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    Clinical Trial Results:
    A Multiple-Site, Phase 2, Safety and Efficacy Trial of a Recombinant Adeno-associated Virus Vector Expressing Alpha 1 Antitrypsin (rAAV1-CB-hAAT) in Patients with Alpha 1 Antitrypsin Deficiency

    Summary
    EudraCT number
    		 2009-014286-20
    Trial protocol
    		 IE  
    Global end of trial date
    01 Oct 2015

    Results information
    Results version number
    		 v1
    This version publication date
    28 Feb 2019
    First version publication date
    28 Feb 2019
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    AGTC-AAT-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01054339
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Applied Genetic Technologies Corporation
    Sponsor organisation address
    14193 NW 119th Terrace, Suite 10, Alachua, United States, 32615
    Public contact
    Ellery Mangas, Executive Director, Regulatory Affairs, Applied Genetic Technologies Corporation, 386 5185526, emangas@agtc.com
    Scientific contact
    Ellery Mangas, Executive Director, Regulatory Affairs, Applied Genetic Technologies Corporation, 386 5185526, emangas@agtc.com
    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
    14 Sep 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Nov 2011
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Oct 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Assessment of the safety and efficacy of intramuscular (IM) administration of a recombinant adenoassociated virus (rAAV) alpha-1 antitrypsin (AAT) vector (rAAV1-CB-hAAT) in AAT-deficient adults at three dosage levels [6.0 × 10e11, 1.9 × 10e12 and 6.0 × 10e12 vector genome particles (vg) per kg body weight].
    Protection of trial subjects
    This study was conducted in full conformity with the current revision of the Declaration of Helsinki, or with ICH GCP regulations and guidelines, whichever affords the greater protection to the subject. This study was reviewed and approved by an appropriate IRB/EC of this protocol, the associated informed consent documents, and other materials were provided to potential study participants. All amendments to the protocol, consent documents or associated materials were approved before they are placed into use. The medical history and physical examination performed during the screening visit identified individuals with medical conditions that would increase the risks associated with participation in the study. Results of all laboratory and safety evaluations were reviewed by the investigators and sponsor throughout the trial, and a Data and Safety Monitoring Board (DSMB) reviewed safety data from completed study cohorts before enrollment into subsequent study cohorts. Informed consent was required for participation.There was at least a 2-week interval between administration of study agent to participants within each cohort and at least a 3-week interval between administration of study agent to the last participant in a cohort and the first participant in the next cohort.
    Background therapy
    		 N/A
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    01 Mar 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 9
    Worldwide total number of subjects
    9
    EEA total number of subjects
    0
    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)
    8
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were recruited from two clinical trial sites (University of Massachusetts Medical Center and Cincinnati Children's Hospital Medical Center).

    Pre-assignment
    Screening details
    		 Subjects were recruited from two clinical trial sites (University of Massachusetts Medical Center and Cincinnati Children's Hospital Medical Center).

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Low Dose
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    rAAV1-CB-hAAT
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    6 x 10e11 vg/kg administered as 10 IM injections distributed across a single muscle site

    Arm title
    		 Middle Dose
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    rAAV1-CB-hAAT
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1.9 x 10e12 vg/kg administered as 32 IM injections distributed across three muscle sites

    Arm title
    		 High Dose
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    rAAV1-CB-hAAT
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    6 x 10e12 vg/kg administered as 100 IM injections distributed across 10 muscle sites

    Number of subjects in period 1
    		Low Dose Middle Dose High Dose
    Started
    3
    3
    3
    Completed
    3
    3
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Low Dose
    Reporting group description
    		 -

    Reporting group title
    Middle Dose
    Reporting group description
    		 -

    Reporting group title
    High Dose
    Reporting group description
    		 -

    Reporting group values
    		 Low Dose Middle Dose High Dose Total
    Number of subjects
    		 3 3 3 9
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 2 3 3 8
        From 65-84 years
    		 1 0 0 1
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 50.3 ( 26.4 ) 48.7 ( 9.3 ) 54.3 ( 3.5 ) -
    Gender categorical
    Units: Subjects
        Female
    		 3 2 2 7
        Male
    		 0 1 1 2
    Alpha-1 antitrypsin phenotype
    Measure Description: Alpha-1 antitrypsin phenotype determined by isoelectric focusing gel electrophoresis
    Units: Subjects
        ZZ
    		 2 3 3 8
        SZ
    		 1 0 0 1
    Serum total alpha-1 antitrypsin concentration
    For serum total AAT, ANOVA showed that there was no significant effect of dose, no significant effect of change over time, and no significant interaction between dose and time
    Units: micromole(s)/litre
        arithmetic mean (standard deviation)
    		 6.65 ( 2.00 ) 3.54 ( 0.12 ) 3.45 ( 0.25 ) -

    End points

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    End points reporting groups
    Reporting group title
    Low Dose
    Reporting group description
    		 -

    Reporting group title
    Middle Dose
    Reporting group description
    		 -

    Reporting group title
    High Dose
    Reporting group description
    		 -

    Primary: Frequency of Grade 3 or 4 Adverse Events

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    End point title
    		 Frequency of Grade 3 or 4 Adverse Events [1]
    End point description
    Analysis based on all subjects enrolled in study
    End point type
    Primary
    End point timeframe
    During 1 year after study agent administration
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: N/A
    End point values
    		 Low Dose Middle Dose High Dose
    Number of subjects analysed
    3
    3
    3
    Units: Number of occurences
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Changes in Serum M-specific Alpha-1 Antitrypsin Concentration

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    End point title
    		 Changes in Serum M-specific Alpha-1 Antitrypsin Concentration
    End point description
    The change in serum M-specific alpha-1 antitrypsin concentration was calculated as the difference between the mean values at the screening and baseline visits and the mean values at the 6, 9 and 12 month visits. The standard error of the difference was calculated as the square root (s1^2/n1 + s2^2/n2), where s1 is the standard deviation of the baseline mean, s2 is the standard deviation of the month 6-12 mean, n1 is the number of baseline values and n2 is the number of month 6-12 values.
    End point type
    Secondary
    End point timeframe
    During months 6-12 after study agent administration.
    End point values
    		 Low Dose Middle Dose High Dose
    Number of subjects analysed
    2
    3
    3
    Units: nanomolar
        arithmetic mean (standard error)
    31.5 ( 7.56 )
    71.8 ( 22.73 )
    239.2 ( 27.57 )
    Statistical analysis title
    		 Serum M-specific AAT measures analysis of variance
    Statistical analysis description
    For serum M-specific AAT, ANOVA showed that there was a significant effect of dose, a significant change over time, and a significant interaction between dose and time
    Comparison groups
    Low Dose v Middle Dose v High Dose
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.0001
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Notes
    [2] - Vector-mediated expression of AAT was monitored using assays for M-specific AAT concentration measured by ELISA, total AAT concentration measured by nephelometry, and AAT phenotype measured by isoelectric focusing (IEF).

    Secondary: Changes in Serum Total Alpha-1 Antitrypsin Concentrations

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    End point title
    		 Changes in Serum Total Alpha-1 Antitrypsin Concentrations
    End point description
    The change in serum total alpha-1 antitrypsin concentration was calculated as the difference between the mean values at the screening and baseline visits and the mean values at the 6, 9 and 12 month visits. The standard error of the difference was calculated as square root (s1^2/n1 + s2^2/n2), where s1 is the standard deviation of the baseline mean, s2 is the standard deviation of the month 6-12 mean, n1 is the number of baseline values and n2 is the number of month 6-12 values.
    End point type
    Secondary
    End point timeframe
    During months 6-12 after study agent administration.
    End point values
    		 Low Dose Middle Dose High Dose
    Number of subjects analysed
    3
    3
    3
    Units: micromolar
        arithmetic mean (standard error)
    0.33 ( 1.14 )
    0.16 ( 0.10 )
    0.19 ( 0.16 )
    Statistical analysis title
    		 Serum total AAT measures analysis of variance
    Statistical analysis description
    For serum total AAT, ANOVA showed that there was no significant effect of dose, no significant effect of change over time, and no significant interaction between dose and time
    Comparison groups
    Middle Dose v High Dose v Low Dose
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1524
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    1 year
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.1
    Reporting groups
    Reporting group title
    Low Dose
    Reporting group description
    		 rAAV1-CB-hAAT at dosage level of 6 x 10e11 vg/kg administered as 10 IM injections distributed across a single muscle site

    Reporting group title
    Middle Dose
    Reporting group description
    		 rAAV1-CB-hAAT at dosage level of 1.9 x 10e12 vg/kg administered as 32 IM injections distributed across three muscle sites

    Reporting group title
    High Dose
    Reporting group description
    		 rAAV1-CB-hAAT at dosage level of 6 x 10e12 vg/kg administered as 100 IM injections distributed across 10 muscle sites

    Serious adverse events
    		 Low Dose Middle Dose High Dose
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Gastrointestinal disorders
    Diverticulitis
    Additional description: A 51 y/o man received high dose of study drug on 5 Oct 2010, diverticulitis diagnosed on 14 Mar 2011, admitted to hospital, treated with antibiotics and symptoms resolved. The adverse event was considered not related to study agent.
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Low Dose Middle Dose High Dose
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    Vascular disorders
    Ecchymosis
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    Phlebitis superficial
    Additional description: Because of small sample size, adverse events are listed only for (1) those considered possibly, probably or definitely related to study agent or study agent administration procedures, or (2) that occurred in more than 1 subject in the study.
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    Aortic aneurysm
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Postmastectomy lymphoedema syndrome
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    Injection site discomfort
    Additional description: Because of small sample size, adverse events are listed only for (1) those considered possibly, probably or definitely related to study agent or study agent administration procedures, or (2) that occurred in more than 1 subject in the study.
         subjects affected / exposed
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    2 / 3 (66.67%)
         occurrences all number
    2
    2
    2
    Influenza-like illness
    Additional description: Because of small sample size, adverse events are listed only for (1) those considered possibly, probably or definitely related to study agent or study agent administration procedures, or (2) that occurred in more than 1 subject in the study.
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Injection site atrophy
    Additional description: Because of small sample size, adverse events are listed only for (1) those considered possibly, probably or definitely related to study agent or study agent administration procedures, or (2) that occurred in more than 1 subject in the study.
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Injection site erythema
    Additional description: Because of small sample size, adverse events are listed only for (1) those considered possibly, probably or definitely related to study agent or study agent administration procedures, or (2) that occurred in more than 1 subject in the study.
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Injection site pain
    Additional description: Because of small sample size, adverse events are listed only for (1) those considered possibly, probably or definitely related to study agent or study agent administration procedures, or (2) that occurred in more than 1 subject in the study.
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Malaise
    Additional description: Because of small sample size, adverse events are listed only for (1) those considered possibly, probably or definitely related to study agent or study agent administration procedures, or (2) that occurred in more than 1 subject in the study.
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Post-procedural discomfort
    Additional description: Because of small sample size, adverse events are listed only for (1) those considered possibly, probably or definitely related to study agent or study agent administration procedures, or (2) that occurred in more than 1 subject in the study.
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
         occurrences all number
    2
    1
    1
    Injection site haemorrhage
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
         occurrences all number
    1
    3
    3
    Pyrexia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Dyspnoea exertional
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Lung neoplasm
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Sinus headache
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Throat irritation
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    Blood creatine phosphokinase increased
    Additional description: Because of small sample size, adverse events are listed only for (1) those considered possibly, probably or definitely related to study agent or study agent administration procedures, or (2) that occurred in more than 1 subject in the study. One othe
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    3 / 3 (100.00%)
         occurrences all number
    0
    1
    3
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Post procedural oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Post procedural haematoma
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Procedural pain
         subjects affected / exposed
    3 / 3 (100.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
         occurrences all number
    3
    1
    1
    Nervous system disorders
    Headache
    Additional description: Because of small sample size, adverse events are listed only for (1) those considered possibly, probably or definitely related to study agent or study agent administration procedures, or (2) that occurred in more than 1 subject in the study.
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    Anosmia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Hiatus hernia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Nausea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Furuncle
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Rash
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Rash erythematous
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Skin haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Urticaria
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
    Additional description: Because of small sample size, adverse events are listed only for (1) those considered possibly, probably or definitely related to study agent or study agent administration procedures, or (2) that occurred in more than 1 subject in the study.
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    Muscle strain
    Additional description: Because of small sample size, adverse events are listed only for (1) those considered possibly, probably or definitely related to study agent or study agent administration procedures, or (2) that occurred in more than 1 subject in the study.
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Muscle twitching
    Additional description: Because of small sample size, adverse events are listed only for (1) those considered possibly, probably or definitely related to study agent or study agent administration procedures, or (2) that occurred in more than 1 subject in the study.
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Back pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Bone lesion
    Additional description: Joint sprain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Limb discomfort
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Myalgia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Ear infection
    Additional description: Because of small sample size, adverse events are listed only for (1) those considered possibly, probably or definitely related to study agent or study agent administration procedures, or (2) that occurred in more than 1 subject in the study.
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    Upper respiratory infection
    Additional description: Because of small sample size, adverse events are listed only for (1) those considered possibly, probably or definitely related to study agent or study agent administration procedures, or (2) that occurred in more than 1 subject in the study.
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    2 / 3 (66.67%)
         occurrences all number
    0
    1
    2
    Bronchitis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Gingival abscess
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Oral candidiasis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Sinusitis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1

    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.
    Study results based on small number of subjects.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/21609134
    http://www.ncbi.nlm.nih.gov/pubmed/24231351
    http://www.ncbi.nlm.nih.gov/pubmed/19706466
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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