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    Clinical Trial Results:
    Efficacy of Switch to Lopinavir/Ritonavir in Improving Cognitive function in Efavirenz treated patients

    Summary
    EudraCT number
    2011-005581-37
    Trial protocol
    GB  
    Global end of trial date
    31 Dec 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    28 Jul 2016
    First version publication date
    06 Feb 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    5946
    Additional study identifiers
    ISRCTN number
    ISRCTN73411795
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    REC Reference: 12/NE/0071
    Sponsors
    Sponsor organisation name
    Newcastle Upon Tyne Hospitals NHS Foundation Trust
    Sponsor organisation address
    Regent Point, Regent Farm Road, Newcastle Upon Tyne, United Kingdom, NE3 3HD
    Public contact
    Dr Ashley Price, The Newcastle upon Tyne Hospitals NHS Foundation Trust, +44 01912823854, david.price@nuth.nhs.uk
    Scientific contact
    Dr Ashley Price, The Newcastle upon Tyne Hospitals NHS Foundation Trust, +44 01912823854, david.price@nuth.nhs.uk
    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
    27 Nov 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Dec 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To explore whether chronic Efavirenz therapy is associated with mild cognitive impairment, and if it is improved by switch to Kaletra after 10 weeks.
    Protection of trial subjects
    There were no specific measures put in place by the DMC to protect trial subjects. On the 4th of Oct 2013 the chief investigator updated the DMC committee with a protocol deviation where the lipid profile and glucose blood tests were stipulated in the current protocol to be performed routinely in clinic within 12 weeks of the screening visit, however as part of routine care lipid profile and glucose blood tests were only checked every 12 months. Ashley informed the DMC that the issue was discussed with Sponsor and the TSC and both had agreed to an amendment to the protocol to allow lipid profile and glucose blood results for screening visit as long as it was completed as per clinical guidelines within the previous 12 months. The Kaletra SmPC was also updated in this amendment. The serious breach was discussed with the DMC on the 28th of November 2014 and there was no further comments.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Nov 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: 16
    Worldwide total number of subjects
    16
    EEA total number of subjects
    16
    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)
    16
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A pilot phase IV open-label controlled trial in HIV-infected patients who had been on suppressive Efavirenz (EFV)-based Highly Active Anti-retroviral Therapy (HAART) for at least 6 months were observed at baseline + 10 weeks after a switch from EFV to Kaletra® (co-formulated lopinavir/ritonavir). To examine the effect of EFV on cognitive function.

    Pre-assignment
    Screening details
    Patients with illicit drug use or excessive alcohol use were excluded. Patients were also unselected with respect to the presence or absence of cognitive symptoms.

    Pre-assignment period milestones
    Number of subjects started
    16
    Number of subjects completed
    16

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

    Arms
    Arm title
    Switch from EFV to Kaletra® for 10 weeks
    Arm description
    Single arm
    Arm type
    Experimental

    Investigational medicinal product name
    Kaletra®
    Investigational medicinal product code
    21-903
    Other name
    co-formulated lopinavir/ritonavir
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400/100mg (2 tablets) every twelve hours. Kaletra was dispensed at study visit immediately prior to treatment switch. Participants were given clear instructions at this time on which date to stop EFV and start Kaletra. This date was no more than 2 weeks following the date of dispensing.

    Number of subjects in period 1
    Switch from EFV to Kaletra® for 10 weeks
    Started
    16
    Completed
    16

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    -

    Reporting group values
    Overall trial Total
    Number of subjects
    16 16
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    16 16
        From 65-84 years
    0 0
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    48.9 ± 9.7 -
    Gender categorical
    Units: Subjects
        Female
    3 3
        Male
    13 13
    Body Mass Index
    BMI was calculated for 12 of the 16 patients. Data was not available for 4 patients
    Units: kg/m2
        arithmetic mean (standard deviation)
    26.5 ± 3.5 -
    HIV-infected patients on HAART therapy (for at least 6 months)
    Time on Antiviral Therapy was calculated for 13 patients. Data was unavailable for 3 of the patients.
    Units: years
        arithmetic mean (standard deviation)
    5.2 ± 2.4 -
    HIV-infected patients on EFV therapy (for at least 6 months)
    Time on Antiviral Therapy was calculated for 13 patients. Data was not available for 3 of the 16 patients
    Units: Years
        arithmetic mean (standard deviation)
    5.3 ± 2.9 -
    Current CD4 Count
    Units: count
        arithmetic mean (standard deviation)
    650.6 ± 136.8 -
    EFV levels
    EFV levels was calculated for 12 patients. Data was not available for 4 of the 16 patients
    Units: ng/mL
        arithmetic mean (standard deviation)
    2950 ± 1948 -

    End points

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    End points reporting groups
    Reporting group title
    Switch from EFV to Kaletra® for 10 weeks
    Reporting group description
    Single arm

    Primary: Change in cognitive test scores- Detection (DET)

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    End point title
    Change in cognitive test scores- Detection (DET) [1]
    End point description
    Speed of performance; mean of the log10 transformed reaction times for correct responses. Data recorded at 2 visits and the change between the two measurements is the primary outcome. Lower score indicates better performance, change is defined as: Session 1 score – Session 2 score so that a positive change indicates improvement.
    End point type
    Primary
    End point timeframe
    10 weeks following switch from Efavirenz to Kaletra®
    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: Due to small numbers formal statistical analysis beyond presentation of summary statistics was not considered appropriate.
    End point values
    Switch from EFV to Kaletra® for 10 weeks
    Number of subjects analysed
    16
    Units: Log10milliseconds
        arithmetic mean (standard deviation)
    -0.03 ± 0.12
    No statistical analyses for this end point

    Primary: Change in cognitive test scores - Identification (IDN)

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    End point title
    Change in cognitive test scores - Identification (IDN) [2]
    End point description
    Speed of performance; mean of the log10 transformed reaction times for correct responses. Data recorded at 2 visits and the change between the two measurements is the primary outcome. Lower score indicates better performance, change is defined as: Session 1 score – Session 2 score so that a positive change indicates improvement.
    End point type
    Primary
    End point timeframe
    10 weeks following switch from Efavirenz to Kaletra®
    Notes
    [2] - 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: Due to small numbers formal statistical analysis beyond presentation of summary statistics was not considered appropriate.
    End point values
    Switch from EFV to Kaletra® for 10 weeks
    Number of subjects analysed
    16
    Units: Log10 milliseconds
        arithmetic mean (standard deviation)
    0.03 ± 0.09
    No statistical analyses for this end point

    Primary: Change in cognitive test scores - One card learning (OCL)

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    End point title
    Change in cognitive test scores - One card learning (OCL) [3]
    End point description
    Accuracy of performance; arcsine transformation of the square root of the proportion of correct responses. Data recorded at 2 visits and the change between the two measurements is the primary outcome. Higher score indicates better performance, change is defined as: Session 2 score – Session 1 score so that a positive change indicates improvement.
    End point type
    Primary
    End point timeframe
    10 weeks following switch from Efavirenz to Kaletra®
    Notes
    [3] - 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: Due to small numbers formal statistical analysis beyond presentation of summary statistics was not considered appropriate.
    End point values
    Switch from EFV to Kaletra® for 10 weeks
    Number of subjects analysed
    16
    Units: Arcsine proportion correct
        arithmetic mean (standard deviation)
    0.03 ± 0.07
    No statistical analyses for this end point

    Primary: Change in cognitive test scores - Working memory (ONB)

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    End point title
    Change in cognitive test scores - Working memory (ONB) [4]
    End point description
    Accuracy of performance; arcsine transformation of the square root of the proportion of correct responses. Data recorded at 2 visits and the change between the two measurements is the primary outcome. Higher score indicates better performance, change is defined as: Session 2 score – Session 1 score so that a positive change indicates improvement.
    End point type
    Primary
    End point timeframe
    10 weeks following switch from Efavirenz to Kaletra®
    Notes
    [4] - 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: Due to small numbers formal statistical analysis beyond presentation of summary statistics was not considered appropriate.
    End point values
    Switch from EFV to Kaletra® for 10 weeks
    Number of subjects analysed
    16
    Units: Arcsine proportion correct
        arithmetic mean (standard deviation)
    -0.001 ± 0.13
    No statistical analyses for this end point

    Primary: Change in cognitive test scores - Associate learning (CPAL)

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    End point title
    Change in cognitive test scores - Associate learning (CPAL) [5]
    End point description
    Accuracy of performance; total number of errors across five rounds. Data recorded at 2 visits and the change between the two measurements is the primary outcome. Lower score indicates better performance, change is defined as: Session 1 score – Session 2 score so that a positive change indicates improvement.
    End point type
    Primary
    End point timeframe
    10 weeks following switch from Efavirenz to Kaletra®
    Notes
    [5] - 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: Due to small numbers formal statistical analysis beyond presentation of summary statistics was not considered appropriate.
    End point values
    Switch from EFV to Kaletra® for 10 weeks
    Number of subjects analysed
    16
    Units: Total errors
        arithmetic mean (standard deviation)
    13.6 ± 43.9
    No statistical analyses for this end point

    Primary: Change in cognitive test scores - Executive function (GML)

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    End point title
    Change in cognitive test scores - Executive function (GML) [6]
    End point description
    Total number of errors made in attempting to learn the same hidden pathway on five consecutive trials at a single session. Data recorded at 2 visits and the change between the two measurements is the primary outcome. Lower score indicates better performance, change is defined as: Session 1 score – Session 2 score so that a positive change indicates improvement.
    End point type
    Primary
    End point timeframe
    10 weeks following switch from Efavirenz to Kaletra®
    Notes
    [6] - 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: Due to small numbers formal statistical analysis beyond presentation of summary statistics was not considered appropriate.
    End point values
    Switch from EFV to Kaletra® for 10 weeks
    Number of subjects analysed
    16
    Units: Total errors
        arithmetic mean (standard deviation)
    2.9 ± 12.2
    No statistical analyses for this end point

    Secondary: Cerebral metabolite profile (magnetic resonance spectroscopy) – Grey matter – Choline to Creatine ratio (Cho/Cre)

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    End point title
    Cerebral metabolite profile (magnetic resonance spectroscopy) – Grey matter – Choline to Creatine ratio (Cho/Cre)
    End point description
    MRS data will measure cerebral metabolites, each of which will be expressed as a ratio to creatine (Cre) to increase inter-scan standardisation. Cho (choline) is a measure of cell turnover and inflammation. It has been reported to be increased in HIV-associated cognitive impairment, and often is increased where NAA is decreased. Single voxel measurement gives the lowest coefficient of variance (CoV) on the measure and hence can detect smallest changes. Raw MRS data will first be registered against a standard model from which the metabolite concentrations will be derived. Change is defined so that an increase from Visit 1 to Visit 3 is positive.
    End point type
    Secondary
    End point timeframe
    Baseline visit (week 1) – each participant had MRI scan to obtain baseline Cerebral metabolite profile (magnetic resonance spectroscopy) and functional Magnetic resonance imaging (fMRI) results. Visit 3 (week 13) - each participant again had MRI scan to
    End point values
    Switch from EFV to Kaletra® for 10 weeks
    Number of subjects analysed
    14 [7]
    Units: ratio
        arithmetic mean (standard deviation)
    0.01 ± 0.03
    Notes
    [7] - Missing data from 2 patients
    No statistical analyses for this end point

    Secondary: Cerebral metabolite profile (magnetic resonance spectroscopy) – Grey matter – N-acetylaspartate to Creatine ratio (NAA/Cre)

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    End point title
    Cerebral metabolite profile (magnetic resonance spectroscopy) – Grey matter – N-acetylaspartate to Creatine ratio (NAA/Cre)
    End point description
    MRS data will measure cerebral metabolites, each of which will be expressed as a ratio to creatine (Cre) to increase inter-scan standardisation. NAA (N-acetylaspartate) is a measure of neuronal integrity / viability. Previous MRS studies suggest that NAA in frontal brain areas may be decreased in HIV infection and associated with cognitive dysfunction. Single voxel measurement gives the lowest coefficient of variance (CoV) on the measure and hence can detect smallest changes. Raw MRS data will first be registered against a standard model from which the metabolite concentrations will be derived. Change is defined so that an increase from Visit 1 to Visit 3 is positive.
    End point type
    Secondary
    End point timeframe
    Baseline visit (week 1) – each participant had MRI scan to obtain baseline Cerebral metabolite profile (magnetic resonance spectroscopy) and functional Magnetic resonance imaging (fMRI) results. Visit 3 (week 13) - each participant again had MRI scan to
    End point values
    Switch from EFV to Kaletra® for 10 weeks
    Number of subjects analysed
    14 [8]
    Units: ratio
        arithmetic mean (standard deviation)
    0.16 ± 0.49
    Notes
    [8] - missing data for 2 patients
    No statistical analyses for this end point

    Secondary: Cerebral metabolite profile (magnetic resonance spectroscopy) – White matter – Choline to Creatine ratio (Cho/Cre)

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    End point title
    Cerebral metabolite profile (magnetic resonance spectroscopy) – White matter – Choline to Creatine ratio (Cho/Cre)
    End point description
    MRS data will measure cerebral metabolites, each of which will be expressed as a ratio to creatine (Cre) to increase inter-scan standardisation. Cho (choline) is a measure of cell turnover and inflammation. It has been reported to be increased in HIV-associated cognitive impairment, and often is increased where NAA is decreased. Single voxel measurement gives the lowest coefficient of variance (CoV) on the measure and hence can detect smallest changes. Raw MRS data will first be registered against a standard model from which the metabolite concentrations will be derived. Change is defined so that an increase from Visit 1 to Visit 3 is positive.
    End point type
    Secondary
    End point timeframe
    Baseline visit (week 1) – each participant had MRI scan to obtain baseline Cerebral metabolite profile (magnetic resonance spectroscopy) and functional Magnetic resonance imaging (fMRI) results. Visit 3 (week 13) - each participant again had MRI scan to
    End point values
    Switch from EFV to Kaletra® for 10 weeks
    Number of subjects analysed
    11 [9]
    Units: ratio
        arithmetic mean (standard deviation)
    0.03 ± 0.08
    Notes
    [9] - Missing data for 5 patients
    No statistical analyses for this end point

    Secondary: Cerebral metabolite profile (magnetic resonance spectroscopy) – White matter – N-acetylaspartate to Creatine ratio (NAA/Cre)

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    End point title
    Cerebral metabolite profile (magnetic resonance spectroscopy) – White matter – N-acetylaspartate to Creatine ratio (NAA/Cre)
    End point description
    MRS data will measure cerebral metabolites, each of which will be expressed as a ratio to creatine (Cre) to increase inter-scan standardisation. NAA (N-acetylaspartate) is a measure of neuronal integrity / viability. Previous MRS studies suggest that NAA in frontal brain areas may be decreased in HIV infection and associated with cognitive dysfunction. Single voxel measurement gives the lowest coefficient of variance (CoV) on the measure and hence can detect smallest changes. Raw MRS data will first be registered against a standard model from which the metabolite concentrations will be derived. Change is defined so that an increase from Visit 1 to Visit 3 is positive.
    End point type
    Secondary
    End point timeframe
    Baseline visit – each participant had MRI scan to obtain baseline Cerebral metabolite profile + fMRI results. Visit 3 (week 13) - each participant again had MRI scan to obtain Cerebral metabolite profile and fMRI results.
    End point values
    Switch from EFV to Kaletra® for 10 weeks
    Number of subjects analysed
    11 [10]
    Units: ratio
        arithmetic mean (standard deviation)
    0.11 ± 0.34
    Notes
    [10] - Missing data from 5 patients
    No statistical analyses for this end point

    Secondary: Cerebral metabolite profile (magnetic resonance spectroscopy) – Basal Ganglia – N-acetylaspartate to Creatine ratio (NAA/Cre)

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    End point title
    Cerebral metabolite profile (magnetic resonance spectroscopy) – Basal Ganglia – N-acetylaspartate to Creatine ratio (NAA/Cre)
    End point description
    MRS data will measure cerebral metabolites, each of which will be expressed as a ratio to creatine (Cre) to increase inter-scan standardisation. NAA (N-acetylaspartate) is a measure of neuronal integrity / viability. Previous MRS studies suggest that NAA in frontal brain areas may be decreased in HIV infection and associated with cognitive dysfunction. Single voxel measurement gives the lowest coefficient of variance (CoV) on the measure and hence can detect smallest changes. Raw MRS data will first be registered against a standard model from which the metabolite concentrations will be derived. Change is defined so that an increase from Visit 1 to Visit 3 is positive.
    End point type
    Secondary
    End point timeframe
    Baseline visit (week 1) – each participant had MRI scan to obtain baseline Cerebral metabolite profile and fMRI results. Visit 3 (week 13) - each participant again had MRI scan to obtain Cerebral metabolite profile and fMRI results.
    End point values
    Switch from EFV to Kaletra® for 10 weeks
    Number of subjects analysed
    8 [11]
    Units: ratio
        arithmetic mean (standard deviation)
    0.03 ± 0.42
    Notes
    [11] - Missing data from 8 patients
    No statistical analyses for this end point

    Secondary: Cerebral metabolite profile (magnetic resonance spectroscopy) – Basal Ganglia – Choline to Creatine ratio (Cho/Cre)

    Close Top of page
    End point title
    Cerebral metabolite profile (magnetic resonance spectroscopy) – Basal Ganglia – Choline to Creatine ratio (Cho/Cre)
    End point description
    MRS data will measure cerebral metabolites, each of which will be expressed as a ratio to creatine (Cre) to increase inter-scan standardisation. Cho (choline) is a measure of cell turnover and inflammation. It has been reported to be increased in HIV-associated cognitive impairment, and often is increased where NAA is decreased. Single voxel measurement gives the lowest coefficient of variance (CoV) on the measure and hence can detect smallest changes. Raw MRS data will first be registered against a standard model from which the metabolite concentrations will be derived. Change is defined so that an increase from Visit 1 to Visit 3 is positive.
    End point type
    Secondary
    End point timeframe
    Baseline visit (week 1) – each participant had MRI scan to obtain baseline Cerebral metabolite profile and fMRI results. Visit 3 (week 13) - MRI scan to obtain Cerebral metabolite profile and fMRI results.
    End point values
    Switch from EFV to Kaletra® for 10 weeks
    Number of subjects analysed
    8 [12]
    Units: ratio
        arithmetic mean (standard deviation)
    0.04 ± 0.07
    Notes
    [12] - Missing data for 8 patients
    No statistical analyses for this end point

    Secondary: Sleep Quality - Sleep questionnaire (Epworth Sleepiness Scale [ESS])

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    End point title
    Sleep Quality - Sleep questionnaire (Epworth Sleepiness Scale [ESS])
    End point description
    Change (increase) between week 1 and week 13 scores
    End point type
    Secondary
    End point timeframe
    Questionnaire completed at baseline visit (week 1) and again at visit 3 (week 13).
    End point values
    Switch from EFV to Kaletra® for 10 weeks
    Number of subjects analysed
    16
    Units: Change between 2 scores
        arithmetic mean (standard deviation)
    -0.9 ± 3.4
    No statistical analyses for this end point

    Secondary: Sleep Quality - Pittsburgh Sleep Quality Index [PSQI]

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    End point title
    Sleep Quality - Pittsburgh Sleep Quality Index [PSQI]
    End point description
    Change (increase) between week 1 and week 13 scores
    End point type
    Secondary
    End point timeframe
    Questionnaire completed at baseline visit (week 1) and again at visit 3 (week 13).
    End point values
    Switch from EFV to Kaletra® for 10 weeks
    Number of subjects analysed
    14 [13]
    Units: Change between 2 scores
        arithmetic mean (standard deviation)
    -3.4 ± 4.7
    Notes
    [13] - Missing data from 2 patients
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from first visit until final visit
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    As reported
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Rhinitis
    Reporting group description
    Please note the pdf generated from EudraCT is incorrect. 16 patients were exposed but only 1 patient reported Rhinitis.

    Reporting group title
    Weight gain to face and abdomen
    Reporting group description
    -

    Reporting group title
    Increase in viral load to 69 copies/ml
    Reporting group description
    -

    Reporting group title
    Increase in viral loads to 107 copies
    Reporting group description
    -

    Reporting group title
    Abdominal bloating
    Reporting group description
    -

    Reporting group title
    Abdominal dicomfort/wind
    Reporting group description
    -

    Reporting group title
    Abdominal cramps
    Reporting group description
    -

    Reporting group title
    Increased fatigue
    Reporting group description
    -

    Reporting group title
    Worsening low mood
    Reporting group description
    -

    Reporting group title
    Under dose of Kaletra
    Reporting group description
    -

    Reporting group title
    Inflamed throat
    Reporting group description
    -

    Reporting group title
    Sore throat
    Reporting group description
    -

    Reporting group title
    Pains in both hands
    Reporting group description
    -

    Reporting group title
    Muscular pain
    Reporting group description
    Night time cramp in left thigh

    Reporting group title
    Muscle pains in thighs and hands
    Reporting group description
    -

    Reporting group title
    Pain in abdomen and secondary to flatulence
    Reporting group description
    -

    Reporting group title
    Aches and pains in legs
    Reporting group description
    -

    Reporting group title
    Upper left Shoulder pain
    Reporting group description
    -

    Reporting group title
    Lower right back pain
    Reporting group description
    -

    Reporting group title
    Night sweats
    Reporting group description
    -

    Reporting group title
    Decreased sleep due to restlessness
    Reporting group description
    -

    Reporting group title
    Infected spots on face
    Reporting group description
    -

    Reporting group title
    Vomiting
    Reporting group description
    -

    Reporting group title
    Dry Cough
    Reporting group description
    -

    Reporting group title
    Hay fever
    Reporting group description
    -

    Reporting group title
    Upper respiratory tract infection
    Reporting group description
    -

    Reporting group title
    Productive Cough
    Reporting group description
    -

    Reporting group title
    Stomach Cramp
    Reporting group description
    -

    Reporting group title
    Oral trush
    Reporting group description
    -

    Reporting group title
    Tiredness increased
    Reporting group description
    -

    Reporting group title
    Headache
    Reporting group description
    -

    Reporting group title
    Loss of appetite
    Reporting group description
    -

    Reporting group title
    Flatulence
    Reporting group description
    -

    Reporting group title
    Nausea (when having flatulence)
    Reporting group description
    -

    Reporting group title
    Loose stool
    Reporting group description
    -

    Reporting group title
    Dizzyness/light-headedness
    Reporting group description
    -

    Reporting group title
    Increased triglycerides
    Reporting group description
    -

    Reporting group title
    Ring worm
    Reporting group description
    Rash on chest ring worm suspected

    Reporting group title
    Ring worm
    Reporting group description
    Rash on chest not diagnosed

    Reporting group title
    Nocturnal enuresis
    Reporting group description
    -

    Reporting group title
    Nausea
    Reporting group description
    -

    Reporting group title
    Tooth extraction
    Reporting group description
    -

    Reporting group title
    Itching to upper body
    Reporting group description
    -

    Reporting group title
    Swollen hands and feet (mild)
    Reporting group description
    -

    Reporting group title
    Dental Abcess
    Reporting group description
    -

    Reporting group title
    On specific viral infection
    Reporting group description
    -

    Reporting group title
    Cramp in left toe
    Reporting group description
    -

    Reporting group title
    Under dose of study medication
    Reporting group description
    -

    Reporting group title
    Aches in legs
    Reporting group description
    -

    Reporting group title
    Numbness in arms
    Reporting group description
    -

    Reporting group title
    Diarrohea
    Reporting group description
    -

    Serious adverse events
    Rhinitis Weight gain to face and abdomen Increase in viral load to 69 copies/ml Increase in viral loads to 107 copies Abdominal bloating Abdominal dicomfort/wind Abdominal cramps Increased fatigue Worsening low mood Under dose of Kaletra Inflamed throat Sore throat Pains in both hands Muscular pain Muscle pains in thighs and hands Pain in abdomen and secondary to flatulence Aches and pains in legs Upper left Shoulder pain Lower right back pain Night sweats Decreased sleep due to restlessness Infected spots on face Vomiting Dry Cough Hay fever Upper respiratory tract infection Productive Cough Stomach Cramp Oral trush Tiredness increased Headache Loss of appetite Flatulence Nausea (when having flatulence) Loose stool Dizzyness/light-headedness Increased triglycerides Ring worm Ring worm Nocturnal enuresis Nausea Tooth extraction Itching to upper body Swollen hands and feet (mild) Dental Abcess On specific viral infection Cramp in left toe Under dose of study medication Aches in legs Numbness in arms Diarrohea
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 1 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Rhinitis Weight gain to face and abdomen Increase in viral load to 69 copies/ml Increase in viral loads to 107 copies Abdominal bloating Abdominal dicomfort/wind Abdominal cramps Increased fatigue Worsening low mood Under dose of Kaletra Inflamed throat Sore throat Pains in both hands Muscular pain Muscle pains in thighs and hands Pain in abdomen and secondary to flatulence Aches and pains in legs Upper left Shoulder pain Lower right back pain Night sweats Decreased sleep due to restlessness Infected spots on face Vomiting Dry Cough Hay fever Upper respiratory tract infection Productive Cough Stomach Cramp Oral trush Tiredness increased Headache Loss of appetite Flatulence Nausea (when having flatulence) Loose stool Dizzyness/light-headedness Increased triglycerides Ring worm Ring worm Nocturnal enuresis Nausea Tooth extraction Itching to upper body Swollen hands and feet (mild) Dental Abcess On specific viral infection Cramp in left toe Under dose of study medication Aches in legs Numbness in arms Diarrohea
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    5 / 16 (31.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    3 / 16 (18.75%)
    2 / 16 (12.50%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    3 / 16 (18.75%)
    1 / 16 (6.25%)
    3 / 16 (18.75%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    3 / 16 (18.75%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 1 (100.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    13 / 16 (81.25%)
    General disorders and administration site conditions
    General disorders
         subjects affected / exposed [1]
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    5 / 5 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    3 / 3 (100.00%)
    2 / 2 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    3 / 3 (100.00%)
    1 / 1 (100.00%)
    3 / 3 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    3 / 3 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    1 / 1 (100.00%)
    13 / 13 (100.00%)
         occurrences all number
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    1
    16
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The pdf created by EudracT gives unrepresentative information when numbers exposed under the general disorders is displayed.

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Aug 2012
    The MHRA issued a Notice of Ground of Non-acceptance and Right to Amend Request letter dated 20th July 2012. The following medical points were raised, and were addressed in our response letter to MHRA dated 31st July 2012. Notice of Acceptance of Amended Request for a Clinical Trial Authorisation was granted on 06 August 2012. We have listed our responses, point by point below Point 1 - The Sponsor is required to enter the prohibited medications and medication not recommended to be co-administrated with efavirenz or Kaletra, as per respective SmPCs, in the exclusion criteria and in the list of prohibited medications during the trial. We have made changes to Section 10.2 Exclusion criteria and Section 12.3 Concomitant medication of the protocol as requested. Point 2 - The Sponsor is required to add breastfeeding to the exclusion criteria, in accordance with the SmPCs of efavirenz and lopinavir. We have added this information to the protocol as requested. Point 3 – the Sponsor is required to follow the SmPC of efavirenz and define the contraceptive methods and duration for both genders. We have made changes to Section 19.5 of the protocol as requested and agreed by Dr Steinberg MHRA. In addition to this we have changed the sub heading to ‘Pregnancy and fertility’ to further clarify this point Point 4 - The Sponsor is required to discontinue Kaletra if a diagnosis of pancreatitis is made during the trial. We have added this information to Section 17.2 Withdrawal of participants of the protocol as requested. Point 5 - The Sponsor must specify that patients who become pregnant during the trial whilst taking efavirenz must discontinue the efavirenz. We have made changes to Section 19.5 Pregnancy and fertility of the protocol as requested and agreed by Dr Steinberg MHRA. These changes are consistent with the BHIVA 2012 Guidelines for the management of HIV infection in pregnant women. In addition to this, we have added further information regarding pat
    24 Oct 2013
    A listed summary of changes is as follows: 1) Change to the protocol section 10.1 Inclusion criteria to delete the first paragraph as it is repeated with the second paragraph. 2) Changes to the protocol section 10.2 Exclusion criteria and 12.3 Concomitant medication to add Rivaroxaban to reflect the Kaletra SmPC update on 19 September 2012. 3) Additional paragraph is added to the protocol section 11.1 Identification and screening of participants to allow the study adding additional Participant Identification Centres (PICs) if the recruitment rate is low. 4) Change to the protocol section 15.1 schedule of events and second paragraph of Explanatory notes on table of events (page 30), screening visit, glucose and lipids blood results time limit to 12 months instead of 12 weeks from the screening visit. This is to bring it in line with the current clinical practice and British HIV Association Guidelines “Routine investigation and monitoring of adult HIV-1-infected individuals (2011). Section: 18.4.1 Recommendations for assessment and monitoring of lipid profile”. Please see attached a copy of the BHIV guidelines for your information. 5) Additional paragraph is added to the protocol section 19.2 Expected adverse reactions to cover the commonest anticipated adverse drug reaction – diarrhoea and suggest routine clinical treatment (Loperamide 2mg as needed). 6) Change to the protocol appendix 1 Summary of Product Characteristics for Kaletra as Kaletra SmPC has been updated on 21 May 2013 on electronic Medicines Compendium (eMC) website. (Kaletra SmPC had been updated three times since the study was granted the REC favourable opinion and MHRA Clinical Trial Authorisation. SmPC dated 21 May 2013 is the most updated version.) 7) Change to the protocol appendix 6 Study poster as a result of feedback from the lay representative for the study. 8) The protocol has been updated to reflect the Marketing Authorisation transfer approval from Abbott Labora

    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.
    17 were recruited, 16 were eligible. Due to an error 1 patient received monotherapy for 4 weeks but was well on follow up. Viral load was not affected. A Serious breach was reported to the MHRA+REC, sponsor identified no other patients were affected.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    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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