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    Clinical Trial Results:
    New pharmacotherapeutic treatment options for crack-cocaine dependent people in the Netherlands: A double-blind, placebo-controlled randomized feasibility study of sustained release dexamphetamine

    Summary
    EudraCT number
    		 2013-004024-11
    Trial protocol
    		 NL  
    Global end of trial date
    30 Jun 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Aug 2022
    First version publication date
    20 Aug 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    60-60600-97-103
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Academic Psychiatric Centre; AMC-UvA
    Sponsor organisation address
    Meibergdreef 5, Amsterdam, Netherlands, 1105 AZ
    Public contact
    Dr. Vincent M. Hendriks, Parnassia Addiction Research Centre (PARC), Brijder Addiction Treatment, Parnassia Groep, +31 0883852034, Vincent.Hendriks@Brijder.nl
    Scientific contact
    Dr. Vincent M. Hendriks, Parnassia Addiction Research Centre (PARC), Brijder Addiction Treatment, Parnassia Groep, +31 0883852034, Vincent.Hendriks@Brijder.nl
    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
    10 Jan 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Jun 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This double-blind, placebo-controlled RCT aims to evaluate, in crack-cocaine dependent patients with comorbid heroin dependence, the response to medically prescribed oral dexamphetamine SR (60 mg/day) as an add-on to heroin-assisted treatment, in terms of cocaine use.
    Protection of trial subjects
    The study was approved by the medical ethics committee of the Academic Medical Centre of the University of Amsterdam. Health assessments included: blood sampling and electrocardiography (at baseline/screening and week 12); weekly medical monitoring of heart rate, blood pressure, and bodyweight; weekly standardised registration of (serious) adverse events and co-medication; monthly pregnancy testing (female patients).
    Background therapy
    		 co-prescription of inhalable or injectable diacetylmorphine and oral methadone
    Evidence for comparator
    		 placebo
    Actual start date of recruitment
    08 Aug 2014
    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
    Netherlands: 73
    Worldwide total number of subjects
    73
    EEA total number of subjects
    73
    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)
    72
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study participants were recruited from the population of patients currently receiving oral methadone plus inhalable or injectable diacetylmorphine for their concurrent heroin dependence in supervised heroin assisted treatment programmes in two treatment centres in Amsterdam, one in Rotterdam, and one in The Hague.

    Pre-assignment
    Screening details
    		 Inclusion criteria: (1) meeting inclusion criteria for heroin assisted treatment; (2) cocaine dependence (DSM-IV); (3) regular cocaine use; (4) primarily by means of basing (smoking crack-cocaine); (5) at least two earlier failed treatments for cocaine; (6) able and willing to participate in the 12-week study; and (7) written informed consent.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst
    Blinding implementation details
    Eligible patients were randomly assigned (1:1) to receive either 12 weeks oral sustained-release dexamfetamine or identical placebo. Randomisation was conducted by the collaborating pharmacist, using a computer-generated random number sequence with stratification by treatment centre (four centres) in blocks of four per stratum. Randomisation was concealed for patients, staff , and researchers throughout the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 dexamfetamine-SR
    Arm description
    		 dexamfetamine (in sustained-release formulation): supervised, single oral dose of 60 mg/day (2 tablets of 30 mg)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dexamfetamine sulphate 30 mg controlled release tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Supervised, daily intake of two tablets in the morning

    Arm title
    		 placebo
    Arm description
    		 placebo: supervised, single oral dose of 60 mg/day (2 tablets of 30 mg)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Supervised, daily intake of two tablets in the morning

    Number of subjects in period 1
    		dexamfetamine-SR placebo
    Started
    38
    35
    Completed
    34
    31
    Not completed
    4
    4
         incarceration
    2
    1
         Adverse event, non-fatal
    2
    2
         Lack of efficacy
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    dexamfetamine-SR
    Reporting group description
    		 dexamfetamine (in sustained-release formulation): supervised, single oral dose of 60 mg/day (2 tablets of 30 mg)

    Reporting group title
    placebo
    Reporting group description
    		 placebo: supervised, single oral dose of 60 mg/day (2 tablets of 30 mg)

    Reporting group values
    		 dexamfetamine-SR placebo Total
    Number of subjects
    		 38 35 73
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 48.4 ± 6.6 49.0 ± 5.3 -
    Gender categorical
    Units: Subjects
        Female
    		 3 4 7
        Male
    		 35 31 66
    Years cocaine use
    Units: years
        arithmetic mean (standard deviation)
    		 19.1 ± 7.7 19.9 ± 7.1 -
    years heroin use
    Units: years
        arithmetic mean (standard deviation)
    		 21.1 ± 8.4 23.0 ± 8.5 -
    previous number addiction treatments
    Units: number
        arithmetic mean (standard deviation)
    		 6.2 ± 3.2 8.4 ± 7.2 -
    duration heroin assisted treatment
    Units: months
        arithmetic mean (standard deviation)
    		 46.2 ± 34.3 57.5 ± 35.1 -
    Days cocaine use (past month)
    Units: days
        arithmetic mean (standard deviation)
    		 23.5 ± 7.6 23.7 ± 7.6 -

    End points

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    End points reporting groups
    Reporting group title
    dexamfetamine-SR
    Reporting group description
    		 dexamfetamine (in sustained-release formulation): supervised, single oral dose of 60 mg/day (2 tablets of 30 mg)

    Reporting group title
    placebo
    Reporting group description
    		 placebo: supervised, single oral dose of 60 mg/day (2 tablets of 30 mg)

    Primary: days cocaine use during 12 week study period

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    End point title
    		 days cocaine use during 12 week study period
    End point description
    days cocaine use during 12 week study period
    End point type
    Primary
    End point timeframe
    12 week study period
    End point values
    		 dexamfetamine-SR placebo
    Number of subjects analysed
    38
    35
    Units: days
        arithmetic mean (standard deviation)
    44.9 ± 29.4
    60.6 ± 24.3
    Statistical analysis title
    		 Primary outcome days cocaine use
    Statistical analysis description
    The primary outcome—ie, number of self-reported days of cocaine use during the 12-week study—was analysed with negative binomial regression analyses with treatment group as the only independent variable and the interaction of treatment group with treatment centre as the only effect modifier. To fit the negative binomial regression model, a reflection transformation was done on the negatively skewed data of the primary outcome (ie, 84 days minus cocaine use days).
    Comparison groups
    dexamfetamine-SR v placebo
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.1 [1]
    Method
    		 negative binomial regression analysis
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.05
         upper limit
    		 2.67
    Notes
    [1] - For this proof-of-principle study, a lenient alpha of 0·10 was chosen to minimise the risk of a false negative outcome (type 2 error).

    Secondary: Consecutive cocaine abstinence for ≥21 days

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    End point title
    		 Consecutive cocaine abstinence for ≥21 days
    End point description
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 dexamfetamine-SR placebo
    Number of subjects analysed
    38
    35
    Units: patients
    11
    2
    No statistical analyses for this end point

    Secondary: Days of cocaine abstinence in fi nal 4 weeks

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    End point title
    		 Days of cocaine abstinence in fi nal 4 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    4 weeks
    End point values
    		 dexamfetamine-SR placebo
    Number of subjects analysed
    38
    35
    Units: days
        arithmetic mean (standard deviation)
    15.2 ± 10.8
    7.5 ± 9.1
    No statistical analyses for this end point

    Secondary: cocaine-negative urine samples in final 4 weeks

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    End point title
    		 cocaine-negative urine samples in final 4 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    4 weeks
    End point values
    		 dexamfetamine-SR placebo
    Number of subjects analysed
    38
    35
    Units: Proportion
        arithmetic mean (standard deviation)
    10.6 ± 25.1
    3.9 ± 17.9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    12 week study period
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 non-specific
    Dictionary version
    1
    Reporting groups
    Reporting group title
    dexamfetamine
    Reporting group description
    		 Twenty-eight patients in the dexamfetamine group reported 69 adverse events, of which 58 (84%) events were possibly, probably, or certainly related to the study medication. Most of these adverse events (51 events; 74%) were resolved before the end of the study treatment. Sleeping problems was the adverse event reported by most patients (n=13; 34%). In four patients, adverse events resulted in (temporary) discontinuation of study treatment. Two patients resumed treatment with a dose of 30 mg/day sustained-release dexamfetamine, one patient discontinued medication intake due to psychotic symptoms, and one patient due to concurrent adverse events of mild to moderate severity.

    Reporting group title
    placebo
    Reporting group description
    		 Sixteen patients in the placebo group reported 26 adverse events, of which 18 (69%) were possibly, probably, or certainly related to the study medication.

    Serious adverse events
    		 dexamfetamine placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 35 (2.86%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Respiratory, thoracic and mediastinal disorders
    COPD assessment test
    Additional description: One serious adverse event occurred: a patient in the placebo group was admitted to hospital during the study period due to an exacerbation of chronic obstructive pulmonary disease, which was not related to the study drug.
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 35 (2.86%)
         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: 2.7%
    Non-serious adverse events
    		 dexamfetamine placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 38 (73.68%)
    16 / 35 (45.71%)
    Nervous system disorders
    Agitation / irritability
         subjects affected / exposed
    6 / 38 (15.79%)
    2 / 35 (5.71%)
         occurrences all number
    6
    2
    Physical arousal
         subjects affected / exposed
    5 / 38 (13.16%)
    2 / 35 (5.71%)
         occurrences all number
    5
    2
    General disorders and administration site conditions
    Influenza
         subjects affected / exposed
    3 / 38 (7.89%)
    3 / 35 (8.57%)
         occurrences all number
    3
    3
    Gastrointestinal disorders
    Changes in appetite
         subjects affected / exposed
    6 / 38 (15.79%)
    2 / 35 (5.71%)
         occurrences all number
    6
    2
    Changes in weight
         subjects affected / exposed
    5 / 38 (13.16%)
    2 / 35 (5.71%)
         occurrences all number
    5
    2
    Diarrhoea
         subjects affected / exposed
    5 / 38 (13.16%)
    3 / 35 (8.57%)
         occurrences all number
    5
    3
    Psychiatric disorders
    Sleeping problems
         subjects affected / exposed
    13 / 38 (34.21%)
    3 / 35 (8.57%)
         occurrences all number
    13
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

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

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/27015909
    http://www.ncbi.nlm.nih.gov/pubmed/31908066
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