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    Clinical Trial Results:
    Prospective randomised controlled trial to investigate the effectiveness of inhalers for the relief of breathlessness in patients with lung cancer and COPD

    Summary
    EudraCT number
    		 2010-021412-42
    Trial protocol
    		 GB  
    Global end of trial date
    14 Jul 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Jul 2019
    First version publication date
    11 Jul 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ADOPT Version 4
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    The Royal Marsden NHS Foundation Trust
    Sponsor organisation address
    Fulham Road, London, United Kingdom, SW3 6JJ
    Public contact
    The Royal Marsden NHS Foundation Trust, The Royal Marsden NHS Foundation Trust, +44 02086426011,
    Scientific contact
    The Royal Marsden NHS Foundation Trust, The Royal Marsden NHS Foundation Trust, +44 02086426011,
    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 Apr 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Jul 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Jul 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To investigate whether optimisation of inhaler therapy in patients with lung cancer and co-existing COPD improves breathlessness (an increase in the proportion of patients with COPD and Lung cancer who have an improvement in their visual analogue scale for breathlessness) at 4 weeks compared to best supportive care.
    Protection of trial subjects
    The study design took into account the possible poor prognosis of patients with lung cancer. The aim was to attain the maximum possible benefit with inhaler therapy in the shortest period of time with minimal disturbance to the patients. Therefore it was decided a priori that the intervention group would be treated with maximum inhaled therapy rather than the stepwise approach suggested by the British Thoracic Society and similar organisations. There were regular meetings to review adverse events and progress of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Apr 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: 65
    Worldwide total number of subjects
    65
    EEA total number of subjects
    65
    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)
    23
    From 65 to 84 years
    42
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 First patient was recruited to the study on 08/04/2011. Recruitment of subjects continued until the last patient recruited to the study on 16/06/2016.

    Pre-assignment
    Screening details
    		 65 patients were screened but 1 patient was a screening failure. Out of the 64 patients consenting to study, 1 patient failed inclusion criteria with only 63 patients being eligible for study.

    Pre-assignment period milestones
    Number of subjects started
    		 65
    Number of subjects completed
    		 63

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 failed inclusion criteria of VAS dyspnoea ≥ 4: 1
    Reason: Number of subjects
    		 ineligible as no spirometry evidence of COPD: 1
    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Inhalers + BSC
    Arm description
    		 Best supportive care and optimisation of inhalers
    Arm type
    		 Experimental

    Investigational medicinal product name
    VentolinTM EvohalerTM
    Investigational medicinal product code
    R03AK04
    Other name
    Pharmaceutical forms
    Inhalation vapour
    Routes of administration
    Inhalation use
    Dosage and administration details
    All patients will be commenced on - EvohalerTM 100 microgram Evohaler 2 puffs inhaled 4 times a day (Maximum dose of 200 micrograms) Maximum duration of treatment of a subject according to the protocol - 4 weeks during the study period but patients may continue after the study

    Investigational medicinal product name
    Spiriva®
    Investigational medicinal product code
    R03BB04
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    All patients will be commenced on - Spiriva® 18 micrograms inhaled once daily via Handihaler® (1 capsule) Maximum dose of 18 micrograms) Maximum duration of treatment of a subject according to the protocol - 4 weeks during the study period but patients may continue after the study

    Investigational medicinal product name
    Seretide® Accuhaler® 50 micrograms (salmeterol)/500 micrograms (fluticasone)
    Investigational medicinal product code
    R03BA04
    Other name
    Fluticasone propionate  
    Pharmaceutical forms
    Inhalation powder, pre-dispensed
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants with an FEV1 of < 50% predicted normal and a history suggestive of repeated exacerbations despite bronchodilator use will also be commenced on - Fluticasone propionate 500 micrograms twice a day (total dose of 14 mg) Maximum duration of treatment of a subject according to the protocol - 4 weeks during the study period but patients may continue after the study

    Arm title
    		 BSC (control)
    Arm description
    		 Best supportive care alone
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Oramorph
    Investigational medicinal product code
    Other name
    oral morphine solution
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Patients will have no alterations to their current COPD management or no intervention if previously not diagnosed with COPD. Breathlessness will be managed according to local practice guidelines for managing breathlessness.The clinician managing the patient, in consultation with the patient, will decide the most appropriate intervention. This may include non-pharmacological as well as pharmacological measures. Current guidelines at the Royal Marsden recommend that oramorph (oral morphine solution) is used if pharmacological measures are required. Opiate naïve patients are prescribed oramorph 10mg/5ml solution and are instructed to take 2.5mg as required at 4 hourly intervals. Patients on regular opioids for pain relief are prescribed 10mg/5ml and are prescribed 5mg at 4 hourly intervals.

    Number of subjects in period 1 [1]
    		Inhalers + BSC BSC (control)
    Started
    32
    31
    Completed
    32
    31
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 65 patients were screened but 1 patient was a screening failure. Out of the 64 patients consenting to the study, 1 patient failed inclusion criteria with only 63 patients being eligible for study.
    Period 2
    Period 2 title
    4 week assessment
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Inhalers + BSC
    Arm description
    		 Best supportive care and optimisation of inhalers
    Arm type
    		 Experimental

    Investigational medicinal product name
    VentolinTM EvohalerTM
    Investigational medicinal product code
    R03AK04
    Other name
    Pharmaceutical forms
    Inhalation vapour
    Routes of administration
    Inhalation use
    Dosage and administration details
    All patients will be commenced on - EvohalerTM 100 microgram Evohaler 2 puffs inhaled 4 times a day (Maximum dose of 200 micrograms) Maximum duration of treatment of a subject according to the protocol - 4 weeks during the study period but patients may continue after the study

    Investigational medicinal product name
    Spiriva®
    Investigational medicinal product code
    R03BB04
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    All patients will be commenced on - Spiriva® 18 micrograms inhaled once daily via Handihaler® (1 capsule) Maximum dose of 18 micrograms) Maximum duration of treatment of a subject according to the protocol - 4 weeks during the study period but patients may continue after the study

    Investigational medicinal product name
    Seretide® Accuhaler® 50 micrograms (salmeterol)/500 micrograms (fluticasone)
    Investigational medicinal product code
    R03BA04
    Other name
    Fluticasone propionate
    Pharmaceutical forms
    Inhalation powder, pre-dispensed
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants with an FEV1 of < 50% predicted normal and a history suggestive of repeated exacerbations despite bronchodilator use will also be commenced on - Fluticasone propionate 500 micrograms twice a day (total dose of 14 mg) Maximum duration of treatment of a subject according to the protocol - 4 weeks during the study period but patients may continue after the study

    Arm title
    		 BSC (control)
    Arm description
    		 Best supportive care alone
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Oramorph
    Investigational medicinal product code
    Other name
    oral morphine solution
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Patients will have no alterations to their current COPD management or no intervention if previously not diagnosed with COPD. Breathlessness will be managed according to local practice guidelines for managing breathlessness.The clinician managing the patient, in consultation with the patient, will decide the most appropriate intervention. This may include non-pharmacological as well as pharmacological measures. Current guidelines at the Royal Marsden recommend that oramorph (oral morphine solution) is used if pharmacological measures are required. Opiate naïve patients are prescribed oramorph 10mg/5ml solution and are instructed to take 2.5mg as required at 4 hourly intervals. Patients on regular opioids for pain relief are prescribed 10mg/5ml and are prescribed 5mg at 4 hourly intervals.

    Number of subjects in period 2
    		Inhalers + BSC BSC (control)
    Started
    32
    31
    Completed
    30
    28
    Not completed
    2
    3
         Adverse event, non-fatal
    2
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Inhalers + BSC
    Reporting group description
    		 Best supportive care and optimisation of inhalers

    Reporting group title
    BSC (control)
    Reporting group description
    		 Best supportive care alone

    Reporting group values
    		 Inhalers + BSC BSC (control) Total
    Number of subjects
    		 32 31 63
    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
    Age (at Diagnosis)
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 68 (59 to 75) 67 (61 to 71) -
    Gender categorical
    Units: Subjects
        Female
    		 21 19 40
        Male
    		 11 12 23
    Smoking History
    Units: Subjects
        Current Smoker
    		 4 8 12
        Ex-Smoker
    		 28 23 51
    Histology/Cytology
    Units: Subjects
        NSCLC
    		 28 25 53
        SCLC
    		 4 6 10
    Staging - NSCLC
    NSCLC categories are 1, 2, 3, 4
    Units: Subjects
        1/2
    		 7 12 19
        03
    		 11 5 16
        04
    		 10 8 18
        Missing
    		 4 6 10
    Staging - SCLC
    Units: Subjects
        Limited
    		 3 4 7
        Extensive
    		 1 2 3
        Missing
    		 28 25 53
    ECOG Performance Status
    Units: Subjects
        ECOG-0
    		 1 0 1
        ECOG-1
    		 25 25 50
        ECOG-2
    		 6 6 12
    Treatment Paradigm
    Units: Subjects
        Radical
    		 16 13 29
        Palliative
    		 16 18 34
    Prior Thoracic Surgery
    Units: Subjects
        Yes
    		 9 13 22
        No
    		 23 18 41
    Prior Thoracic Radiotherapy
    Units: Subjects
        Yes
    		 15 16 31
        No
    		 17 15 32
    Tumour position
    Units: Subjects
        Large airway
    		 14 10 24
        Peripheral
    		 17 20 37
        Not Applicable
    		 1 1 2
    VAS dyspnoea
    Units: 0 to 10cm scale
        median (inter-quartile range (Q1-Q3))
    		 7.1 (5.4 to 7.7) 7.1 (4.9 to 7.7) -
    Six-minute walk distance (6MWD)
    Units: Meters
        median (inter-quartile range (Q1-Q3))
    		 375 (325 to 450) 396.5 (333 to 450) -
    MRC Dyspnoea
    MRC Dyspnoea scale ranges from score 1 (Breathless only with strenuous exercise) up to score 5 (Too breathless to leave the house) ; taking integer values
    Units: integer score (1 to 5)
        median (inter-quartile range (Q1-Q3))
    		 3 (2 to 4) 3 (2 to 3) -
    BODE index
    Units: integer score 0 to 10
        median (inter-quartile range (Q1-Q3))
    		 3 (2 to 4) 3.5 (2.5 to 4.5) -
    FEV1
    Forced Expiratory Volume which calculates the amount of air that a person can force out of their lungs in 1 second
    Units: Litres
        median (inter-quartile range (Q1-Q3))
    		 1.5 (1.2 to 1.9) 1.5 (1.2 to 2.1) -
    FEV1 (% predicted normal)
    Units: % predicted normal
        median (inter-quartile range (Q1-Q3))
    		 64 (53 to 74.5) 63 (53 to 73) -
    PEFR
    Peak Expiratory Flow Rate
    Units: Liters per minute (L/min)
        median (inter-quartile range (Q1-Q3))
    		 198.5 (154 to 283) 204 (172 to 292) -
    QOL Global Health
    Health-related Quality of Life Assessed by the EORTC QLQ-C30 Questionnaire - scores are for global health-status scale
    Units: score from 0 to 100
        median (inter-quartile range (Q1-Q3))
    		 66.7 (50 to 75) 66.7 (50 to 83.3) -
    QOL Dyspnoea
    Health-related Quality of Life Assessed by the EORTC QLQ-C30 Questionnaire - scores are for dyspnoea scale
    Units: score from 0 to 100
        median (inter-quartile range (Q1-Q3))
    		 38.9 (33.3 to 44.4) 33.3 (22.2 to 55.6) -
    SGRQ physical activity scale
    St George’s Respiratory Questionnaire (SGRQ) Activity scale. The Activity score measures disturbances to patients daily physical activity that cause or are limited by breathlessness. Scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status.
    Units: score from 0 to 100
        median (inter-quartile range (Q1-Q3))
    		 66.3 (53.5 to 79.1) 66.2 (47.7 to 73.2) -

    End points

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    End points reporting groups
    Reporting group title
    Inhalers + BSC
    Reporting group description
    		 Best supportive care and optimisation of inhalers

    Reporting group title
    BSC (control)
    Reporting group description
    		 Best supportive care alone
    Reporting group title
    Inhalers + BSC
    Reporting group description
    		 Best supportive care and optimisation of inhalers

    Reporting group title
    BSC (control)
    Reporting group description
    		 Best supportive care alone

    Subject analysis set title
    VAS Dyspnoea response at 4 weeks (Inhalers + BSC)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients are classed as responders if their VAS dyspnoea measurement at 4 weeks is recorded as a >/= 2 point reduction compared to baseline. Patients whose score is not recorded or withdrawn before the 4 week assessment for any reason are considered to be non-responders.

    Subject analysis set title
    VAS Dyspnoea response at 4 weeks (BSC control)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients are classed as responders if their VAS dyspnoea measurement at 4 weeks is recorded as a >/= 2 point reduction compared to baseline. Patients whose score is not recorded or withdrawn before the 4 week assessment for any reason are considered to be non-responders.

    Subject analysis set title
    VAS Dyspnoea response at 4 weeks - All eligible subjects
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients are classed as responders if their VAS dyspnoea measurement at 4 weeks is recorded as a >/= 2 point reduction compared to baseline. Patients whose score is not recorded or withdrawn before the 4 week assessment for any reason are considered to be non-responders.

    Primary: To investigate whether optimisation of inhaler therapy increases the proportion of patients who have a >/= 2 point change in their visual analogue scale (VAS) for dyspnoea (breathlessness) at 4 weeks compared to best supportive care

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    End point title
    		 To investigate whether optimisation of inhaler therapy increases the proportion of patients who have a >/= 2 point change in their visual analogue scale (VAS) for dyspnoea (breathlessness) at 4 weeks compared to best supportive care
    End point description
    Patients are classed as responders if their VAS dyspnoea measurement at 4 weeks is recorded as a >/= 2 point reduction compared to baseline. Patients whose score is not recorded or withdrawn before the 4 week assessment for any reason are considered to be non-responders. Analysed as per ITT population i.e. all randomised patients fulfilling the eligibility criteria (63 patients).
    End point type
    Primary
    End point timeframe
    VAS Dyspnoea measure at baseline and 4 weeks
    End point values
    		 VAS Dyspnoea response at 4 weeks (Inhalers + BSC) VAS Dyspnoea response at 4 weeks (BSC control) VAS Dyspnoea response at 4 weeks - All eligible subjects
    Number of subjects analysed
    32
    31
    63
    Units: proportion
    number (confidence interval 95%)
        Response rate
    53 (35 to 71)
    26 (12 to 45)
    40 (28 to 53)
        Non-response rate
    47 (29 to 65)
    74 (55 to 88)
    60 (47 to 72)
    Attachments
    		 Response rate
    Statistical analysis title
    		 VAS response at 4 weeks from baseline between arms
    Statistical analysis description
    Difference between responders and non-responders of 2-points (or more) reduction in VAS dyspnoea at 4 weeks compared to baseline, when compared between the two treatment groups
    Comparison groups
    VAS Dyspnoea response at 4 weeks (Inhalers + BSC) v VAS Dyspnoea response at 4 weeks (BSC control)
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.027
    Method
    		 Chi-squared
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event that develops or worsens in severity during the course of the study, as well as worsening of a pre-existing medical condition from the time that a patient has signed informed consent to the time of initiation of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    3.0
    Reporting groups
    Reporting group title
    Inhalers + BSC
    Reporting group description
    		 Best supportive care and optimisation of inhalers

    Reporting group title
    BSC (control)
    Reporting group description
    		 Best supportive care alone

    Serious adverse events
    		 Inhalers + BSC BSC (control)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 31 (3.23%)
         number of deaths (all causes)
    2
    5
         number of deaths resulting from adverse events
    0
    0
    General disorders and administration site conditions
    Fatigue
    Additional description: Grade 3
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchial infection
    Additional description: Grade 3
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 31 (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: 5%
    Non-serious adverse events
    		 Inhalers + BSC BSC (control)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    Psychiatric disorders
    Insomnia
    Additional description: Grade 2
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Jul 2014
    Protocol updated to version 4.0 dated 01-May-2014, revised to add new secondary end points. More information provided about assessment schedule and process of blood samples.

    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 did not meet its recruitment target but due to changes in the treatment landscapes, it was not beneficial to continue. The trial was slow to recruit reflecting a trend towards wider prescribing of long-acting bronchodilators by physicians.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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