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    Clinical Trial Results:
    BREATHER (PENTA 16): Short-cycle therapy (SCT) (5 days on/ 2 days off) in young people with chronic HIV-infection

    Summary
    EudraCT number
    		 2009-012947-40
    Trial protocol
    		 IE   GB   ES   DK   BE   DE  
    Global end of trial date
    31 Jul 2014

    Results information
    Results version number
    		 v2(current)
    This version publication date
    16 May 2019
    First version publication date
    04 Feb 2017
    Other versions
    		 v1
    Version creation reason
    • Changes to summary attachments
    The results posted to EudraCT for the BREATHER trial were reviewed by the senior statistician on the trial and as a result changes were required to be made.

    Trial information

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    Trial identification
    Sponsor protocol code
    PENTA16
    Additional study identifiers
    ISRCTN number
    		 ISRCTN97755073
    US NCT number
    		 NCT01641016
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    The PENTA foundation
    Sponsor organisation address
    Torre della Ricerca Pediatrica Corso Stati Uniti 4, Padova, Italy, 35127
    Public contact
    University College London, University College London, penta.mrcctu@ucl.ac.uk
    Scientific contact
    University College London, University College London, penta.mrcctu@ucl.ac.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
    31 Jul 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Jul 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jul 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The overall aim of the BREATHER trial is to evaluate the role of Short-Cycle Therapy (SCT) in the management of HIV-infected young people who have responded well to antiretroviral therapy (ART) and to determine whether young people with chronic HIV infection undergoing Short-Cycle Therapy of five days on ART and two days off maintain the same level of viral load suppression as those on continuous therapy, over 48 weeks.
    Protection of trial subjects
    In order to assess the safety of the SCT strategy, a pilot study was carried out in 32 young people, who were seen on the Monday morning following having Saturday and Sunday off treatment. Their viral loads were assessed on this visit and the main trial did not commense until the IDMC had confirmed they had no saftey concerns as a result of the pilot phase.
    Background therapy
    		 Every young person was on a first-line HAART regimen containing at least 2 NRTI/NtRTIs and EFV.
    Evidence for comparator
    		 Current WHO guidelines recommend a first-line ART regimen containing 2 NRTI/NtRTIs and EFV for treatment of HIV in children.
    Actual start date of recruitment
    01 Apr 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Scientific research
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    United Kingdom: 26
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Ireland: 3
    Country: Number of subjects enrolled
    Thailand: 36
    Country: Number of subjects enrolled
    Argentina: 11
    Country: Number of subjects enrolled
    United States: 14
    Country: Number of subjects enrolled
    Uganda: 70
    Country: Number of subjects enrolled
    Ukraine: 20
    Worldwide total number of subjects
    199
    EEA total number of subjects
    48
    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)
    53
    Adolescents (12-17 years)
    104
    Adults (18-64 years)
    42
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 225 [1]
    Number of subjects completed
    		 199

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 3
    Reason: Number of subjects
    		 Protocol deviation: 21
    Reason: Number of subjects
    		 Car crash prevented them making randomsation visit: 1
    Reason: Number of subjects
    		 Unreliable attendance: 1
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 225 young people were screened, but 199 randomised. Reasons for not randomising are documented here.
    Period 1
    Period 1 title
    Main trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Continuous therapy
    Arm description
    		 Patients randomised to continuing their ART strategy, taking ART every day.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Short Cycle Therapy
    Arm description
    		 Patients take their ART as normal for 5 days a week, with a break at the weekends, taking no ART for 2 days every week. The only product entered here is Efavirenz, as all young people in the trial were on Efavirenz. However, it is not the drug that is being investigated in this trial, it is the strategy by which the ART regimen is taken.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Efavirenz
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dosed as perscribed by the clinician.

    Number of subjects in period 1
    		Continuous therapy Short Cycle Therapy
    Started
    100
    99
    Completed
    99
    99
    Not completed
    1
    0
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Continuous therapy
    Reporting group description
    		 Patients randomised to continuing their ART strategy, taking ART every day.

    Reporting group title
    Short Cycle Therapy
    Reporting group description
    		 Patients take their ART as normal for 5 days a week, with a break at the weekends, taking no ART for 2 days every week. The only product entered here is Efavirenz, as all young people in the trial were on Efavirenz. However, it is not the drug that is being investigated in this trial, it is the strategy by which the ART regimen is taken.

    Reporting group values
    		 Continuous therapy Short Cycle Therapy Total
    Number of subjects
    		 100 99 199
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 25 28 53
        Adolescents (12-17 years)
    		 55 49 104
        Adults (18-64 years)
    		 20 22 42
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 14.4 (12 to 17.5) 13.7 (11.7 to 17.7) -
    Gender categorical
    Units: Subjects
        Female
    		 52 42 94
        Male
    		 48 57 105
    Route of infection
    Mode of transmission of HIV
    Units: Subjects
        Vertical
    		 90 90 180
        Sexual contact
    		 7 7 14
        Blood product
    		 2 1 3
        Unknown
    		 1 1 2
    Ethnic origin
    Ethnicity
    Units: Subjects
        White
    		 17 24 41
        Black
    		 54 58 112
        Mixed black/white
    		 4 0 4
        Asian
    		 22 15 37
        Other
    		 3 2 5
    CDC stage
    CDC stage event at randomisation
    Units: Subjects
        Stage N
    		 10 16 26
        Stage A
    		 25 25 50
        Stage B
    		 43 45 88
        Stage C
    		 21 13 34
        Missing
    		 1 0 1
    Classes of drugs exposed to
    Classes of drugs exposed to by randomisation
    Units: Subjects
        NRTIs, NNRTIs and PIs
    		 12 17 29
        NRTIs and NNRTIs only
    		 88 82 170
    Baseline regimen first regimen
    Is the baseline regimen their first ART regimen?
    Units: Subjects
        Yes
    		 42 40 82
        No
    		 58 59 117
    Young person questionnaire - how will taking weekends off make things for you?
    Question from acceptability questionnaire answerred by the young person.
    Units: Subjects
        A lot easier
    		 0 50 50
        A little easier
    		 0 20 20
        No difference
    		 0 8 8
        A little more difficult
    		 0 2 2
        A lot more difficult
    		 0 0 0
        Question not answerred
    		 100 19 119
    Carer questionnaire - how will stopping meds at weekend make things for the young person?
    Question from acceptability questionnaire answered by the carer.
    Units: Subjects
        A lot easier
    		 0 45 45
        A little easier
    		 0 16 16
        No difference
    		 0 7 7
        A little more difficult
    		 0 4 4
        A lot more difficult
    		 0 1 1
        Question not answered
    		 100 26 126
    Weight
    Weight at randomisation
    Units: kilogram(s)
        median (inter-quartile range (Q1-Q3))
    		 45.1 (33.9 to 55.7) 45.5 (33.1 to 56.2) -
    CD4%
    Mean of CD4% from screening and randomisation visit.
    Units: percent
        median (inter-quartile range (Q1-Q3))
    		 34 (29.5 to 38.1) 34.5 (29.3 to 39) -
    Absolute CD4 count
    Mean of CD4 count from screening and randomisation visit.
    Units: cells/microlitre
        median (inter-quartile range (Q1-Q3))
    		 747.3 (575.3 to 972.8) 722.5 (581 to 965) -
    Creatinine
    Creatinine at randomisation
    Units: milligram(s)/decilitre
        median (inter-quartile range (Q1-Q3))
    		 0.6 (0.5 to 0.7) 0.5 (0.4 to 0.7) -
    Total bilirubin
    Total bilirubin at randomisation
    Units: milligram(s)/decilitre
        median (inter-quartile range (Q1-Q3))
    		 0.3 (0.2 to 0.4) 0.2 (0.2 to 0.3) -
    Alkaline phosphatase
    Alkaline phosphatase at randomisation
    Units: milligram(s)/decilitre
        median (inter-quartile range (Q1-Q3))
    		 224 (130 to 320) 260.5 (136 to 347) -
    Aspartate transaminase
    Aspartate transaminase at randomisation
    Units: unit(s)/litre
        median (inter-quartile range (Q1-Q3))
    		 25 (20 to 30) 25 (19 to 34) -
    Alanine transaminase
    Alanine transaminase at randomisation
    Units: unit(s)/litre
        median (inter-quartile range (Q1-Q3))
    		 17.5 (14 to 25) 18 (12 to 26) -
    Glucose
    Glucose at randomisation
    Units: milligram(s)/decilitre
        median (inter-quartile range (Q1-Q3))
    		 86.5 (81.5 to 90.9) 86.4 (82.9 to 91.9) -
    Triglycerides
    Triglycerides at randomisation
    Units: milligram(s)/decilitre
        median (inter-quartile range (Q1-Q3))
    		 81 (61.7 to 121) 74.8 (54.8 to 102.7) -
    LDL Cholesterol
    LDL Cholesterol at randomisation
    Units: milligram(s)/decilitre
        median (inter-quartile range (Q1-Q3))
    		 85.6 (76 to 108) 89 (78.1 to 107.4) -
    HDL Cholesterol
    HDL Cholesterol at randomisation
    Units: milligram(s)/decilitre
        median (inter-quartile range (Q1-Q3))
    		 54.9 (46.3 to 68.2) 51 (42.5 to 62) -
    Total cholesterol
    Total cholesterol at randomisation
    Units: milligram(s)/decilitre
        median (inter-quartile range (Q1-Q3))
    		 164.1 (147.3 to 181.5) 158.2 (142.9 to 181) -
    Haemoglobin
    Haemoglobin at randomisation
    Units: gram(s)/decilitre
        median (inter-quartile range (Q1-Q3))
    		 13.2 (12.3 to 14.2) 13.2 (12.2 to 14) -
    MCV
    MCV at randomisation
    Units: femtolitres
        median (inter-quartile range (Q1-Q3))
    		 92 (86 to 100.5) 94 (87.3 to 100.5) -
    White cell count
    White cell count at randomisation
    Units: /litre
        median (inter-quartile range (Q1-Q3))
    		 5 (4 to 6.3) 4.6 (3.9 to 6) -
    Lymphocytes
    Lymphocytes at randomisation
    Units: /litre
        median (inter-quartile range (Q1-Q3))
    		 2.2 (1.7 to 2.9) 2.2 (1.7 to 2.6) -
    Neutrophils
    Neutrophils at randomisation
    Units: /litre
        median (inter-quartile range (Q1-Q3))
    		 1.9 (1.2 to 3.4) 1.9 (1.4 to 2.9) -
    Platelets
    Platelet count at randomisation
    Units: /litre
        median (inter-quartile range (Q1-Q3))
    		 292.5 (247.5 to 352.5) 293 (244 to 352) -

    End points

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    End points reporting groups
    Reporting group title
    Continuous therapy
    Reporting group description
    		 Patients randomised to continuing their ART strategy, taking ART every day.

    Reporting group title
    Short Cycle Therapy
    Reporting group description
    		 Patients take their ART as normal for 5 days a week, with a break at the weekends, taking no ART for 2 days every week. The only product entered here is Efavirenz, as all young people in the trial were on Efavirenz. However, it is not the drug that is being investigated in this trial, it is the strategy by which the ART regimen is taken.

    Primary: Virological failure (>=50c/ml confirmed).

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    End point title
    		 Virological failure (>=50c/ml confirmed).
    End point description
    The primary endpoint was a confirmed viral load >=50c/ml within 54 weeks of randomisation.
    End point type
    Primary
    End point timeframe
    Any time from randomisation to 48(+6) weeks after randomisation.
    End point values
    		 Continuous therapy Short Cycle Therapy
    Number of subjects analysed
    100
    99
    Units: People
        Reached endpoint
    7
    6
        Did not reach endpoint
    93
    93
    Statistical analysis title
    		 Primary analysis - diff in adj. KM estimates
    Statistical analysis description
    Difference in adjusted (for stratification factors) Kaplan-Meier survival function estimates at 54 weeks after randomisation.
    Comparison groups
    Continuous therapy v Short Cycle Therapy
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.012
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.073
         upper limit
    		 0.049
    Notes
    [1] - Non-inferiority margin = 12%. Calculated SCT arm survival function - CT arm survival function, so if the upper bound of the 90% confidence interval was <0.12, the results were consistent with non-inferiority of SCT compared with CT.
    Statistical analysis title
    		 Secondary analysis - unadjusted diff
    Statistical analysis description
    Difference in Kaplan-Meier survival function estimates at 54 weeks after randomisation.
    Comparison groups
    Short Cycle Therapy v Continuous therapy
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.011
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.068
         upper limit
    		 0.046
    Notes
    [2] - Non-inferiority margin = 12%. Calculated SCT arm survival function - CT arm survival function, so if the upper bound of the 90% confidence interval was <0.12, the results were consistent with non-inferiority of SCT compared with CT.
    Statistical analysis title
    		 Secondary analysis - crude diff
    Statistical analysis description
    Difference in proportion of YP with confirmed VL>=50c/ml.
    Comparison groups
    Short Cycle Therapy v Continuous therapy
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.009
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.067
         upper limit
    		 0.048
    Notes
    [3] - Non-inferiority margin = 12%. Calculated proportion of YP with virological failure in the SCT arm - proportion of YP with virological failure in the CT arm, so if the upper bound of the 90% confidence interval was <0.12, the results were consistent with non-inferiority of SCT compared with CT.
    Statistical analysis title
    		 Secondary analysis - unadj. Cox model
    Statistical analysis description
    Cox model examining time to confirmed viral load >=50c/ml
    Comparison groups
    Continuous therapy v Short Cycle Therapy
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.755 [4]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.34
         upper limit
    		 2.1
    Notes
    [4] - Non-significant difference between arms.
    Statistical analysis title
    		 Secondary analysis - adj. Cox model
    Statistical analysis description
    Cox model examining time to confirmed viral load >=50c/ml, adjusting for stratification factors.
    Comparison groups
    Short Cycle Therapy v Continuous therapy
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.743 [5]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.83
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.33
         upper limit
    		 2.08
    Notes
    [5] - Non-significant difference between arms.

    Secondary: Virological failure (>=400c/ml confirmed).

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    End point title
    		 Virological failure (>=400c/ml confirmed).
    End point description
    Confirmed viral load >=400c/ml within 54 weeks of randomisation.
    End point type
    Secondary
    End point timeframe
    Any time from randomisation to 48(+6) weeks after randomisation.
    End point values
    		 Continuous therapy Short Cycle Therapy
    Number of subjects analysed
    100
    99
    Units: People
        Reached endpoint
    4
    2
        Did not reach endpoint
    96
    97
    Statistical analysis title
    		 Diff. in adj. KM estimates
    Statistical analysis description
    Difference in adjusted (for stratification factors) Kaplan-Meier survival function estimates at 54 weeks after randomisation.
    Comparison groups
    Continuous therapy v Short Cycle Therapy
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.021
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.062
         upper limit
    		 0.019
    Notes
    [6] - Calculated SCT arm survival function - CT arm survival function, so if the upper bound of the 90% confidence interval was <0.12, the results were consistent with non-inferiority of SCT compared with CT.
    Statistical analysis title
    		 Unadj. diff. in KM estimates
    Statistical analysis description
    Difference in Kaplan-Meier survival function estimates at 54 weeks after randomisation.
    Comparison groups
    Continuous therapy v Short Cycle Therapy
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.02
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.061
         upper limit
    		 0.02
    Notes
    [7] - Calculated SCT arm survival function - CT arm survival function, so if the upper bound of the 90% confidence interval was <0.12, the results were consistent with non-inferiority of SCT compared with CT.
    Statistical analysis title
    		 Crude diff. in proportion
    Statistical analysis description
    Difference in proportion of YP with confirmed VL>=400c/ml.
    Comparison groups
    Continuous therapy v Short Cycle Therapy
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [8]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.02
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.06
         upper limit
    		 0.02
    Notes
    [8] - Calculated proportion of YP with virological failure in the SCT arm - proportion of YP with virological failure in the CT arm, so if the upper bound of the 90% confidence interval was <0.12, the results were consistent with non-inferiority of SCT compared with CT.
    Statistical analysis title
    		 Unadj. Cox model
    Statistical analysis description
    Cox model examining time to confirmed viral load >=400c/ml
    Comparison groups
    Continuous therapy v Short Cycle Therapy
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.48
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.12
         upper limit
    		 2.01
    Statistical analysis title
    		 Adj. Cox model
    Statistical analysis description
    Cox model examining time to confirmed viral load >=400c/ml, adjusting for stratification factors.
    Comparison groups
    Continuous therapy v Short Cycle Therapy
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.399
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.48
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.12
         upper limit
    		 2

    Secondary: SCT change strategy to continuous therapy

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    End point title
    		 SCT change strategy to continuous therapy [9]
    End point description
    Any young person that changed strategy from SCT to return to taking daily ART, and reasons for changing. The protocol states that young people should return to continuous therapy if they experience the primary endpoint, or have 3 viral load "blips" >=50c/ml, which have a subsequent VL reading that is <50c/ml.
    End point type
    Secondary
    End point timeframe
    Any time from randomisation to week 48(+6).
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Acceptability questionnaires only completed by those randomised to SCT.
    End point values
    		 Short Cycle Therapy
    Number of subjects analysed
    99
    Units: People
        Due to reaching primary endpoint
    6
        Due to 3 unconfirmed blips
    0
        Due to other reasons
    2
    No statistical analyses for this end point

    Secondary: Changes in ART regimen

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    End point title
    		 Changes in ART regimen
    End point description
    Number of individuals on a different ART regimen at week 48 to at week 0.
    End point type
    Secondary
    End point timeframe
    Randomisation to week 48(+6).
    End point values
    		 Continuous therapy Short Cycle Therapy
    Number of subjects analysed
    99 [10]
    99
    Units: People
        Change in ART regimen
    9
    3
        No change in ART regimen
    90
    96
    Notes
    [10] - 1 young person lost to follow up before week 48 visit
    Statistical analysis title
    		 Snapshot comparison at week 48 visit
    Statistical analysis description
    Fisher's exact test comparing number of young people still on their randomised regimen at week 48 from each arm.
    Comparison groups
    Continuous therapy v Short Cycle Therapy
    Number of subjects included in analysis
    198
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.134
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Young people with major resistance mutations - any class

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    End point title
    		 Young people with major resistance mutations - any class
    End point description
    Resistance tests were performed on everyone that reached the primary endpoint. "Major mutation" defined as in Johnson et. al., 2013, Topics in antiviral medicine.
    End point type
    Secondary
    End point timeframe
    Randomisation to week 48(+6)
    End point values
    		 Continuous therapy Short Cycle Therapy
    Number of subjects analysed
    7 [11]
    6 [12]
    Units: People
        Major mutations present
    5
    2
        No major mutations present
    1
    1
        Test failed to amplify (insufficient viral load)
    1
    3
    Notes
    [11] - Only performed on young people that reached the primary endpoint.
    [12] - Only performed on young people that reached the primary endpoint.
    No statistical analyses for this end point

    Secondary: Mean change in CD4% at week 48 from randomisation

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    End point title
    		 Mean change in CD4% at week 48 from randomisation
    End point description
    Reporting mean change from the global baseline value (across both arms).
    End point type
    Secondary
    End point timeframe
    Randomisation and week 48 visit.
    End point values
    		 Continuous therapy Short Cycle Therapy
    Number of subjects analysed
    94 [13]
    93 [14]
    Units: percent
        arithmetic mean (standard error)
    0.1 ( 0.4 )
    0.2 ( 0.4 )
    Notes
    [13] - All patients with a reading at week 48 and week 0.
    [14] - All patients with a reading at week 48 and week 0.
    Statistical analysis title
    		 Linear regression
    Statistical analysis description
    Linear regression of CD4% at week 48, adjusting for randomised arm, baseline CD4% and stratification factors. Presenting mean difference between arms.
    Comparison groups
    Continuous therapy v Short Cycle Therapy
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.76
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 1.3

    Secondary: Mean change in absolute CD4 count at week 48 from randomisation

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    End point title
    		 Mean change in absolute CD4 count at week 48 from randomisation
    End point description
    Reporting mean change from the global baseline value (across both arms).
    End point type
    Secondary
    End point timeframe
    Randomisation and week 48 visit.
    End point values
    		 Continuous therapy Short Cycle Therapy
    Number of subjects analysed
    91 [15]
    92 [16]
    Units: cells/microlitre
        arithmetic mean (standard error)
    -21.6 ( 21.1 )
    -34.2 ( 20.9 )
    Notes
    [15] - All patients with a reading at week 48 and week 0.
    [16] - All patients with a reading at week 48 and week 0.
    Statistical analysis title
    		 Linear regression.
    Statistical analysis description
    Linear regression of absolute CD4 count at week 48, adjusting for randomised arm, baseline absolute CD4 count and stratification factors. Presenting mean difference between arms.
    Comparison groups
    Continuous therapy v Short Cycle Therapy
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.68
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -12.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -71.9
         upper limit
    		 46.9

    Secondary: Mean change in Creatinine at week 48 from randomisation

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    End point title
    		 Mean change in Creatinine at week 48 from randomisation
    End point description
    Reporting mean change from the global baseline value (across both arms).
    End point type
    Secondary
    End point timeframe
    Randomisation and week 48 visit.
    End point values
    		 Continuous therapy Short Cycle Therapy
    Number of subjects analysed
    90 [17]
    93 [18]
    Units: milligram(s)/decilitre
        arithmetic mean (standard error)
    0 ( 0 )
    0 ( 0 )
    Notes
    [17] - All patients with a reading at week 48 and week 0.
    [18] - All patients with a reading at week 48 and week 0.
    Statistical analysis title
    		 Linear regression.
    Statistical analysis description
    Linear regression of creatinine at week 48, adjusting for randomised arm, baseline creatinine and stratification factors. Presenting mean difference between arms.
    Comparison groups
    Short Cycle Therapy v Continuous therapy
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.42
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.1

    Secondary: Mean change in bilirubin at week 48 from randomisation

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    End point title
    		 Mean change in bilirubin at week 48 from randomisation
    End point description
    Reporting mean change from the global baseline value (across both arms).
    End point type
    Secondary
    End point timeframe
    Randomisation and week 48 visit.
    End point values
    		 Continuous therapy Short Cycle Therapy
    Number of subjects analysed
    92 [19]
    91 [20]
    Units: milligram(s)/decilitre
        arithmetic mean (standard error)
    0 ( 0 )
    0 ( 0 )
    Notes
    [19] - All patients with a reading at week 48 and week 0.
    [20] - All patients with a reading at week 48 and week 0.
    Statistical analysis title
    		 Linear regression.
    Statistical analysis description
    Linear regression of bilirubin at week 48, adjusting for randomised arm, baseline bilirubin and stratification factors. Presenting mean difference between arms.
    Comparison groups
    Continuous therapy v Short Cycle Therapy
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.45
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.1

    Secondary: Mean change in Alkaline phosphatase at week 48 from randomisation

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    End point title
    		 Mean change in Alkaline phosphatase at week 48 from randomisation
    End point description
    Reporting mean change from the global baseline value (across both arms).
    End point type
    Secondary
    End point timeframe
    Randomisation and week 48 visit.
    End point values
    		 Continuous therapy Short Cycle Therapy
    Number of subjects analysed
    90 [21]
    90 [22]
    Units: milligram(s)/decilitre
        arithmetic mean (standard error)
    -17.4 ( 9.3 )
    -24.8 ( 9.3 )
    Notes
    [21] - All patients with a reading at week 48 and week 0.
    [22] - All patients with a reading at week 48 and week 0.
    Statistical analysis title
    		 Linear regression.
    Statistical analysis description
    Linear regression of Alkaline phosphatase at week 48, adjusting for randomised arm, baseline Alkaline phosphatase and stratification factors. Presenting mean difference between arms.
    Comparison groups
    Continuous therapy v Short Cycle Therapy
    Number of subjects included in analysis
    180
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.77
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -28.3
         upper limit
    		 21

    Secondary: Mean change in Aspartate transaminase at week 48 from randomisation

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    End point title
    		 Mean change in Aspartate transaminase at week 48 from randomisation
    End point description
    Reporting mean change from the global baseline value (across both arms).
    End point type
    Secondary
    End point timeframe
    Randomisation and week 48 visit.
    End point values
    		 Continuous therapy Short Cycle Therapy
    Number of subjects analysed
    87 [23]
    87 [24]
    Units: unit(s)/litre
        arithmetic mean (standard error)
    0.5 ( 1 )
    -1.2 ( 1 )
    Notes
    [23] - All patients with a reading at week 48 and week 0.
    [24] - All patients with a reading at week 48 and week 0.
    Statistical analysis title
    		 Linear regression.
    Statistical analysis description
    Linear regression of aspartate transaminase at week 48, adjusting for randomised arm, baseline aspartate transaminase and stratification factors. Presenting mean difference between arms.
    Comparison groups
    Continuous therapy v Short Cycle Therapy
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.22
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.4
         upper limit
    		 1

    Secondary: Mean change in Alanine transaminase at week 48 from randomisation

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    End point title
    		 Mean change in Alanine transaminase at week 48 from randomisation
    End point description
    Reporting mean change from the global baseline value (across both arms).
    End point type
    Secondary
    End point timeframe
    Randomisation and week 48 visit.
    End point values
    		 Continuous therapy Short Cycle Therapy
    Number of subjects analysed
    91 [25]
    92 [26]
    Units: unit(s)/litre
        arithmetic mean (standard error)
    1.8 ( 1.3 )
    -0.4 ( 1.3 )
    Notes
    [25] - All patients with a reading at week 48 and week 0.
    [26] - All patients with a reading at week 48 and week 0.
    Statistical analysis title
    		 Linear regression.
    Statistical analysis description
    Linear regression of alanine transaminase at week 48, adjusting for randomised arm, baseline alanine transaminase and stratification factors. Presenting mean difference between arms.
    Comparison groups
    Continuous therapy v Short Cycle Therapy
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.23
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.8
         upper limit
    		 1.4

    Secondary: Mean change in Glucose at week 48 from randomisation

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    End point title
    		 Mean change in Glucose at week 48 from randomisation
    End point description
    Reporting mean change from the global baseline value (across both arms).
    End point type
    Secondary
    End point timeframe
    Randomisation and week 48 visit.
    End point values
    		 Continuous therapy Short Cycle Therapy
    Number of subjects analysed
    89 [27]
    90 [28]
    Units: milligram(s)/decilitre
        arithmetic mean (standard error)
    1.7 ( 1.1 )
    1.6 ( 1.1 )
    Notes
    [27] - All patients with a reading at week 48 and week 0.
    [28] - All patients with a reading at week 48 and week 0.
    Statistical analysis title
    		 Linear regression.
    Statistical analysis description
    Linear regression of glucose at week 48, adjusting for randomised arm, baseline glucose and stratification factors. Presenting mean difference between arms.
    Comparison groups
    Continuous therapy v Short Cycle Therapy
    Number of subjects included in analysis
    179
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.93
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.3
         upper limit
    		 3

    Secondary: Mean change in Triglycerides at week 48 from randomisation

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    End point title
    		 Mean change in Triglycerides at week 48 from randomisation
    End point description
    Reporting mean change from the global baseline value (across both arms).
    End point type
    Secondary
    End point timeframe
    Randomisation and week 48 visit.
    End point values
    		 Continuous therapy Short Cycle Therapy
    Number of subjects analysed
    93 [29]
    93 [30]
    Units: milligram(s)/decilitre
        arithmetic mean (standard error)
    -2.8 ( 4.8 )
    6.3 ( 4.8 )
    Notes
    [29] - All patients with a reading at week 48 and week 0.
    [30] - All patients with a reading at week 48 and week 0.
    Statistical analysis title
    		 Linear regression.
    Statistical analysis description
    Linear regression of triglycerides at week 48, adjusting for randomised arm, baseline triglycerides and stratification factors. Presenting mean difference between arms.
    Comparison groups
    Continuous therapy v Short Cycle Therapy
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.2
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    8.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.7
         upper limit
    		 22.2

    Secondary: Mean change in LDL Cholesterol at week 48 from randomisation

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    End point title
    		 Mean change in LDL Cholesterol at week 48 from randomisation
    End point description
    Reporting mean change from the global baseline value (across both arms).
    End point type
    Secondary
    End point timeframe
    Randomisation and week 48 visit.
    End point values
    		 Continuous therapy Short Cycle Therapy
    Number of subjects analysed
    92 [31]
    89 [32]
    Units: milligram(s)/decilitre
        arithmetic mean (standard error)
    -0.3 ( 1.6 )
    1.3 ( 1.7 )
    Notes
    [31] - All patients with a reading at week 48 and week 0.
    [32] - All patients with a reading at week 48 and week 0.
    Statistical analysis title
    		 Linear regression.
    Statistical analysis description
    Linear regression of LDL cholesterol at week 48, adjusting for randomised arm, baseline LDL cholesterol and stratification factors. Presenting mean difference between arms.
    Comparison groups
    Continuous therapy v Short Cycle Therapy
    Number of subjects included in analysis
    181
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.52
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.1
         upper limit
    		 6.1

    Secondary: Mean change in VLDL cholesterol at week 48 from randomisation

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    End point title
    		 Mean change in VLDL cholesterol at week 48 from randomisation
    End point description
    Reporting mean change from the global baseline value (across both arms).
    End point type
    Secondary
    End point timeframe
    Randomisation and week 48 visit.
    End point values
    		 Continuous therapy Short Cycle Therapy
    Number of subjects analysed
    52 [33]
    49 [34]
    Units: milligram(s)/decilitre
        arithmetic mean (standard error)
    -1.9 ( 1.1 )
    -3.1 ( 1.2 )
    Notes
    [33] - All patients with a reading at week 48 and week 0.
    [34] - All patients with a reading at week 48 and week 0.
    Statistical analysis title
    		 Linear regression.
    Statistical analysis description
    Linear regression of VLDL cholesterol at week 48, adjusting for randomised arm, baseline VLDL cholesterol and stratification factors. Presenting mean difference between arms.
    Comparison groups
    Continuous therapy v Short Cycle Therapy
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.44
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.3
         upper limit
    		 1.9

    Secondary: Mean change in HDL cholesterol at week 48 from randomisation

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    End point title
    		 Mean change in HDL cholesterol at week 48 from randomisation
    End point description
    Reporting mean change from the global baseline value (across both arms).
    End point type
    Secondary
    End point timeframe
    Randomisation and week 48 visit.
    End point values
    		 Continuous therapy Short Cycle Therapy
    Number of subjects analysed
    92 [35]
    92 [36]
    Units: milligram(s)/decilitre
        arithmetic mean (standard error)
    -0.5 ( 1 )
    -2.1 ( 1 )
    Notes
    [35] - All patients with a reading at week 48 and week 0.
    [36] - All patients with a reading at week 48 and week 0.
    Statistical analysis title
    		 Linear regression.
    Statistical analysis description
    Linear regression of HDL cholesterol at week 48, adjusting for randomised arm, baseline HDL cholesterol and stratification factors. Presenting mean difference between arms.
    Comparison groups
    Continuous therapy v Short Cycle Therapy
    Number of subjects included in analysis
    184
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.28
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.5
         upper limit
    		 1.3

    Secondary: Mean change in total cholesterol at week 48 from randomisation

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    End point title
    		 Mean change in total cholesterol at week 48 from randomisation
    End point description
    Reporting mean change from the global baseline value (across both arms).
    End point type
    Secondary
    End point timeframe
    Randomisation and week 48 visit.
    End point values
    		 Continuous therapy Short Cycle Therapy
    Number of subjects analysed
    93 [37]
    93 [38]
    Units: milligram(s)/decilitre
        arithmetic mean (standard error)
    -2.2 ( 2.1 )
    0.6 ( 2 )
    Notes
    [37] - All patients with a reading at week 48 and week 0.
    [38] - All patients with a reading at week 48 and week 0.
    Statistical analysis title
    		 Linear regression.
    Statistical analysis description
    Linear regression of total cholesterol at week 48, adjusting for randomised arm, baseline total cholesterol and stratification factors. Presenting mean difference between arms.
    Comparison groups
    Continuous therapy v Short Cycle Therapy
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.35
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3
         upper limit
    		 8.5

    Secondary: Mean change in Haemoglobin at week 48 from randomisation

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    End point title
    		 Mean change in Haemoglobin at week 48 from randomisation
    End point description
    Reporting mean change from the global baseline value (across both arms).
    End point type
    Secondary
    End point timeframe
    Randomisation and week 48 visit.
    End point values
    		 Continuous therapy Short Cycle Therapy
    Number of subjects analysed
    94 [39]
    95 [40]
    Units: gram(s)/decilitre
        arithmetic mean (standard error)
    0 ( 0.1 )
    0.1 ( 0.1 )
    Notes
    [39] - All patients with a reading at week 48 and week 0.
    [40] - All patients with a reading at week 48 and week 0.
    Statistical analysis title
    		 Linear regression.
    Statistical analysis description
    Linear regression of haemoglobin at week 48, adjusting for randomised arm, baseline haemoglobin and stratification factors. Presenting mean difference between arms.
    Comparison groups
    Continuous therapy v Short Cycle Therapy
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.37
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0.4

    Secondary: Mean change in MCV at week 48 from randomisation

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    End point title
    		 Mean change in MCV at week 48 from randomisation
    End point description
    Reporting mean change from the global baseline value (across both arms).
    End point type
    Secondary
    End point timeframe
    Randomisation and week 48 visit.
    End point values
    		 Continuous therapy Short Cycle Therapy
    Number of subjects analysed
    93 [41]
    94 [42]
    Units: femtolitres
        arithmetic mean (standard error)
    -1.6 ( 0.5 )
    -3.6 ( 0.5 )
    Notes
    [41] - All patients with a reading at week 48 and week 0.
    [42] - All patients with a reading at week 48 and week 0.
    Statistical analysis title
    		 Linear regression.
    Statistical analysis description
    Linear regression of MCV at week 48, adjusting for randomised arm, baseline MCV and stratification factors. Presenting mean difference between arms.
    Comparison groups
    Continuous therapy v Short Cycle Therapy
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.01 [43]
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.5
         upper limit
    		 -0.6
    Notes
    [43] - Significicant difference between arms - higher MCV in the continuous therapy arm.

    Secondary: Mean change in white blood cell count at week 48 from randomisation

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    End point title
    		 Mean change in white blood cell count at week 48 from randomisation
    End point description
    Reporting mean change from the global baseline value (across both arms).
    End point type
    Secondary
    End point timeframe
    Randomisation and week 48 visit.
    End point values
    		 Continuous therapy Short Cycle Therapy
    Number of subjects analysed
    94 [44]
    95 [45]
    Units: /litre
        arithmetic mean (standard error)
    0.1 ( 0.1 )
    0.4 ( 0.1 )
    Notes
    [44] - All patients with a reading at week 48 and week 0.
    [45] - All patients with a reading at week 48 and week 0.
    Statistical analysis title
    		 Linear regression.
    Statistical analysis description
    Linear regression of white blood cell count at week 48, adjusting for randomised arm, baseline white blood cell count and stratification factors. Presenting mean difference between arms.
    Comparison groups
    Continuous therapy v Short Cycle Therapy
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.09
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.7

    Secondary: Mean change in Lymphocyte count at week 48 from randomisation

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    End point title
    		 Mean change in Lymphocyte count at week 48 from randomisation
    End point description
    Reporting mean change from the global baseline value (across both arms).
    End point type
    Secondary
    End point timeframe
    Randomisation and week 48 visit.
    End point values
    		 Continuous therapy Short Cycle Therapy
    Number of subjects analysed
    91 [46]
    91 [47]
    Units: /litre
        arithmetic mean (standard error)
    0 ( 0.5 )
    0.7 ( 0.5 )
    Notes
    [46] - All patients with a reading at week 48 and week 0.
    [47] - All patients with a reading at week 48 and week 0.
    Statistical analysis title
    		 Linear regression.
    Statistical analysis description
    Linear regression of lymphocyte count at week 48, adjusting for randomised arm, baseline lymphocyte count and stratification factors. Presenting mean difference between arms.
    Comparison groups
    Continuous therapy v Short Cycle Therapy
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.34
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 2.1

    Secondary: Mean change in Neutrophil count at week 48 from randomisation

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    End point title
    		 Mean change in Neutrophil count at week 48 from randomisation
    End point description
    Reporting mean change from the global baseline value (across both arms).
    End point type
    Secondary
    End point timeframe
    Randomisation and week 48 visit.
    End point values
    		 Continuous therapy Short Cycle Therapy
    Number of subjects analysed
    91 [48]
    91 [49]
    Units: /litre
        arithmetic mean (standard error)
    0.1 ( 0.1 )
    0.4 ( 0.1 )
    Notes
    [48] - All patients with a reading at week 48 and week 0.
    [49] - All patients with a reading at week 48 and week 0.
    Statistical analysis title
    		 Linear regression.
    Statistical analysis description
    Linear regression of neutrophil count at week 48, adjusting for randomised arm, baseline neutrophil count and stratification factors. Presenting mean difference between arms.
    Comparison groups
    Short Cycle Therapy v Continuous therapy
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.12
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.7

    Secondary: Mean change in platelet count at week 48 from randomisation

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    End point title
    		 Mean change in platelet count at week 48 from randomisation
    End point description
    Reporting mean change from the global baseline value (across both arms).
    End point type
    Secondary
    End point timeframe
    Randomisation and week 48 visit.
    End point values
    		 Continuous therapy Short Cycle Therapy
    Number of subjects analysed
    94 [50]
    95 [51]
    Units: /litre
        arithmetic mean (standard error)
    7.4 ( 6.6 )
    -13.4 ( 6.5 )
    Notes
    [50] - All patients with a reading at week 48 and week 0.
    [51] - All patients with a reading at week 48 and week 0.
    Statistical analysis title
    		 Linear regression.
    Statistical analysis description
    Linear regression of platelet count at week 48, adjusting for randomised arm, baseline platelet count and stratification factors. Presenting mean difference between arms.
    Comparison groups
    Short Cycle Therapy v Continuous therapy
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.03 [52]
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -20.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -39.1
         upper limit
    		 -2.1
    Notes
    [52] - Significant difference between the arms, higher platelet count in the continuous therapy arm.

    Secondary: Young person questionnaire - how did taking weekends off make things for you?

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    End point title
    		 Young person questionnaire - how did taking weekends off make things for you? [53]
    End point description
    This questionnaire was only completed in the SCT arm.
    End point type
    Secondary
    End point timeframe
    Week 48 assessment/time of switch to continuous therapy/ last main trial visit (if after week 48).
    Notes
    [53] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Acceptability questionnaires only completed by those randomised to SCT.
    End point values
    		 Short Cycle Therapy
    Number of subjects analysed
    99 [54]
    Units: People
        Lot easier
    67
        Little easier
    14
        No difference
    7
        Little more difficult
    0
        Lot more difficult
    2
        Question not answerred
    9
    Notes
    [54] - Only answerred by those randomised to SCT arm
    No statistical analyses for this end point

    Secondary: Carer questionnaire - how did stopping meds at weekend make things for the young person?

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    End point title
    		 Carer questionnaire - how did stopping meds at weekend make things for the young person? [55]
    End point description
    This questionnaire was only asked in the SCT arm.
    End point type
    Secondary
    End point timeframe
    Week 48 assessment/time of switch to continuous therapy/ last main trial visit (if after week 48).
    Notes
    [55] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Acceptability questionnaires only completed by those randomised to SCT.
    End point values
    		 Short Cycle Therapy
    Number of subjects analysed
    99 [56]
    Units: People
        Lot easier
    49
        Little easier
    9
        No difference
    3
        Little more difficult
    0
        Lot more difficult
    0
        Question not answerred
    38
    Notes
    [56] - Only answerred by those randomised to the SCT arm.
    No statistical analyses for this end point

    Secondary: Adherence- Missed Doses at Last Visit

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    End point title
    		 Adherence- Missed Doses at Last Visit
    End point description
    Participants were asked if they missed any doses since the last visit.
    End point type
    Secondary
    End point timeframe
    Collected at Week 4, 12, 24, 36, and 48.
    End point values
    		 Continuous therapy Short Cycle Therapy
    Number of subjects analysed
    100 [57]
    99 [58]
    Units: Number of Questionnaires
        Missed doses since last visit: Week 4
    23
    13
        Missed doses since last visit: Week 12
    22
    17
        Missed doses since last visit: Week 24
    23
    19
        Missed doses since last visit: Week 36
    22
    15
        Missed doses since last visit: Week 48
    20
    18
    Notes
    [57] - Denominator differed by study week Week 4=79 Week 12=84 Week 24=86 Week 36=81 Week 48=86
    [58] - Denominator differed by study week Week 4=80 Week 12=84 Week 24=86 Week 36=83 Week 48=86
    Statistical analysis title
    		 Comparison of missed doses at week 4
    Comparison groups
    Short Cycle Therapy v Continuous therapy
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.087
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Comparison of missed doses at week 12
    Comparison groups
    Continuous therapy v Short Cycle Therapy
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.464
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Comparison of missed doses at week 24
    Comparison groups
    Continuous therapy v Short Cycle Therapy
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.481
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Comparison of missed doses at week 36
    Comparison groups
    Continuous therapy v Short Cycle Therapy
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.193
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Comparison of missed doese at week 48
    Comparison groups
    Continuous therapy v Short Cycle Therapy
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.854
    Method
    		 Fisher exact
    Confidence interval

    Other pre-specified: Mean change in CD8% at week 48 from randomisation

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    End point title
    		 Mean change in CD8% at week 48 from randomisation
    End point description
    Reporting mean change from the global baseline value (across both arms).
    End point type
    Other pre-specified
    End point timeframe
    Randomisation and week 48 visit.
    End point values
    		 Continuous therapy Short Cycle Therapy
    Number of subjects analysed
    86 [59]
    89 [60]
    Units: percent
        arithmetic mean (standard error)
    -0.3 ( 0.5 )
    -0.5 ( 0.5 )
    Notes
    [59] - All patients with a reading at week 48 and week 0.
    [60] - All patients with a reading at week 48 and week 0.
    Statistical analysis title
    		 Linear regression.
    Statistical analysis description
    Linear regression of CD8% at week 48, adjusting for randomised arm, baseline CD8% and stratification factors. Presenting mean difference between arms.
    Comparison groups
    Continuous therapy v Short Cycle Therapy
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.8
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 1.2

    Other pre-specified: Mean change in absolute CD8 count at week 48 from randomisation

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    End point title
    		 Mean change in absolute CD8 count at week 48 from randomisation
    End point description
    Reporting mean change from the global baseline value (across both arms).
    End point type
    Other pre-specified
    End point timeframe
    Randomisation and week 48 visit.
    End point values
    		 Continuous therapy Short Cycle Therapy
    Number of subjects analysed
    86 [61]
    89 [62]
    Units: cells/microlitre
        arithmetic mean (standard error)
    -14.8 ( 24.5 )
    -22.1 ( 23.8 )
    Notes
    [61] - All patients with a reading at week 48 and week 0.
    [62] - All patients with a reading at week 48 and week 0.
    Statistical analysis title
    		 Linear regression.
    Statistical analysis description
    Linear regression of absolute CD8 count at week 48, adjusting for randomised arm, baseline absolute CD8 count and stratification factors. Presenting mean difference between arms.
    Comparison groups
    Continuous therapy v Short Cycle Therapy
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.85
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -6.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -74.5
         upper limit
    		 61.7

    Other pre-specified: Mean change in CD3% at week 48 from randomisation

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    End point title
    		 Mean change in CD3% at week 48 from randomisation
    End point description
    Reporting mean change from the global baseline value (across both arms).
    End point type
    Other pre-specified
    End point timeframe
    Randomisation and week 48 visit.
    End point values
    		 Continuous therapy Short Cycle Therapy
    Number of subjects analysed
    86 [63]
    88 [64]
    Units: percent
        arithmetic mean (standard error)
    -0.7 ( 0.7 )
    -0.7 ( 0.7 )
    Notes
    [63] - All patients with a reading at week 48 and week 0.
    [64] - All patients with a reading at week 48 and week 0.
    Statistical analysis title
    		 Linear regression.
    Statistical analysis description
    Linear regression of CD3% at week 48, adjusting for randomised arm, baseline CD3% and stratification factors. Presenting mean difference between arms.
    Comparison groups
    Short Cycle Therapy v Continuous therapy
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.99
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.9
         upper limit
    		 1.9

    Other pre-specified: Mean change in absolute CD3 count at week 48 from randomisation

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    End point title
    		 Mean change in absolute CD3 count at week 48 from randomisation
    End point description
    Reporting mean change from the global baseline value (across both arms).
    End point type
    Other pre-specified
    End point timeframe
    Randomisation and week 48 visit.
    End point values
    		 Continuous therapy Short Cycle Therapy
    Number of subjects analysed
    86 [65]
    88 [66]
    Units: cells/microlitre
        arithmetic mean (standard error)
    -25.9 ( 49.5 )
    -56.6 ( 48.4 )
    Notes
    [65] - All patients with a reading at week 48 and week 0.
    [66] - All patients with a reading at week 48 and week 0.
    Statistical analysis title
    		 Linear regression.
    Statistical analysis description
    Linear regression of absolute CD3 count at week 48, adjusting for randomised arm, baseline absolute CD3 count and stratification factors. Presenting mean difference between arms.
    Comparison groups
    Continuous therapy v Short Cycle Therapy
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.72
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -25.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -163.7
         upper limit
    		 112.7

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Randomisation to 54 weeks after randomisation.
    Adverse event reporting additional description
    For non-serious adverse events we reported grade three or four adverse clinical or laboratory adverse events or ART-related adverse events (any grade), excluding those meeting criteria for SAE.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Continuous therapy
    Reporting group description
    		 Patients randomised to continuing their ART strategy, taking ART every day.

    Reporting group title
    Short Cycle Therapy
    Reporting group description
    		 Patients take their ART as normal for 5 days a week, with a break at the weekends, taking no ART for 2 days every week.

    Serious adverse events
    		 Continuous therapy Short Cycle Therapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 100 (3.00%)
    6 / 99 (6.06%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Kaposi's sarcoma AIDS related
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hospitalisation (following contusion of chest)
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigation (Collapsed)
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Measles
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of bronchiectasis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurosyphilis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Continuous therapy Short Cycle Therapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 100 (19.00%)
    7 / 99 (7.07%)
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Blood calcium decreased
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Blood glucose decreased
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1
    Low density lipoprotein increased
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 99 (1.01%)
         occurrences all number
    1
    1
    Neutrophil count decreased
         subjects affected / exposed
    6 / 100 (6.00%)
    2 / 99 (2.02%)
         occurrences all number
    6
    2
    Transaminases increased
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 99 (0.00%)
         occurrences all number
    2
    0
    Surgical and medical procedures
    Inguinal hernia repair
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Dizziness
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Gynaecomastia
         subjects affected / exposed
    2 / 100 (2.00%)
    1 / 99 (1.01%)
         occurrences all number
    2
    1
    Skin and subcutaneous tissue disorders
    Lipohypertrophy
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 99 (0.00%)
         occurrences all number
    1
    0
    Lipodystrophy acquired
         subjects affected / exposed
    5 / 100 (5.00%)
    0 / 99 (0.00%)
         occurrences all number
    5
    0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 99 (1.01%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Apr 2014
    The TSC recommended that the participants are followed for 2 years after completion of the main trial (long term follow up).

    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
    For support, Contact us.
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