periods 2 and 3). Participants for whom one eye was enrolled (unilateral participants) in the study had this eye randomly assigned to one of four groups. Participants for whom both eyes were enrolled (bilateral participants) had the right eye randomly assigned; the left eye was assigned to the group with the schedule inverse to that for the right eye. Participants randomly assigned to Group 2: 12 unilateral and 1 bilateral (left eye assigned to Group 4) Participants' eyes assigned to Group 2: 15
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ranibizumab
    Investigational medicinal product code
    Other name
    Lucentis
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Series of three intravitreous injections of ranibizumab [0.3 milligrams (mg)]* or bevacizumab (1.25 mg) administered every 4 weeks for three 12-week periods. Following this crossover phase, eyes received ranibizumab or bevacizumab to which they were originally assigned and treated on an as-needed basis until study completion. *Eleven doses of ranibizumab 0.5 mg were given to participants at the start of the study; after the United States (US) Food and Drug Administration (FDA) approval of the 0.3 mg dose for diabetic macular edema (DME), the protocol was amended and 0.3 mg was used for the remainder of the study (98% of all injections).

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Series of three intravitreous injections of ranibizumab [0.3 milligrams (mg)]* or bevacizumab (1.25 mg) administered every 4 weeks for three 12-week periods. Following this crossover phase, eyes received ranibizumab or bevacizumab to which they were originally assigned and treated on an as-needed basis until study completion. *Eleven doses of ranibizumab 0.5 mg were given to participants at the start of the study; after the United States (US) Food and Drug Administration (FDA) approval of the 0.3 mg dose for diabetic macular edema (DME), the protocol was amended and 0.3 mg was used for the remainder of the study (98% of all injections).

    Arm title
    		 Group 3 - Bevacizumab-Bevacizumab-Ranibizumab Injection Series
    Arm description
    		 Group 3 eyes were assigned to the Bevacizumab-Bevacizumab-Ranibizumab (BBR) treatment sequence and received intravitreal injections of bevacizumab at baseline and Weeks 4, 8, 12, 16 and 20 (periods 1 and 2), then crossed over to receive intravitreal injections of ranibizumab at Weeks 24, 28 and 32 (period 3). Participants for whom one eye was enrolled (unilateral participants) in the study had this eye randomly assigned to one of four groups. Participants for whom both eyes were enrolled (bilateral participants) had the right eye randomly assigned; the left eye was assigned to the group with the schedule inverse to that for the right eye. Participants randomly assigned to Group 3: 13 unilateral and 1 bilateral (left eye assigned to Group 1) Participants' eyes assigned to Group 3: 16
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ranibizumab
    Investigational medicinal product code
    Other name
    Lucentis
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Series of three intravitreous injections of ranibizumab [0.3 milligrams (mg)]* or bevacizumab (1.25 mg) administered every 4 weeks for three 12-week periods. Following this crossover phase, eyes received ranibizumab or bevacizumab to which they were originally assigned and treated on an as-needed basis until study completion. *Eleven doses of ranibizumab 0.5 mg were given to participants at the start of the study; after the United States (US) Food and Drug Administration (FDA) approval of the 0.3 mg dose for diabetic macular edema (DME), the protocol was amended and 0.3 mg was used for the remainder of the study (98% of all injections).

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Series of three intravitreous injections of ranibizumab [0.3 milligrams (mg)]* or bevacizumab (1.25 mg) administered every 4 weeks for three 12-week periods. Following this crossover phase, eyes received ranibizumab or bevacizumab to which they were originally assigned and treated on an as-needed basis until study completion. *Eleven doses of ranibizumab 0.5 mg were given to participants at the start of the study; after the United States (US) Food and Drug Administration (FDA) approval of the 0.3 mg dose for diabetic macular edema (DME), the protocol was amended and 0.3 mg was used for the remainder of the study (98% of all injections).

    Arm title
    		 Group 4 - Bevacizumab-Ranibizumab-Ranibizumab Injection Series
    Arm description
    		 Group 4 eyes were assigned to the Bevacizumab-Ranibizumab-Ranibizumab (BRR) treatment sequence and received intravitreal injections of bevacizumab at baseline and Weeks 4 and 8 (period 1), then crossed over to receive intravitreal injections of ranibizumab at Weeks 12, 16, 20, 24, 28 and 32 (periods 2 and 3). Participants for whom one eye was enrolled (unilateral participants) in the study had this eye randomly assigned to one of four groups. Participants for whom both eyes were enrolled (bilateral participants) had the right eye randomly assigned; the left eye was assigned to the group with the schedule inverse to that for the right eye. Participants randomly assigned to Group 4: 11 unilateral and 2 bilateral (left eye assigned to Group 2) Participants' eyes assigned to Group 4: 14
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ranibizumab
    Investigational medicinal product code
    Other name
    Lucentis
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Series of three intravitreous injections of ranibizumab [0.3 milligrams (mg)]* or bevacizumab (1.25 mg) administered every 4 weeks for three 12-week periods. Following this crossover phase, eyes received ranibizumab or bevacizumab to which they were originally assigned and treated on an as-needed basis until study completion. *Eleven doses of ranibizumab 0.5 mg were given to participants at the start of the study; after the United States (US) Food and Drug Administration (FDA) approval of the 0.3 mg dose for diabetic macular edema (DME), the protocol was amended and 0.3 mg was used for the remainder of the study (98% of all injections).

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Series of three intravitreous injections of ranibizumab [0.3 milligrams (mg)]* or bevacizumab (1.25 mg) administered every 4 weeks for three 12-week periods. Following this crossover phase, eyes received ranibizumab or bevacizumab to which they were originally assigned and treated on an as-needed basis until study completion. *Eleven doses of ranibizumab 0.5 mg were given to participants at the start of the study; after the United States (US) Food and Drug Administration (FDA) approval of the 0.3 mg dose for diabetic macular edema (DME), the protocol was amended and 0.3 mg was used for the remainder of the study (98% of all injections).

    Number of subjects in period 1
    		Group 1 - Ranibizumab-Ranibizumab-Bevacizumab Injection Series Group 2 - Ranibizumab-Bevacizumab-Bevacizumab Injection Series Group 3 - Bevacizumab-Bevacizumab-Ranibizumab Injection Series Group 4 - Bevacizumab-Ranibizumab-Ranibizumab Injection Series
    Started
    16
    13
    14
    13
    Completed
    16
    12
    14
    13
    Not completed
    0
    1
    0
    0
         Consent withdrawn by subject
    -
    1
    -
    -
    Period 2
    Period 2 title
    Post-36-Week Extension Phase
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Ranibizumab/Bevacizumab As Needed
    Arm description
    		 Post-36-Week Extension Phase: Eyes assigned to Group 1 or Group 2 in the crossover phase were injected with ranibizumab on an as-needed basis. Eyes assigned to Group 3 or Group 4 in the crossover phase were injected with bevacizumab on an as-needed basis. 53 participants attended at least one follow-up visit in the post-36-week extension phase: 49 participants who had one eye enrolled and 4 participants who had two eyes enrolled. Two bilateral participants withdrew before their first post-36-week extension visit
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ranibizumab
    Investigational medicinal product code
    Other name
    Lucentis
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Series of three intravitreous injections of ranibizumab [0.3 milligrams (mg)]* or bevacizumab (1.25 mg) administered every 4 weeks for three 12-week periods. Following this crossover phase, eyes received ranibizumab or bevacizumab to which they were originally assigned and treated on an as-needed basis until study completion. *Eleven doses of ranibizumab 0.5 mg were given to participants at the start of the study; after the United States (US) Food and Drug Administration (FDA) approval of the 0.3 mg dose for diabetic macular edema (DME), the protocol was amended and 0.3 mg was used for the remainder of the study (98% of all injections).

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Series of three intravitreous injections of ranibizumab [0.3 milligrams (mg)]* or bevacizumab (1.25 mg) administered every 4 weeks for three 12-week periods. Following this crossover phase, eyes received ranibizumab or bevacizumab to which they were originally assigned and treated on an as-needed basis until study completion. *Eleven doses of ranibizumab 0.5 mg were given to participants at the start of the study; after the United States (US) Food and Drug Administration (FDA) approval of the 0.3 mg dose for diabetic macular edema (DME), the protocol was amended and 0.3 mg was used for the remainder of the study (98% of all injections).

    Number of subjects in period 2
    		Ranibizumab/Bevacizumab As Needed
    Started
    55
    Completed
    52
    Not completed
    3
         Consent withdrawn by subject
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1 - Ranibizumab-Ranibizumab-Bevacizumab Injection Series
    Reporting group description
    		 Group 1 eyes were assigned to the Ranibizumab-Ranibizumab-Bevacizumab (RRB) treatment sequence and received intravitreal injections of ranibizumab at baseline, Weeks 4, and 8 (period 1), and Weeks 12, 16 and 20 (period 2), then crossed over to receive intravitreal injections of bevacizumab at Weeks 24, 28 and 32 (period 3). Participants for whom one eye was enrolled (unilateral participants) in the study had this eye randomly assigned to one of four groups. Participants for whom both eyes were enrolled (bilateral participants) had the right eye randomly assigned; the left eye was assigned to the group with the schedule inverse to that for the right eye. Participants randomly assigned to Group 1: 14 unilateral and 2 bilateral (left eye assigned to Group 3) Participants' eyes assigned to Group 1: 17

    Reporting group title
    Group 2 - Ranibizumab-Bevacizumab-Bevacizumab Injection Series
    Reporting group description
    		 Group 2 eyes were assigned to the Ranibizumab-Bevacizumab-Bevacizumab (RBB) treatment sequence and received intravitreal injections of ranibizumab at baseline and Weeks 4 and 8 (period 1), then crossed over to receive intravitreal injections of bevacizumab at Weeks 12, 16, 20, 24, 28 and 32 (periods 2 and 3). Participants for whom one eye was enrolled (unilateral participants) in the study had this eye randomly assigned to one of four groups. Participants for whom both eyes were enrolled (bilateral participants) had the right eye randomly assigned; the left eye was assigned to the group with the schedule inverse to that for the right eye. Participants randomly assigned to Group 2: 12 unilateral and 1 bilateral (left eye assigned to Group 4) Participants' eyes assigned to Group 2: 15

    Reporting group title
    Group 3 - Bevacizumab-Bevacizumab-Ranibizumab Injection Series
    Reporting group description
    		 Group 3 eyes were assigned to the Bevacizumab-Bevacizumab-Ranibizumab (BBR) treatment sequence and received intravitreal injections of bevacizumab at baseline and Weeks 4, 8, 12, 16 and 20 (periods 1 and 2), then crossed over to receive intravitreal injections of ranibizumab at Weeks 24, 28 and 32 (period 3). Participants for whom one eye was enrolled (unilateral participants) in the study had this eye randomly assigned to one of four groups. Participants for whom both eyes were enrolled (bilateral participants) had the right eye randomly assigned; the left eye was assigned to the group with the schedule inverse to that for the right eye. Participants randomly assigned to Group 3: 13 unilateral and 1 bilateral (left eye assigned to Group 1) Participants' eyes assigned to Group 3: 16

    Reporting group title
    Group 4 - Bevacizumab-Ranibizumab-Ranibizumab Injection Series
    Reporting group description
    		 Group 4 eyes were assigned to the Bevacizumab-Ranibizumab-Ranibizumab (BRR) treatment sequence and received intravitreal injections of bevacizumab at baseline and Weeks 4 and 8 (period 1), then crossed over to receive intravitreal injections of ranibizumab at Weeks 12, 16, 20, 24, 28 and 32 (periods 2 and 3). Participants for whom one eye was enrolled (unilateral participants) in the study had this eye randomly assigned to one of four groups. Participants for whom both eyes were enrolled (bilateral participants) had the right eye randomly assigned; the left eye was assigned to the group with the schedule inverse to that for the right eye. Participants randomly assigned to Group 4: 11 unilateral and 2 bilateral (left eye assigned to Group 2) Participants' eyes assigned to Group 4: 14

    Reporting group values
    		 Group 1 - Ranibizumab-Ranibizumab-Bevacizumab Injection Series Group 2 - Ranibizumab-Bevacizumab-Bevacizumab Injection Series Group 3 - Bevacizumab-Bevacizumab-Ranibizumab Injection Series Group 4 - Bevacizumab-Ranibizumab-Ranibizumab Injection Series Total
    Number of subjects
    		 16 13 14 13 56
    Age categorical
    Units: Subjects
    Age continuous
    Participants with both eyes enrolled are counted twice (by eye), once for each of the treatment sequences to which an eye was assigned randomly. Although 56 participants enrolled, 6 participants had two eyes enrolled for a total of 62 eyes. This age baseline characteristic reflects the number of eyes enrolled in each group: Group 1 had 17 eyes enrolled, Group 2 had 15 eyes enrolled, Group 3 had 16 eyes enrolled and Group 4 had 14 eyes enrolled.
    Units: years
        arithmetic mean (full range (min-max))
    		 62.4 (39 to 85) 65.9 (39 to 87) 62.3 (39 to 83) 61.8 (51 to 82) -
    Gender categorical
    The gender baseline characteristic reflects the number of participants enrolled rather than the number of eyes enrolled.
    Units: Subjects
        Female
    		 3 7 7 4 21
        Male
    		 13 6 7 9 35
    Subject analysis sets

    Subject analysis set title
    Ranibizumab
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Represents the estimated effect of ranibizumab for a 3-month period, adjusted for period and baseline value. A total of 56 participants (62 eyes) were enrolled and 55 participants (61 eyes) completed the 36-week crossover phase of the study.

    Subject analysis set title
    Bevacizumab
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Represents the estimated effect of bevacizumab for a 3-month period, adjusted for period and baseline value. A total of 56 participants (62 eyes) were enrolled and 55 participants (61 eyes) completed the 36-week crossover phase of the study.

    Subject analysis sets values
    		 Ranibizumab Bevacizumab
    Number of subjects
    55
    55
    Age categorical
    Units: Subjects
    Age continuous
    Participants with both eyes enrolled are counted twice (by eye), once for each of the treatment sequences to which an eye was assigned randomly. Although 56 participants enrolled, 6 participants had two eyes enrolled for a total of 62 eyes. This age baseline characteristic reflects the number of eyes enrolled in each group: Group 1 had 17 eyes enrolled, Group 2 had 15 eyes enrolled, Group 3 had 16 eyes enrolled and Group 4 had 14 eyes enrolled.
    Units: years
        arithmetic mean (full range (min-max))
    Gender categorical
    The gender baseline characteristic reflects the number of participants enrolled rather than the number of eyes enrolled.
    Units: Subjects
        Female
    21
    21
        Male
    34
    34

    End points

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    End points reporting groups
    Reporting group title
    Group 1 - Ranibizumab-Ranibizumab-Bevacizumab Injection Series
    Reporting group description
    		 Group 1 eyes were assigned to the Ranibizumab-Ranibizumab-Bevacizumab (RRB) treatment sequence and received intravitreal injections of ranibizumab at baseline, Weeks 4, and 8 (period 1), and Weeks 12, 16 and 20 (period 2), then crossed over to receive intravitreal injections of bevacizumab at Weeks 24, 28 and 32 (period 3). Participants for whom one eye was enrolled (unilateral participants) in the study had this eye randomly assigned to one of four groups. Participants for whom both eyes were enrolled (bilateral participants) had the right eye randomly assigned; the left eye was assigned to the group with the schedule inverse to that for the right eye. Participants randomly assigned to Group 1: 14 unilateral and 2 bilateral (left eye assigned to Group 3) Participants' eyes assigned to Group 1: 17

    Reporting group title
    Group 2 - Ranibizumab-Bevacizumab-Bevacizumab Injection Series
    Reporting group description
    		 Group 2 eyes were assigned to the Ranibizumab-Bevacizumab-Bevacizumab (RBB) treatment sequence and received intravitreal injections of ranibizumab at baseline and Weeks 4 and 8 (period 1), then crossed over to receive intravitreal injections of bevacizumab at Weeks 12, 16, 20, 24, 28 and 32 (periods 2 and 3). Participants for whom one eye was enrolled (unilateral participants) in the study had this eye randomly assigned to one of four groups. Participants for whom both eyes were enrolled (bilateral participants) had the right eye randomly assigned; the left eye was assigned to the group with the schedule inverse to that for the right eye. Participants randomly assigned to Group 2: 12 unilateral and 1 bilateral (left eye assigned to Group 4) Participants' eyes assigned to Group 2: 15

    Reporting group title
    Group 3 - Bevacizumab-Bevacizumab-Ranibizumab Injection Series
    Reporting group description
    		 Group 3 eyes were assigned to the Bevacizumab-Bevacizumab-Ranibizumab (BBR) treatment sequence and received intravitreal injections of bevacizumab at baseline and Weeks 4, 8, 12, 16 and 20 (periods 1 and 2), then crossed over to receive intravitreal injections of ranibizumab at Weeks 24, 28 and 32 (period 3). Participants for whom one eye was enrolled (unilateral participants) in the study had this eye randomly assigned to one of four groups. Participants for whom both eyes were enrolled (bilateral participants) had the right eye randomly assigned; the left eye was assigned to the group with the schedule inverse to that for the right eye. Participants randomly assigned to Group 3: 13 unilateral and 1 bilateral (left eye assigned to Group 1) Participants' eyes assigned to Group 3: 16

    Reporting group title
    Group 4 - Bevacizumab-Ranibizumab-Ranibizumab Injection Series
    Reporting group description
    		 Group 4 eyes were assigned to the Bevacizumab-Ranibizumab-Ranibizumab (BRR) treatment sequence and received intravitreal injections of bevacizumab at baseline and Weeks 4 and 8 (period 1), then crossed over to receive intravitreal injections of ranibizumab at Weeks 12, 16, 20, 24, 28 and 32 (periods 2 and 3). Participants for whom one eye was enrolled (unilateral participants) in the study had this eye randomly assigned to one of four groups. Participants for whom both eyes were enrolled (bilateral participants) had the right eye randomly assigned; the left eye was assigned to the group with the schedule inverse to that for the right eye. Participants randomly assigned to Group 4: 11 unilateral and 2 bilateral (left eye assigned to Group 2) Participants' eyes assigned to Group 4: 14
    Reporting group title
    Ranibizumab/Bevacizumab As Needed
    Reporting group description
    		 Post-36-Week Extension Phase: Eyes assigned to Group 1 or Group 2 in the crossover phase were injected with ranibizumab on an as-needed basis. Eyes assigned to Group 3 or Group 4 in the crossover phase were injected with bevacizumab on an as-needed basis. 53 participants attended at least one follow-up visit in the post-36-week extension phase: 49 participants who had one eye enrolled and 4 participants who had two eyes enrolled. Two bilateral participants withdrew before their first post-36-week extension visit

    Subject analysis set title
    Ranibizumab
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Represents the estimated effect of ranibizumab for a 3-month period, adjusted for period and baseline value. A total of 56 participants (62 eyes) were enrolled and 55 participants (61 eyes) completed the 36-week crossover phase of the study.

    Subject analysis set title
    Bevacizumab
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Represents the estimated effect of bevacizumab for a 3-month period, adjusted for period and baseline value. A total of 56 participants (62 eyes) were enrolled and 55 participants (61 eyes) completed the 36-week crossover phase of the study.

    Primary: Mean Change in Early Treatment Diabetic Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) From Baseline to 36 Weeks (Crossover Phase of the Study)

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    End point title
    		 Mean Change in Early Treatment Diabetic Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) From Baseline to 36 Weeks (Crossover Phase of the Study)
    End point description
    The primary outcome for 3-months change in BCVA utilized data from Weeks 12, 24 and 36 aggregated in a linear mixed-effects model. This model included adjustments accounting for period (i.e., Weeks 12, 24 and 36), treatment in current period, treatment in prior period, and baseline BCVA to provide the estimated 3-month BCVA change. A positive change from baseline indicated improvement. Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20.
    End point type
    Primary
    End point timeframe
    Baseline, 36 Weeks
    End point values
    		 Ranibizumab Bevacizumab
    Number of subjects analysed
    55 [1]
    55 [2]
    Units: ETDRS letters
        arithmetic mean (confidence interval 95%)
    5.3 (3.2 to 7.4)
    6.6 (4.5 to 8.7)
    Notes
    [1] - The total number of eyes included in the analysis is 61.
    [2] - The total number of eyes included in the analysis is 61.
    Statistical analysis title
    		 Ranibizumab versus Bevacizumab
    Statistical analysis description
    The comparison groups are ranibizumab and bevacizumab with a total of 55 participants (61 eyes) included in the analysis. The difference represents the estimated difference between ranibizumab and bevacizumab, adjusted for baseline visual acuity, study period, and clinical site and a subject effect for eyes nested within subject.
    Comparison groups
    Ranibizumab v Bevacizumab
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.039
    Method
    		 Linear mixed-effects model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.07
         upper limit
    		 2.5

    Secondary: Change in Central Retinal Thickness Assessed by Optical Coherence Tomography (OCT) Central Subfield Mean Thickness (CSMT) From Baseline to 36 Weeks (Crossover Phase of the Study)

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    End point title
    		 Change in Central Retinal Thickness Assessed by Optical Coherence Tomography (OCT) Central Subfield Mean Thickness (CSMT) From Baseline to 36 Weeks (Crossover Phase of the Study)
    End point description
    Optical Coherence Tomography (OCT) scans were graded in masked fashion by Duke University Reading Center (Durham, North Carolina). Per the initial protocol specifications, OCT scans were to be performed on a Cirrus OCT machine; however, some scans were performed on a Spectralis OCT machine at one of the sites due to technical difficulties. The protocol was amended to allow for Cirrus and Spectralis OCT scans at subsequent visits at the affected site. Spectralis values were then converted to Cirrus central subfield mean thickness (CSMT) values through a validated linear conversion function. A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, 36 Weeks
    End point values
    		 Ranibizumab Bevacizumab
    Number of subjects analysed
    55 [3]
    55 [4]
    Units: micrometers
        arithmetic mean (confidence interval 95%)
    -89 (-116 to -62)
    -137 (-164 to -110)
    Notes
    [3] - The total number of eyes included in the analysis is 61.
    [4] - The total number of eyes included in the analysis is 61.
    Statistical analysis title
    		 Ranibizumab versus Bevacizumab
    Statistical analysis description
    The comparison groups are ranibizumab and bevacizumab with a total of 55 participants (61 eyes) included in the analysis.
    Comparison groups
    Ranibizumab v Bevacizumab
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Linear mixed-effects model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -65
         upper limit
    		 -31

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Data were collected from 56 participants randomly-assigned to Groups 1 through 4 during the 36-week crossover period. After 36 weeks, data were collected from the 53 participants who completed at least one post-36-week visit up to the termination visit.
    Adverse event reporting additional description
    36-week crossover period:Of the 56 participants, 50 had one eye and 6 had two eyes enrolled; data collected from the 6 participants with two eyes enrolled are reflected in the group to which the participant's right eye was randomly assigned. Post-36-weeks:Of the 53 participants, data were collected from 49 with one eye and 4 with two eyes enrolled.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0-17.1
    Reporting groups
    Reporting group title
    Group 1 - Ranibizumab-Ranibizumab-Bevacizumab Injection Series
    Reporting group description
    		 Group 1 eyes were assigned to the Ranibizumab-Ranibizumab-Bevacizumab (RRB) treatment sequence and received intravitreal injections of ranibizumab at baseline, Weeks 4, and 8 (period 1), and Weeks 12, 16 and 20 (period 2), then crossed over to receive intravitreal injections of bevacizumab at Weeks 24, 28 and 32 (period 3). Participants for whom one eye was enrolled in the study had this eye randomly assigned to one of four groups. Participants for whom both eyes were enrolled had the right eye randomly assigned; the left eye was assigned to the group with the schedule inverse to that for the right eye. Participants randomly assigned to Group 1: 14 unilateral and 2 bilateral (left eye assigned to Group 3)

    Reporting group title
    Group 2 - Ranibizumab-Bevacizumab-Bevacizumab Injection Series
    Reporting group description
    		 Group 2 eyes were assigned to the Ranibizumab-Bevacizumab-Bevacizumab (RBB) treatment sequence and received intravitreal injections of ranibizumab at baseline and Weeks 4 and 8 (period 1), then crossed over to receive intravitreal injections of bevacizumab at Weeks 12, 16, 20, 24, 28 and 32 (periods 2 and 3). Participants for whom one eye was enrolled in the study had this eye randomly assigned to one of four groups. Participants for whom both eyes were enrolled had the right eye randomly assigned; the left eye was assigned to the group with the schedule inverse to that for the right eye. Participants randomly assigned to Group 2: 12 unilateral and 1 bilateral (left eye assigned to Group 4)

    Reporting group title
    Group 3 - Bevacizumab-Bevacizumab-Ranibizumab Injection Series
    Reporting group description
    		 Group 3 eyes were assigned to the Bevacizumab-Bevacizumab-Ranibizumab (BBR) treatment sequence and received intravitreal injections of bevacizumab at baseline and Weeks 4, 8, 12, 16 and 20 (periods 1 and 2), then crossed over to receive intravitreal injections of ranibizumab at Weeks 24, 28 and 32 (period 3). Participants for whom one eye was enrolled in the study had this eye randomly assigned to one of four groups. Participants for whom both eyes were enrolled had the right eye randomly assigned; the left eye was assigned to the group with the schedule inverse to that for the right eye. Participants randomly assigned to Group 3: 13 unilateral and 1 bilateral (left eye assigned to Group 1)

    Reporting group title
    Group 4 - Bevacizumab-Ranibizumab-Ranibizumab Injection Series
    Reporting group description
    		 Group 4 eyes were assigned to the Bevacizumab-Ranibizumab-Ranibizumab (BRR) treatment sequence and received intravitreal injections of bevacizumab at baseline and Weeks 4 and 8 (period 1), then crossed over to receive intravitreal injections of ranibizumab at Weeks 12, 16, 20, 24, 28 and 32 (periods 2 and 3). Participants for whom one eye was enrolled in the study had this eye randomly assigned to one of four groups. Participants for whom both eyes were enrolled had the right eye randomly assigned; the left eye was assigned to the group with the schedule inverse to that for the right eye.

    Reporting group title
    Ranibizumab As Needed (Post-36-Week Extension)
    Reporting group description
    		 Post-36-Week Extension Phase: Eyes assigned to Group 1 or Group 2 in the crossover phase were injected with ranibizumab on an as-needed basis. Participants with one eye assigned in either Group 1 or Group 2 who had at least one follow-up visit in the post-36-week extension are included in the number of participants at risk. Participants for whom two eyes were assigned (bilateral participants) are not included.

    Reporting group title
    Bevacizumab As Needed (Post-36-Week Extension)
    Reporting group description
    		 Post-36-Week Extension Phase: Eyes assigned to Group 3 or Group 4 in the crossover phase were injected with bevacizumab on an as-needed basis. Participants with one eye assigned in either Group 3 or Group 4 who had at least one follow-up visit in the post-36-week extension are included in the number of participants at risk. Participants for whom two eyes were assigned (bilateral participants) are not included.

    Reporting group title
    Ranibizumab and Bevacizumab As Needed (Post-36-Week Extension)
    Reporting group description
    		 Post-36-Week Extension Phase: Eyes assigned to Group 1 or Group 2 in the crossover phase were injected with ranibizumab on an as-needed basis. Eyes assigned to Group 3 or Group 4 in the crossover phase were injected with bevacizumab on an as-needed basis. Participants with two eyes assigned who had at least one follow-up visit in the post-36-week extension are included in the number of participants at risk. Participants for whom one eye was assigned (unilateral participants) are not included.

    Serious adverse events
    		 Group 1 - Ranibizumab-Ranibizumab-Bevacizumab Injection Series Group 2 - Ranibizumab-Bevacizumab-Bevacizumab Injection Series Group 3 - Bevacizumab-Bevacizumab-Ranibizumab Injection Series Group 4 - Bevacizumab-Ranibizumab-Ranibizumab Injection Series Ranibizumab As Needed (Post-36-Week Extension) Bevacizumab As Needed (Post-36-Week Extension) Ranibizumab and Bevacizumab As Needed (Post-36-Week Extension)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 16 (18.75%)
    1 / 13 (7.69%)
    1 / 14 (7.14%)
    1 / 13 (7.69%)
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    Investigations
    Blood glucose increased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 13 (7.69%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Group 1 - Ranibizumab-Ranibizumab-Bevacizumab Injection Series Group 2 - Ranibizumab-Bevacizumab-Bevacizumab Injection Series Group 3 - Bevacizumab-Bevacizumab-Ranibizumab Injection Series Group 4 - Bevacizumab-Ranibizumab-Ranibizumab Injection Series Ranibizumab As Needed (Post-36-Week Extension) Bevacizumab As Needed (Post-36-Week Extension) Ranibizumab and Bevacizumab As Needed (Post-36-Week Extension)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 16 (81.25%)
    12 / 13 (92.31%)
    9 / 14 (64.29%)
    9 / 13 (69.23%)
    13 / 25 (52.00%)
    12 / 24 (50.00%)
    4 / 4 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    1 / 13 (7.69%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    Hypotension
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    Surgical and medical procedures
    Cyst removal
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 13 (7.69%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Adverse drug reaction
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Chest pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Influenza like illness
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    2 / 24 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    Malaise
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    1
    0
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 13 (7.69%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Hypersensitivity
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Reproductive system and breast disorders
    Breast mass
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    Cough
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 13 (7.69%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    1
    Epistaxis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    1 / 13 (7.69%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    Sinus congestion
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Depressed mood
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Depression
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 13 (7.69%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Investigations
    Albumin urine present
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Blood iron decreased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Intraocular pressure increased
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Lymphocte count decreased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Chest injury
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Corneal abrasion
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 25 (4.00%)
    1 / 24 (4.17%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    1
    1
    0
    Fall
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Procedural nausea
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Stress fracture
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Wound
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Wrist fracture
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    2 / 13 (15.38%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Nervous system disorders
    Diabetic neuropathy
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Dizziness
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Hyposmia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    IIIrd nerve paralysis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    IVth nerve paralysis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 13 (7.69%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Sciatica
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    VIIth nerve paralysis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Eye disorders
    Blepharitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 13 (7.69%)
    1 / 14 (7.14%)
    1 / 13 (7.69%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    2
    2
    0
    0
    0
    Blepharospasm
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Cataract
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 13 (15.38%)
    2 / 14 (14.29%)
    1 / 13 (7.69%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    2
    1
    0
    0
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 13 (7.69%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    Corneal erosion
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Dry eye
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Eye pain
         subjects affected / exposed
    2 / 16 (12.50%)
    2 / 13 (15.38%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    2
    0
    0
    1
    0
    0
    Eye pruritis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Eyelid oedema
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Lenticular opacities
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 13 (7.69%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    Posterior capsule opacification
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Retinal haemorrhage
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    2
    Vision blurred
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 13 (15.38%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    0
    0
    1
    0
    0
    Vitreous haematoma
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Vitreous detachment
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    Vitreous haemorrhage
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    3 / 24 (12.50%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    4
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    1
    Colitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Constipation
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    2 / 24 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    Diarrhoea
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 13 (7.69%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    1
    0
    0
    Tongue ulceration
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Hepatobiliary disorders
    Early satiety
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    Dermatitis contact
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Rash
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Skin lesion
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    0
    0
    Back pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    2 / 13 (15.38%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Neck pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 13 (7.69%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 25 (4.00%)
    2 / 24 (8.33%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    1
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Ear infection
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    1
    Influenza
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Localised infection
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    1 / 24 (4.17%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 13 (7.69%)
    1 / 14 (7.14%)
    3 / 13 (23.08%)
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    1
    3
    1
    0
    1
    Otitis media
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Pneumonia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Sinusitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    Tonsillitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    1 / 25 (4.00%)
    2 / 24 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    1
    2
    0
    Viral infection
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Gout
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 13 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 13 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 25 (4.00%)
    0 / 24 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/26875003
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