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    Clinical Trial Results:
    The metabolic impact of Darunavir/ritonavir maintenance monotherapy after successful viral suppression with standard Atripla in HIV-1-infected patients (MIDAs).

    Summary
    EudraCT number
    2010-022120-72
    Trial protocol
    GB  
    Global end of trial date
    17 Sep 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    06 Oct 2018
    First version publication date
    06 Oct 2018
    Other versions
    Summary report(s)
    FINAL STUDY REPORT

    Trial information

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    Trial identification
    Sponsor protocol code
    JF-001
    Additional study identifiers
    ISRCTN number
    ISRCTN11504121
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Guy's and St Thomas' NHS Foundation Trust
    Sponsor organisation address
    Great Maze Pond, London, United Kingdom, SE19RT
    Public contact
    Dr Alastair Teague, Guy’s & St. Thomas’ NHS Foundation Trust, 0044 02071887188, alastair.teague@gstt.nhs.uk
    Scientific contact
    Dr Alastair Teague, Guy’s & St. Thomas’ NHS Foundation Trust, 0044 02071887188, alastair.teague@gstt.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
    01 Jan 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Sep 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Sep 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This project aims to assess the potential long-term advantages of switching HIV patients from the standard therapy (Atripla) to a different regime of treatment (darunavir 800 mg / ritonavir 100 mg). This will be assessed by measuring Vitamin D levels, calcium and phosphate homeostasis (balance), kidney (tubular) function, bone turnover and bone mineralisation, and HIV disease progression in all the patients who take part in the study.
    Protection of trial subjects
    Safety blood tests (FBC, Urea and electrolytes and liver function tests) and adherence review are incorporated into the visit schedule. Any abnormalities or concerns will be addressed immediately and reported.
    Background therapy
    -
    Evidence for comparator
    While Highly Active Anti-Retroviral Therapy (HAART) has dramatically reduced AIDS-related morbidity and mortality, the absence of HIV eradication with those drugs requires their prolonged used for a lifetime, making long-term toxicity a critical issue in the management of HIV-infected patients. Protease inhibitor (PI) monotherapy maintains plasma HIV-RNA suppression in a large proportion of patients already suppressed on a standard triple combination1. However, the more frequent occurrence of low-level viremia does not allow the use of such a strategy outside of clinical studies at this time. Darunavir has a high genetic barrier and low propensity to induce resistance-conferring mutations in cases of virologic failure. Early results showed non-inferiority with Darunavir/ritonovir monotherapy when compared to 2 NRTIs/ritonovir/darunavir [MONET and MONOI]. However, it remains unclear which patient populations might benefit most, and the potential risks and benefits associated with this therapeutic strategy remain to be defined. Hypothesis for this trial is that oosted Darunavir, given once a day as monotherapy, confers less toxicity than Atripla while maintaining undetectable HIV RNA levels
    Actual start date of recruitment
    02 May 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 70
    Worldwide total number of subjects
    70
    EEA total number of subjects
    70
    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)
    70
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Inclusion Criteria 1. Males and Females aged between 18 and 65 2. Documented Positive HIV 1-antibody test 3. Plasma HIV RNA <100 copies/ml and on Atripla for at least six months prior to study start 4. Agreeable NOT take vitamin D supplements for the duration of the study 5. Ability to give informed consent

    Pre-assignment
    Screening details
    Inclusion Criteria  Males and Females aged between 18 and 65  Documented Positive HIV 1-antibody test  Plasma HIV RNA <100 copies/ml and on ATP for at least six months prior to study start  Agreeable NOT take vitamin D supplements for the duration of the study  Ability to give informed consent

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    Randomization will take place on a 1:1 basis, with randomisation/allocation to study arm being determined using the MS Excel RAND() function

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Atripla
    Arm description
    Atripla 1 tablet once daily for 48 weeks
    Arm type
    Active comparator

    Investigational medicinal product name
    Atripla
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Atripla® is efavirenz 600mg, emtricitabine 200mg with tenofovir disoproxil (as fumarate) 245mg. This will be taken orally once a day for 48 weeks.

    Arm title
    Darunavir/ ritonovir
    Arm description
    Participants were randomised to receive Darunavir 800mg / ritonovir 100mg orally once per day for 48 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Darunavir
    Investigational medicinal product code
    Other name
    PREZISTA
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Darunavir 800mg once daily taken orally for 48 weeks

    Investigational medicinal product name
    Ritonovir
    Investigational medicinal product code
    Other name
    Norvir
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ritonovir 100mg taken orally once per day for 48 weeks

    Number of subjects in period 1
    Atripla Darunavir/ ritonovir
    Started
    34
    36
    12 week visit
    32
    32
    Completed
    31
    25
    Not completed
    3
    11
         Discontinued IMP
    -
    2
         Adverse event, non-fatal
    -
    1
         Intolerance to IMP
    -
    2
         Consent withdrawn by subject
    1
    6
         Concomitant vitamin d therapy
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Atripla
    Reporting group description
    Atripla 1 tablet once daily for 48 weeks

    Reporting group title
    Darunavir/ ritonovir
    Reporting group description
    Participants were randomised to receive Darunavir 800mg / ritonovir 100mg orally once per day for 48 weeks.

    Reporting group values
    Atripla Darunavir/ ritonovir Total
    Number of subjects
    34 36 70
    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)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    34 36 70
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    41.6 ± 8.8 43.8 ± 9.2 -
    Gender categorical
    Units: Subjects
        Female
    7 9 16
        Male
    27 27 54

    End points

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    End points reporting groups
    Reporting group title
    Atripla
    Reporting group description
    Atripla 1 tablet once daily for 48 weeks

    Reporting group title
    Darunavir/ ritonovir
    Reporting group description
    Participants were randomised to receive Darunavir 800mg / ritonovir 100mg orally once per day for 48 weeks.

    Primary: Mean change in Vitamin D level at Week 48 from baseline

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    End point title
    Mean change in Vitamin D level at Week 48 from baseline
    End point description
    Change in 25(OH)D at week 48
    End point type
    Primary
    End point timeframe
    From baseline to week 48
    End point values
    Atripla Darunavir/ ritonovir
    Number of subjects analysed
    31
    25
    Units: mm/l
        arithmetic mean (standard deviation)
    1.2 ± 6
    5 ± 5.9
    Statistical analysis title
    Primary endpoint
    Statistical analysis description
    For sample size calculation, an increase of 15 nmol/L in 25(OH)D in the DRV/R arm compared to ATP was considered clinically relevant. With a 1:1 randomisation, 35 patients per arm and a continue-switch design, the study had 90% power to detect this difference. In addition, the study had 90% power to detect a fall in ALP of 10 IU/L in the DRV/r arm, compared with ATP. These calculations allowed for 5 patients in the DRV/r arm switching back to ATP for tolerability reasons.
    Comparison groups
    Atripla v Darunavir/ ritonovir
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    P-value
    = 0.2
    Method
    aa
    Parameter type
    Median difference (net)
    Confidence interval
    Variability estimate
    Standard deviation
    Notes
    [1] - The study was not statistically powered to assess virological efficacy. In addition to the proportion of participants with two consecutive HIV viral load values > 50 copies/ml, an FDA snapshot analysis was performed at week 48. The frequencies of adverse events (AEs), AEs leading to discontinuation and laboratory test abnormalities were described by treatment arm. All analyses were performed on an intention to treat basis and conducted using Stata (version12).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Duration of the trial and 4 weeks post last dose of IMP.
    Adverse event reporting additional description
    Darunavir is a licensed antiretroviral therapy which is well tolerated. The commonest side effects are nausea, headaches and diarrhoea which tend to be mild and self limiting. All side effects will be documented and Grade 2-4 AEs
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Group 1 ATRIPLA
    Reporting group description
    Atripla 1 tablet od for 48 weeks

    Reporting group title
    Group 2 DRV/r
    Reporting group description
    Darunavir 800mg od/ ritonovir 100mg od for 48 weeks

    Serious adverse events
    Group 1 ATRIPLA Group 2 DRV/r
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 34 (8.82%)
    3 / 36 (8.33%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Immune system disorders
    Meningoencephalitis
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
    Additional description: Seizures due to scar tissue after toxoplasmosis infection
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Uveitis
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperparathypodism
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 36 (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
    Arthritic Sepsis
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Group 1 ATRIPLA Group 2 DRV/r
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 34 (88.24%)
    31 / 36 (86.11%)
    Investigations
    High HIV Viral Load
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    High Alkaline Phosphatase
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    1
    High Cholesterol
         subjects affected / exposed
    5 / 34 (14.71%)
    6 / 36 (16.67%)
         occurrences all number
    5
    6
    High LDL Cholesterol
         subjects affected / exposed
    3 / 34 (8.82%)
    4 / 36 (11.11%)
         occurrences all number
    3
    4
    Low serum phophate
         subjects affected / exposed
    2 / 34 (5.88%)
    3 / 36 (8.33%)
         occurrences all number
    2
    3
    Low white blood cells
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    1
    High Gamma-GT
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Dizziness
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    1
    Neurosensory alteration
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Syncope
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    1
    Altered Mood
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    Cognitive & Behavioral change
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Eye disorders
    Altered vision
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Bloating
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    1 / 34 (2.94%)
    5 / 36 (13.89%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    0 / 34 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    0
    0
    Bleeding Rectum
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    Fracture
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Sexually transmitted disease
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    1
    Gastroenteritis
         subjects affected / exposed
    3 / 34 (8.82%)
    0 / 36 (0.00%)
         occurrences all number
    3
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Apr 2011
    Addition of 4 exclusion criteria. Additional lab tests added and change in CI and PI for the study
    08 Aug 2011
    Amendment to the inclusion criteria. Amendment to the DXA scan from partial to full body scan and amendment to data analysis section of the protocol.
    13 Mar 2012
    changes and clarifications have been made to both the inclusion and exclusion criteria. change in the CI and PI

    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.
    The study was not statistically powered to assess virological efficacy. In addition to the proportion of participants with two consecutive HIV viral load values > 50 copies/ml, an FDA snapshot analysis was performed at week 48. The frequencies of adv

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/26460504
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