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    Clinical Trial Results:
    An open-label, randomized, controlled clinical trial to assess the safety, tolerability and efficacy of two dolutegravir-based simplification strategies in HIV-infected patients with prolonged virological suppression

    Summary
    EudraCT number
    		 2015-000274-35
    Trial protocol
    		 ES  
    Global end of trial date
    21 Nov 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Feb 2022
    First version publication date
    02 Feb 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DOLAM
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    FUNDACIÓ CLÍNIC PER A LA RECERCA BIOMÈDICA
    Sponsor organisation address
    C/ Rosselló, 149-153, Barcelona, Spain,
    Public contact
    Sponsor, FUNDACIÓ CLÍNIC PER A LA RECERCA BIOMÈDICA (ESPAÑA), ++34 93 227 55 74, ESTEBANM@clinic.cat
    Scientific contact
    Clinical Research Associates, Fundació Lluita contra la SIDA, ++34 934978414, cherrero@fls-rs.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Oct 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Nov 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the virological efficacy at week 48 of the bitherapy dolutegravir plus lamivudine and the monotherapy dolutegravir in comparison with a triple antiretroviral regimen.
    Protection of trial subjects
    not specific
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Jun 2015
    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
    Spain: 265
    Worldwide total number of subjects
    265
    EEA total number of subjects
    265
    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)
    265
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was done at six major HIV clinics in Catalonia, Spain (July 2015 - October 2018): - H. Germans Trias i Pujol, Badalona - H. Clínic de Barcelona - H. U. de Bellvitge, Hospitalet de Llobregat - H. U. Vall d’Hebron, Barcelona - H. de la Santa Creu i Sant Pau, Barcelona - H. Arnau de Vilanova, Lleida

    Pre-assignment
    Screening details
    		 DOLAM is a phase 4, randomised, open-label, non-inferiority trial. Adults with HIV-1 receiving a triple ART regimen, aged 18 years or older, with virological suppression, a CD4 nadir of at least 200 cells per µL, who were HBsAg-negative, and without previous viral failure or resistance mutations to study drugs were eligible.

    Period 1
    Period 1 title
    overall 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
    		 Control Arm
    Arm description
    		 To continue current triple ART
    Arm type
    		 Control

    Investigational medicinal product name
    Triple ART
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Orally once daily

    Arm title
    		 Experimental Arm
    Arm description
    		 switched to dolutegravir 50 mg plus lamivudine 300 mg orally once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dolutegravir 50 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Orally once daily (every 24 hours)

    Investigational medicinal product name
    Lamivudine 300 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lamivudine 300mg orally once daily (every 24 hours)

    Number of subjects in period 1
    		Control Arm Experimental Arm
    Started
    134
    131
    Completed
    124
    122
    Not completed
    10
    9
         Consent withdrawn by subject
    2
    1
         Treatment discontinuation
    4
    3
         Virological failure
    2
    3
         Lost to follow-up
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Control Arm
    Reporting group description
    		 To continue current triple ART

    Reporting group title
    Experimental Arm
    Reporting group description
    		 switched to dolutegravir 50 mg plus lamivudine 300 mg orally once daily

    Reporting group values
    		 Control Arm Experimental Arm Total
    Number of subjects
    		 134 131 265
    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)
    		 134 131 265
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 46 (39 to 51) 45 (37 to 53) -
    Gender categorical
    Units: Subjects
        Female
    		 18 20 38
        Male
    		 116 111 227

    End points

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    End points reporting groups
    Reporting group title
    Control Arm
    Reporting group description
    		 To continue current triple ART

    Reporting group title
    Experimental Arm
    Reporting group description
    		 switched to dolutegravir 50 mg plus lamivudine 300 mg orally once daily

    Primary: Proportion of people with HIV RNA values of at least 50 copies per mL at week 48

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    End point title
    		 Proportion of people with HIV RNA values of at least 50 copies per mL at week 48
    End point description
    The primary endpoint was the proportion of people with HIV RNA values of at least 50 copies per mL at week 48 (US Food and Drug Administration [FDA] snapshot algorithm, 8% non-inferiority margin) evaluated in the intention-to-treat exposed population
    End point type
    Primary
    End point timeframe
    at week 48
    End point values
    		 Control Arm Experimental Arm
    Number of subjects analysed
    134
    131
    Units: Proportion of people
        number (confidence interval 95%)
    2 (-3.3 to 5.2)
    3 (-3.3 to 5.2)
    Statistical analysis title
    		 Newcombe Method
    Statistical analysis description
    The proportions of people with confirmed HIV of at least 50 copies per mL were assessed in each group and the 95% CI of the difference was based on the Newcombe method. Non-inferiority would be proven if the upper bound of the CI of the difference in proportions did not cross over the prespecified margin of 8%. If the lower bound was above 0, then superiority would be assessed using the Fisher’s exact test.
    Comparison groups
    Control Arm v Experimental Arm
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.05
    Method
    		 Diff. in proportion (Newcombe method 10)
    Confidence interval

    Secondary: Changes in CD4 cells

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    End point title
    		 Changes in CD4 cells
    End point description
    End point type
    Secondary
    End point timeframe
    at week 48
    End point values
    		 Control Arm Experimental Arm
    Number of subjects analysed
    134
    131
    Units: cells per µl
        number (confidence interval 95%)
    32 (-11 to 75)
    30 (-15 to 74)
    No statistical analyses for this end point

    Secondary: Changes in CD8 cells

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    End point title
    		 Changes in CD8 cells
    End point description
    End point type
    Secondary
    End point timeframe
    at week 48
    End point values
    		 Control Arm Experimental Arm
    Number of subjects analysed
    134
    131
    Units: Cells per µL
        number (confidence interval 95%)
    -7 (-56 to 41)
    24 (-26 to 74)
    No statistical analyses for this end point

    Secondary: Changes in fasting plasma lipids: Total Cholesterol

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    End point title
    		 Changes in fasting plasma lipids: Total Cholesterol
    End point description
    End point type
    Secondary
    End point timeframe
    baseline Vs Week 48
    End point values
    		 Control Arm Experimental Arm
    Number of subjects analysed
    134
    131
    Units: mg/dL
    number (confidence interval 95%)
        Baseline
    186 (179 to 192)
    188 (180 to 193)
        At week 48
    187 (181 to 194)
    185 (178 to 192)
    No statistical analyses for this end point

    Secondary: Changes in fasting plasma lipids: LDL Cholesterol

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    End point title
    		 Changes in fasting plasma lipids: LDL Cholesterol
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline Vs Week 48
    End point values
    		 Control Arm Experimental Arm
    Number of subjects analysed
    134
    131
    Units: mg/dL
    number (confidence interval 95%)
        Baseline
    112 (106 to 119)
    112 (107 to 118)
        Week 48
    114 (108 to 121)
    112 (106 to 118)
    No statistical analyses for this end point

    Secondary: Changes in fasting plasma lipids: Total-to-HDL cholesterol ratio

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    End point title
    		 Changes in fasting plasma lipids: Total-to-HDL cholesterol ratio
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline Vs Week 48
    End point values
    		 Control Arm Experimental Arm
    Number of subjects analysed
    134
    131
    Units: mg/dL
    number (confidence interval 95%)
        Baseline
    4.07 (3.87 to 4.27)
    4.36 (4.16 to 4.56)
        Week 48
    3.88 (3.68 to 4.08)
    4.05 (3.85 to 4.25)
    No statistical analyses for this end point

    Secondary: Changes in fasting plasma lipids: HDL Cholesterol

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    End point title
    		 Changes in fasting plasma lipids: HDL Cholesterol
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline Vs Week 48
    End point values
    		 Control Arm Experimental Arm
    Number of subjects analysed
    134
    131
    Units: mg/dL
    number (confidence interval 95%)
        Baseline
    47 (44 to 49)
    47 (45 to 49)
        48 Weeks
    50 (47 to 52)
    48 (46 to 51)
    No statistical analyses for this end point

    Secondary: Estimated glomerular filtration rate

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    End point title
    		 Estimated glomerular filtration rate
    End point description
    End point type
    Secondary
    End point timeframe
    at week 48
    End point values
    		 Control Arm Experimental Arm
    Number of subjects analysed
    134
    131
    Units: mL/min per 1.73 m2
        median (inter-quartile range (Q1-Q3))
    98 (82 to 107)
    96 (84 to 106)
    No statistical analyses for this end point

    Secondary: Proteinuria

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    End point title
    		 Proteinuria
    End point description
    End point type
    Secondary
    End point timeframe
    At week 48
    End point values
    		 Control Arm Experimental Arm
    Number of subjects analysed
    134
    131
    Units: mg/g creatinine
        median (inter-quartile range (Q1-Q3))
    63 (41 to 85)
    70 (41 to 98)
    No statistical analyses for this end point

    Secondary: Weight

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    End point title
    		 Weight
    End point description
    End point type
    Secondary
    End point timeframe
    At week 48
    End point values
    		 Control Arm Experimental Arm
    Number of subjects analysed
    134
    131
    Units: Kg
        median (inter-quartile range (Q1-Q3))
    72 (67 to 79)
    75 (67 to 83)
    No statistical analyses for this end point

    Secondary: Incidence of blips

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    End point title
    		 Incidence of blips
    End point description
    End point type
    Secondary
    End point timeframe
    At week 48
    End point values
    		 Control Arm Experimental Arm
    Number of subjects analysed
    134
    131
    Units: Episodes per 100 patient-years
        number (not applicable)
    9.3
    14.7
    No statistical analyses for this end point

    Secondary: Number of participants with one or more blips

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    End point title
    		 Number of participants with one or more blips
    End point description
    End point type
    Secondary
    End point timeframe
    At week 48
    End point values
    		 Control Arm Experimental Arm
    Number of subjects analysed
    134
    131
    Units: Participants
        number (not applicable)
    10
    15
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline to week 48 follow up
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 DAIDS AE GRADING
    Dictionary version
    2.0
    Reporting groups
    Reporting group title
    Control Arm
    Reporting group description
    		 To continue current triple ART

    Reporting group title
    Experimental Arm
    Reporting group description
    		 switched to dolutegravir 50 mg plus lamivudine 300 mg orally once daily

    Serious adverse events
    		 Control Arm Experimental Arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 134 (3.73%)
    3 / 131 (2.29%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Severe Aortic Stenosis
         subjects affected / exposed
    1 / 134 (0.75%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Appendicitis
         subjects affected / exposed
    1 / 134 (0.75%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Hip Fracture
         subjects affected / exposed
    0 / 134 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Listeria monodytogenes bacteremia
         subjects affected / exposed
    1 / 134 (0.75%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial endocarditis
         subjects affected / exposed
    1 / 134 (0.75%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Liver abscess
         subjects affected / exposed
    0 / 134 (0.00%)
    1 / 131 (0.76%)
         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: 5%
    Non-serious adverse events
    		 Control Arm Experimental Arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    78 / 134 (58.21%)
    73 / 131 (55.73%)
    Cardiac disorders
    Cardiovascular disorder
         subjects affected / exposed
    3 / 134 (2.24%)
    0 / 131 (0.00%)
         occurrences all number
    3
    0
    Nervous system disorders
    Neurological
         subjects affected / exposed
    8 / 134 (5.97%)
    14 / 131 (10.69%)
         occurrences all number
    8
    14
    Blood and lymphatic system disorders
    Systemic
         subjects affected / exposed
    16 / 134 (11.94%)
    19 / 131 (14.50%)
         occurrences all number
    16
    19
    Laboratory test abnormal
         subjects affected / exposed
    5 / 134 (3.73%)
    1 / 131 (0.76%)
         occurrences all number
    5
    1
    Eye disorders
    Ocular o visual
         subjects affected / exposed
    0 / 134 (0.00%)
    2 / 131 (1.53%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Gastrointestinal disorders
         subjects affected / exposed
    23 / 134 (17.16%)
    26 / 131 (19.85%)
         occurrences all number
    23
    26
    Respiratory, thoracic and mediastinal disorders
    Respiratory
         subjects affected / exposed
    17 / 134 (12.69%)
    18 / 131 (13.74%)
         occurrences all number
    17
    18
    Skin and subcutaneous tissue disorders
    Dermatological
         subjects affected / exposed
    8 / 134 (5.97%)
    14 / 131 (10.69%)
         occurrences all number
    8
    14
    Renal and urinary disorders
    Genitourinary
         subjects affected / exposed
    16 / 134 (11.94%)
    12 / 131 (9.16%)
         occurrences all number
    16
    12
    Musculoskeletal and connective tissue disorders
    Musculoskeletal
         subjects affected / exposed
    19 / 134 (14.18%)
    16 / 131 (12.21%)
         occurrences all number
    19
    16
    Infections and infestations
    Infections
         subjects affected / exposed
    35 / 134 (26.12%)
    28 / 131 (21.37%)
         occurrences all number
    35
    28

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 May 2016
    (1) Interim Analysis report at 6 months from the last patient included in the phase A. (2) No-follow up after virological failure
    27 May 2017
    (1) Study design modification: Deletion of the monotherapy arm in phase B (following DSMB recommendation) (2) Sites extension (3) Update of concomitant medication for the control arm (4) New sample number, modification of the study inclusion. (3) Update of the statistical analysis according to the new legislation (RD 1090/2015).
    26 Feb 2018
    (1) Sponsor Change (From Fundació Lluita Contra la Sida to Fundació Clínic per la recerca biomèdica) (2) Change of the PI from Hospital Arnau de Vilanova (3) Update of the study calendar (4) Update of the selection criteria (5) Update of the study Schedule (6) Update secundary variables and endpoints. (7) Safety and adverse events section update (8) Section update of Insurance policy and budget (9) Creation of a new substudy protocol about lumbar punction.

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

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34358497
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