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    Clinical Trial Results:
    Combined Immunotherapy and Trophic Adrenocortical Stimulation in New Onset Autoimmune Addison’s Disease

    Summary
    EudraCT number
    		 2012-001682-33
    Trial protocol
    		 GB  
    Global end of trial date
    16 May 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Mar 2019
    First version publication date
    29 Mar 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    6176/RADS2
    Additional study identifiers
    ISRCTN number
    		 ISRCTN20220821
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    The Newcastle upon Tyne Hospitals NHS Foundation Trust
    Sponsor organisation address
    Regent Point, Newcastle upon Tyne, United Kingdom, NE3 3HD
    Public contact
    Prof. Simon Pearce, Newcastle University, 44 01912418674, simon.pearce@ncl.ac.uk
    Scientific contact
    Prof. Simon Pearce, Newcastle University, 44 01912418674, simon.pearce@ncl.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
    03 Jul 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 May 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to restore adrenal function in patients with recent onset autoimmune Addison's disease. This study will answer the following questions: In people with new-onset autoimmune Addison’s disease will the therapeutic regimen of rituximab and ACTH allow improvement or recovery of adrenal function?
    Protection of trial subjects
    Rituximab infusion can be associated with transient adverse reactions in 50% of people including rash, flushing, shivers, fever, runny nose, hypotension, hypertension. Premedication with methylprednisolone, paracetamol and piriton will be given to minimise the risk of reactions. ACTH injections will be self administered subcutaneously every other day for the first 12 weeks, going to twice a week during week 12-16 and once weekly weeks 16-20. There is frequently itchiness and discomfort over the injection site that lasts for 48-72hrs. Bruising and swelling may also occur. Two education sessions about the best technique for avoiding pain and bruising at the injection sites will be given.
    Background therapy
    		 -
    Evidence for comparator
    		 No comparator was used in this trial.
    Actual start date of recruitment
    02 Jul 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 17
    Worldwide total number of subjects
    17
    EEA total number of subjects
    17
    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)
    17
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Clinicians from general hospitals/main centres identified patients with newly diagnosed Addison's disease and invited them to contact the centres if they were interested, or to access the information direct from the Addison's disease self help group website. Potential participants could request the PIS from Principal Investigators.

    Pre-assignment
    Screening details
    		 The screening visit included; confirmation of eligibility and written consent, and blood tests including SST, urine test, chest X-ray, CT scan adrenals, ACTH injection education.

    Period 1
    Period 1 title
    Baseline (Day 0)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Treatment
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Mabthera
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1g on days 1 and 15, by slow intravenous infusion under cover from methylprednisolone 125mg IV, piriton 10mg IV and paracetamol 1g PO.

    Investigational medicinal product name
    Synacthen Depot
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Parenteral use
    Dosage and administration details
    Depot synacthen 1mg self-administered on alternate days (week 1-12, followed by an 8 week tail)

    Investigational medicinal product name
    Methylprednisolone
    Investigational medicinal product code
    Other name
    Solu-Medrone
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Day 0 and Day 15, 125mg IV methylprednisolone

    Number of subjects in period 1
    		Treatment
    Started
    17
    Completed
    13
    Not completed
    4
         Ineligible
    4
    Period 2
    Period 2 title
    Treatment (Day 0 to Day 15)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Treatment
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Mabthera
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1g on days 1 and 15, by slow intravenous infusion under cover from methylprednisolone 125mg IV, piriton 10mg IV and paracetamol 1g PO.

    Investigational medicinal product name
    Synacthen Depot
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Parenteral use
    Dosage and administration details
    Depot synacthen 1mg self-administered on alternate days (week 1-12, followed by an 8 week tail)

    Investigational medicinal product name
    Methylprednisolone
    Investigational medicinal product code
    Other name
    Solu-Medrone
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Day 0 and Day 15, 125mg IV methylprednisolone

    Number of subjects in period 2
    		Treatment
    Started
    13
    Completed
    13
    Period 3
    Period 3 title
    Follow up 6 weeks
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Treatment
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Mabthera
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1g on days 1 and 15, by slow intravenous infusion under cover from methylprednisolone 125mg IV, piriton 10mg IV and paracetamol 1g PO.

    Investigational medicinal product name
    Synacthen Depot
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Parenteral use
    Dosage and administration details
    Depot synacthen 1mg self-administered on alternate days (week 1-12, followed by an 8 week tail)

    Investigational medicinal product name
    Methylprednisolone
    Investigational medicinal product code
    Other name
    Solu-Medrone
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Day 0 and Day 15, 125mg IV methylprednisolone

    Number of subjects in period 3
    		Treatment
    Started
    13
    Completed
    13
    Period 4
    Period 4 title
    Follow up 12 weeks
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Treatment
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Mabthera
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1g on days 1 and 15, by slow intravenous infusion under cover from methylprednisolone 125mg IV, piriton 10mg IV and paracetamol 1g PO.

    Investigational medicinal product name
    Synacthen Depot
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Parenteral use
    Dosage and administration details
    Depot synacthen 1mg self-administered on alternate days (week 1-12, followed by an 8 week tail)

    Investigational medicinal product name
    Methylprednisolone
    Investigational medicinal product code
    Other name
    Solu-Medrone
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Day 0 and Day 15, 125mg IV methylprednisolone

    Number of subjects in period 4
    		Treatment
    Started
    13
    Completed
    13
    Period 5
    Period 5 title
    Follow up 24 weeks
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Treatment
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Mabthera
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1g on days 1 and 15, by slow intravenous infusion under cover from methylprednisolone 125mg IV, piriton 10mg IV and paracetamol 1g PO.

    Investigational medicinal product name
    Synacthen Depot
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Parenteral use
    Dosage and administration details
    Depot synacthen 1mg self-administered on alternate days (week 1-12, followed by an 8 week tail)

    Investigational medicinal product name
    Methylprednisolone
    Investigational medicinal product code
    Other name
    Solu-Medrone
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Day 0 and Day 15, 125mg IV methylprednisolone

    Number of subjects in period 5
    		Treatment
    Started
    13
    Completed
    13
    Period 6
    Period 6 title
    Follow up 48 weeks
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Treatment
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Mabthera
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1g on days 1 and 15, by slow intravenous infusion under cover from methylprednisolone 125mg IV, piriton 10mg IV and paracetamol 1g PO.

    Investigational medicinal product name
    Synacthen Depot
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Parenteral use
    Dosage and administration details
    Depot synacthen 1mg self-administered on alternate days (week 1-12, followed by an 8 week tail)

    Investigational medicinal product name
    Methylprednisolone
    Investigational medicinal product code
    Other name
    Solu-Medrone
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Day 0 and Day 15, 125mg IV methylprednisolone

    Number of subjects in period 6
    		Treatment
    Started
    13
    Completed
    13
    Period 7
    Period 7 title
    Follow up 72 weeks
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Treatment
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Mabthera
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1g on days 1 and 15, by slow intravenous infusion under cover from methylprednisolone 125mg IV, piriton 10mg IV and paracetamol 1g PO.

    Investigational medicinal product name
    Synacthen Depot
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Parenteral use
    Dosage and administration details
    Depot synacthen 1mg self-administered on alternate days (week 1-12, followed by an 8 week tail)

    Investigational medicinal product name
    Methylprednisolone
    Investigational medicinal product code
    Other name
    Solu-Medrone
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Day 0 and Day 15, 125mg IV methylprednisolone

    Number of subjects in period 7
    		Treatment
    Started
    13
    Completed
    13

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline (Day 0)
    Reporting group description
    		 -

    Reporting group values
    		 Baseline (Day 0) Total
    Number of subjects
    		 17 17
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 17 17
    Gender categorical
    Units: Subjects
        Female
    		 11 11
        Male
    		 6 6

    End points

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    End points reporting groups
    Reporting group title
    Treatment
    Reporting group description
    		 -
    Reporting group title
    Treatment
    Reporting group description
    		 -
    Reporting group title
    Treatment
    Reporting group description
    		 -
    Reporting group title
    Treatment
    Reporting group description
    		 -
    Reporting group title
    Treatment
    Reporting group description
    		 -
    Reporting group title
    Treatment
    Reporting group description
    		 -
    Reporting group title
    Treatment
    Reporting group description
    		 -

    Primary: Proportion achieving restoration of normal glucocorticoid secretion (peak cortisol >550nmol/l) after repeat synacthen testing at 48 weeks

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    End point title
    		 Proportion achieving restoration of normal glucocorticoid secretion (peak cortisol >550nmol/l) after repeat synacthen testing at 48 weeks [1]
    End point description
    End point type
    Primary
    End point timeframe
    Serum cortisol levels will be measured at 6, 12, 24, 48 or 72 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistically significant results at 6, 12, 24, 48 or 72 weeks
    End point values
    		 Treatment
    Number of subjects analysed
    13
    Units: nmol/l
        number (not applicable)
    0
    No statistical analyses for this end point

    Secondary: Proportion achieving improvement of basal and peak cortisol response (>100nmol/l over baseline) to synacthen testing at 12 weeks

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    End point title
    		 Proportion achieving improvement of basal and peak cortisol response (>100nmol/l over baseline) to synacthen testing at 12 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Synacthen testing at 12 weeks Non significant for this secondary endpoint at all time points
    End point values
    		 Treatment
    Number of subjects analysed
    13 [2]
    Units: nmol/l
        number (not applicable)
    8
    Notes
    [2] - 1/13 (8%)
    No statistical analyses for this end point

    Secondary: Proportion achieving improvement of basal and peak cortisol response (>100nmol/l over baseline) to synacthen testing at 24 weeks

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    End point title
    		 Proportion achieving improvement of basal and peak cortisol response (>100nmol/l over baseline) to synacthen testing at 24 weeks
    End point description
    Basal and peak cortisol response >100nmol/l over baseline
    End point type
    Secondary
    End point timeframe
    Synacthen testing at 24 weeks Non significant for this secondary endpoint at all time points
    End point values
    		 Treatment
    Number of subjects analysed
    13
    Units: Number of participants
        number (not applicable)
    0
    No statistical analyses for this end point

    Secondary: Proportion achieving improvement of basal and peak cortisol response (>100nmol/l over baseline) to synacthen testing at 48 weeks

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    End point title
    		 Proportion achieving improvement of basal and peak cortisol response (>100nmol/l over baseline) to synacthen testing at 48 weeks
    End point description
    >100nmol/l over baseline
    End point type
    Secondary
    End point timeframe
    Response to synacthen testing at 48 weeks Non significant for this secondary endpoint at all time points
    End point values
    		 Treatment
    Number of subjects analysed
    13
    Units: Number
        number (not applicable)
    0
    No statistical analyses for this end point

    Secondary: Proportion achieving improvement of basal and peak cortisol response (>100nmol/l over baseline) to synacthen testing at 72 weeks

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    End point title
    		 Proportion achieving improvement of basal and peak cortisol response (>100nmol/l over baseline) to synacthen testing at 72 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Response to synacthen testing at 72 weeks Non significant for this secondary endpoint at all time points
    End point values
    		 Treatment
    Number of subjects analysed
    13
    Units: nmol/l
        number (not applicable)
    0
    No statistical analyses for this end point

    Secondary: Urine GCMS/MS steroid profile

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    End point title
    		 Urine GCMS/MS steroid profile
    End point description
    See attached document
    End point type
    Secondary
    End point timeframe
    Measured at baseline, week 12 and week 48
    End point values
    		 Treatment
    Number of subjects analysed
    13 [3]
    Units: Participants
    8
    Attachments
    		 Urine steroids
    Notes
    [3] - Steroid Metabolite Response in 8/13 Patients with an Increase in Urinary Steroid Excretion
    No statistical analyses for this end point

    Secondary: Change in peripheral B lymphocyte count at baseline

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    End point title
    		 Change in peripheral B lymphocyte count at baseline
    End point description
    Change in peripheral B lymphocyte count at baseline. CD19* population expressed as a percentage of parent lymphocyte population. 10,000 lymphocyte events counted twice for each measurement. Complete depletion was judged as CD19* <0.1% of lymphocytes. Change in peripheral T lymphocyte count at baseline, 6, 12, 24, 36, 48 and 72 weeks was not measured.
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Treatment
    Number of subjects analysed
    13
    Units: percentage
    number (not applicable)
        NCL01
    9.8
        NCL04
    22.4
        NCL05
    10.7
        NCL06
    27.2
        NCL08
    9.4
        NCL09
    16.6
        NCL10
    15.8
        EXE01
    11.2
        EXE02
    15.5
        EXE04
    2.8
        EXE05
    24.6
        CAMB01
    10.4
        CARD01
    12.3
    Attachments
    		 B-lymphocyte depletion
    No statistical analyses for this end point

    Secondary: Patient reported quality of life (EQ5D)

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    End point title
    		 Patient reported quality of life (EQ5D)
    End point description
    Number of patients scoring 1, 2 or 3 for each domain. 1 = 'no problems'; 2 = 'some problems'; 3 = 'extreme problems'
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12 and Week 48
    End point values
    		 Treatment Treatment Treatment
    Number of subjects analysed
    13 [4]
    13 [5]
    13 [6]
    Units: Scale Score
    number (not applicable)
        Mobility (1)
    1
    11
    11
        Mobility (2)
    10
    2
    2
        Mobility (3)
    2
    0
    0
        Self-care (1)
    1
    12
    10
        Self-care (2)
    12
    1
    3
        Self-care (3)
    0
    0
    0
        Usual activities (1)
    0
    9
    8
        Usual activities (2)
    7
    4
    5
        Usual activities (3)
    6
    0
    0
        Pain/Discomfort (1)
    0
    9
    6
        Pain/Discomfort (2)
    9
    4
    7
        Pain/Discomfort (3)
    4
    0
    0
        Anxiety/Depression (1)
    1
    11
    8
        Anxiety/Depression (2)
    7
    1
    5
        Anxiety/Depression (3)
    5
    1
    0
    Notes
    [4] - Baseline
    [5] - Week 12
    [6] - Week 48
    No statistical analyses for this end point

    Secondary: Patient reported quality of life (AddiQoL)

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    End point title
    		 Patient reported quality of life (AddiQoL)
    End point description
    AddiQoL scores at Week 12 and Week 48 vs. Baseline. Total score 120, higher score is better subjective QoL. Non-significant change in QoL at all time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12 and Week 48
    End point values
    		 Treatment Treatment Treatment
    Number of subjects analysed
    13 [7]
    13 [8]
    13 [9]
    Units: Scale Score
        arithmetic mean (standard deviation)
    84.62 ( 15.9 )
    88.15 ( 14.9 )
    87.69 ( 14.24 )
    Notes
    [7] - Baseline
    [8] - Baseline vs Week 12, p = 0.41
    [9] - Baseline vs Week 48, p = 0.41
    No statistical analyses for this end point

    Secondary: VAS wellbeing score

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    End point title
    		 VAS wellbeing score
    End point description
    Visual Analogue Scale Scores. Highest score is 100 (= best health state you can imagine). Non-significant change in QoL as measured by VAS at all time points.
    End point type
    Secondary
    End point timeframe
    Week 12 and Week 48 vs. Baseline
    End point values
    		 Treatment Treatment Treatment
    Number of subjects analysed
    13 [10]
    13 [11]
    13 [12]
    Units: Scale Score
        arithmetic mean (standard deviation)
    74.77 ( 19.19 )
    75.31 ( 24.51 )
    77.5 ( 17.74 )
    Notes
    [10] - Baseline
    [11] - Baseline vs Week 12, p = 0.94
    [12] - Baseline vs Week 48, p = 0.39
    No statistical analyses for this end point

    Secondary: Change in peripheral B lymphocyte count at 6 weeks

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    End point title
    		 Change in peripheral B lymphocyte count at 6 weeks
    End point description
    Change in peripheral B lymphocyte count at 6 weeks. CD19* population expressed as a percentage of parent lymphocyte population. 10,000 lymphocyte events counted twice for each measurement. Complete depletion was judged as CD19* <0.1% of lymphocytes.
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Treatment
    Number of subjects analysed
    11
    Units: percent
    number (not applicable)
        NCL01
    0.2
        NCL04
    0.3
        NCL05
    0.1
        NCL06
    0.1
        NCL08
    0.1
        NCL09
    0.2
        NCL10
    0.1
        EXE01
    0.2
        EXE04
    0.2
        EXE05
    0.1
        CARD01
    0.1
    No statistical analyses for this end point

    Secondary: Change in peripheral B lymphocyte count at 12 weeks.

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    End point title
    		 Change in peripheral B lymphocyte count at 12 weeks.
    End point description
    Change in peripheral B lymphocyte count at 12 weeks. CD19* population expressed as a percentage of parent lymphocyte population. 10,000 lymphocyte events counted twice for each measurement. Complete depletion was judged as CD19* <0.1% of lymphocytes.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Treatment
    Number of subjects analysed
    12
    Units: percent
    number (not applicable)
        NCL01
    0.9
        NCL04
    0.2
        NCL05
    0.2
        NCL06
    0.1
        NCL08
    0.1
        NCL09
    0.1
        NCL10
    0.0
        EXE01
    0.4
        EXE02
    0.1
        EXE04
    0.2
        EXE05
    0.1
        CAMB01
    0.1
    No statistical analyses for this end point

    Secondary: Change in peripheral B lymphocyte count at 24 weeks

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    End point title
    		 Change in peripheral B lymphocyte count at 24 weeks
    End point description
    Change in peripheral B lymphocyte count at 24 weeks. CD19* population expressed as a percentage of parent lymphocyte population. 10,000 lymphocyte events counted twice for each measurement. Complete depletion was judged as CD19* <0.1% of lymphocytes.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Treatment
    Number of subjects analysed
    11
    Units: percent
    number (not applicable)
        NCL01
    0.1
        NCL04
    0.1
        NCL05
    0.1
        NCL06
    0.2
        NCL08
    0.1
        NCL09
    0.0
        NCL10
    0.6
        EXE01
    2.1
        EXE04
    0.1
        EXE05
    0.1
        CAMB01
    0.5
    No statistical analyses for this end point

    Secondary: Change in peripheral B lymphocyte count at 48 weeks

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    End point title
    		 Change in peripheral B lymphocyte count at 48 weeks
    End point description
    Change in peripheral B lymphocyte count at 48 weeks. CD19* population expressed as a percentage of parent lymphocyte population. 10,000 lymphocyte events counted twice for each measurement. Complete depletion was judged as CD19* <0.1% of lymphocytes.
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    		 Treatment
    Number of subjects analysed
    13
    Units: percent
    number (not applicable)
        NCL01
    2.1
        NCL04
    0.0
        NCL05
    2.6
        NCL06
    9.7
        NCL08
    2.5
        NCL09
    3.9
        NCL10
    3.3
        EXE01
    18.8
        EXE02
    8.2
        EXE04
    5.9
        EXE05
    5.9
        CAMB01
    3.7
        CARD01
    0.8
    No statistical analyses for this end point

    Secondary: Change in peripheral B lymphocyte count at 72 weeks.

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    End point title
    		 Change in peripheral B lymphocyte count at 72 weeks.
    End point description
    Change in peripheral B lymphocyte count at 72 weeks. CD19+ population expressed as a percentage of parent lymphocyte population. 10,000 lymphocyte events counted twice for each measurement. Complete depletion was judged as CD19+ <0.1% of lymphocytes. 12/13 patients achieved CD19+ lymphocyte counts measured as 0.0 or 0.1% of the parent population following treatment with rituximab. These included NCL06 who achieved the highest peak cortisol post-intervention and NCL08 who achieved the secondary outcome measure of a rise in cortisol of 100nmol/L post-intervention. In most patients, counts remained low for several months (minimum 12 - maximum 48 depleted weeks), with CD19+ population counts measured as 0.0 - 0.2% of parent population across several major outcome visits. Resurgence (>0.05%) of parent population) was detectable in all patients by the end of study and occurred after a mean period of 48 week (SEM 3.84).
    End point type
    Secondary
    End point timeframe
    72 weeks
    End point values
    		 Treatment
    Number of subjects analysed
    12
    Units: percent
    number (not applicable)
        NCL01
    7.7
        NCL04
    0.6
        NCL05
    9.6
        NCL06
    16.2
        NCL08
    3.3
        NCL09
    8.5
        EXE01
    15.2
        EXE02
    13.8
        EXE04
    7.0
        EXE05
    6.9
        CAMB01
    14.9
        CARD01
    2.4
    No statistical analyses for this end point

    Secondary: Normalisation of DHEAS levels at 48 weeks

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    End point title
    		 Normalisation of DHEAS levels at 48 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    		 Treatment
    Number of subjects analysed
    13 [13]
    Units: percent
        number (not applicable)
    0
    Notes
    [13] - 0% of patients achieved normalisation at 48 weeks. Non-significant (p=0.13)
    No statistical analyses for this end point

    Secondary: Normalisation of 17αOH progesterone levels

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    End point title
    		 Normalisation of 17αOH progesterone levels
    End point description
    46% (6/13) patients had results in the normal lab reference range at 48 weeks, non significant p=0.52 (BUT, all 6/13 also had results in normal range at the point of trial entry/first biochemical screening)
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    		 Treatment
    Number of subjects analysed
    13 [14]
    Units: percent
        number (not applicable)
    46
    Notes
    [14] - 6/13 (46%) also had results in normal range at the point of trial entry/first biochemical screening)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to end of study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Treatment group
    Reporting group description
    		 -

    Serious adverse events
    		 Treatment group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 17 (23.53%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Laceration
    Additional description: Laceration to face after fall
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Gastroenteritis
    Additional description: Gastroenteritis including dehydration
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting and watery diarrhoea
    Additional description: High temperature
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
    Additional description: Diarrhoea and vomiting
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Treatment group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 17 (70.59%)
    Injury, poisoning and procedural complications
    Black eye
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Fall
    Additional description: Fall from bike
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    General disorders and administration site conditions
    Headache
         subjects affected / exposed
    5 / 17 (29.41%)
         occurrences all number
    5
    Sore throat
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    Viral illness
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Flu symptoms
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Back pain
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    'Cold'
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Insomnia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Dizziness
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Paraesthesia
    Additional description: In both hands
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Swelling/bruising to abdomen
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    'Cold'/URTI
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Short of breath/fatigue
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Dehydration
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Weight loss and dizziness
    Additional description: Later diagnosed with Grave's disease
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    2
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 17 (17.65%)
         occurrences all number
    6
    Nausea
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    3
    Vomiting
         subjects affected / exposed
    3 / 17 (17.65%)
         occurrences all number
    3
    Abdominal pain
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    Abdominal pain upper
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Stomach bloating
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 17 (29.41%)
         occurrences all number
    15
    Cough
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    dyspnoea
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Renal and urinary disorders
    Urinary tract infection
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    3
    Endocrine disorders
    Hypothyroidism (subclinical)
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Infections and infestations
    Sinusitis
         subjects affected / exposed
    3 / 17 (17.65%)
         occurrences all number
    3
    Ear infection
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Tonsillitis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Folliculitis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Bronchitis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Feb 2013
    Update to information in the Participant Information Sheet to reflect the radiation risks in the study.
    24 Mar 2014
    Amendment to inclusion criteria, to increase the time allowed from diagnosis of autoimmune Addison’s disease from 28 days (4 weeks) to 56 days (8 weeks). Increase the number of sites from 3 to 5 centres across the UK. Addition of a ‘Study Patient ID Card’ for Rituximab, as specified in the Rituximab (Mabthera) SmPC. Addition of GP letter and Study Withdrawal Form. Amendments to the protocol in accordance with current SPIRIT guidelines for protocol format.

    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
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    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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