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    Clinical Trial Results:
    A randomised, multi-centre, double-blind, active-controlled, parallel group study to assess the efficacy and safety of modified release prednisone (Lodotra®) compared to immediate release prednisone (prednisone IR) in subjects suffering from polymyalgia rheumatica (PMR).

    Summary
    EudraCT number
    		 2011-002353-57
    Trial protocol
    		 DE   CZ   GB   HU   ES   DK   IT  
    Global end of trial date
    25 Mar 2014

    Results information
    Results version number
    		 v3(current)
    This version publication date
    08 Jul 2016
    First version publication date
    07 Aug 2015
    Other versions
    		 v1 , v2
    Version creation reason
    • Changes to summary attachments
    Removal of user due to them leaving the company.

    Trial information

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    Trial identification
    Sponsor protocol code
    LOD3501
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Mundipharma Research Ltd
    Sponsor organisation address
    Cambridge Science Park, Cambridge, United Kingdom, CB4 0GW
    Public contact
    European Medical Operations, Mundipharma Research Ltd, 44 1223 424900, info@contact-clinical-trials.com
    Scientific contact
    European Medical Operations, Mundipharma Research Ltd, 44 1223 424900, info@contact-clinical-trials.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
    25 Mar 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Mar 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Mar 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To show that treatment with Lodotra® (starting dose of 15 mg daily), administered in the evening, is non-inferior to treatment with prednisone IR (starting dose of 15 mg daily), administered in the morning, with regards to the percentage of complete responders to treatment 4 weeks after randomisation.
    Protection of trial subjects
    All subjects were provided with oral and written information describing the nature and duration of the study, its purpose, the procedures to be performed, the potential risks and benefits involved, and any potential discomfort. Each subject was given a copy of the Patient Information Sheet (PIS) and Informed Consent Form (ICF). The subject was asked to sign and date an ICF prior to any study-specific procedures being performed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Nov 2012
    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
    Poland: 8
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Czech Republic: 8
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    Germany: 21
    Country: Number of subjects enrolled
    Hungary: 11
    Country: Number of subjects enrolled
    Italy: 3
    Worldwide total number of subjects
    62
    EEA total number of subjects
    62
    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)
    16
    From 65 to 84 years
    45
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 124 Subjects were enrolled into the study across 41 sites in 9 countries (Germany (11 sites) Czech Republic (six sites), Spain (six sites), Poland (five sites), Hungary (five sites), United Kingdom (four sites), Denmark (two sites), Romania (one site) and Italy (one site)) between 20 March 2013 and 25 March 2014.

    Pre-assignment
    Screening details
    		 124 subjects provided written informed consent, were enrolled and screened. 62 subjects failed screening therefore 62 subjects were randomised into the study. The most common reasons for screen failure were 'Failed screening procedure' (34 subjects) and 'Subject did not meet randomisation criteria' (26 subjects).

    Period 1
    Period 1 title
    Double-Blind Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    The subject and all personnel involved with the conduct and interpretation of the study (Investigators, site personnel, and the Sponsor's staff), were blinded to the medication codes. The randomisation schedule was filed securely, such that blinding was properly maintained throughout the study. Medication codes of the double-blind were not available until all subjects completed the double-blind phase of the study and until after final data review (clinical database lock) of the core phase.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Prednisone
    Arm description
    		 Prednisone (immediate-release tablets) 15 mg daily dose administered orally in the morning and placebo Lodotra(R) administered in the evening, both with a light meal.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Prednisone IR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    15 mg daily dose, administered orally.

    Investigational medicinal product name
    placebo Lodotra(R)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    oral administration with a light meal in the evening.

    Arm title
    		 Lodotra(R)
    Arm description
    		 Lodotra(R) tablets (modified-release) 15 mg daily dose administered in the evening and placebo prednisone tablets administered in the morning, both administered with a light meal.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lodotra(R)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    15 mg daily, administered orally.

    Investigational medicinal product name
    Placebo prednisone IR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    oral administration with a light meal in the morning.

    Number of subjects in period 1
    		Prednisone Lodotra(R)
    Started
    30
    32
    Completed
    23
    27
    Not completed
    7
    5
         Consent withdrawn by subject
    2
    1
         Administrative
    -
    2
         Adverse event, non-fatal
    2
    1
         Lack of efficacy
    3
    1
    Period 2
    Period 2 title
    Open-Label period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Open-label period therefore no blinding was implemented.

    Arms
    Arm title
    		 Open-Label
    Arm description
    		 Lodotra(R) (modified-release) at a starting dose of 12 mg daily or prednisone (immediate-release) at a starting dose of 12 mg daily.
    Arm type
    		 Open-Label

    Investigational medicinal product name
    Lodotra(R)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Starting dose of 12 mg daily, administered orally.

    Investigational medicinal product name
    Prednisone IR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Starting dose of 12 mg daily, administered orally.

    Number of subjects in period 2 [1]
    		Open-Label
    Started
    27
    Completed
    27
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Subjects had to fulfill criteria for entry into the open-label period (re-randomisation) and not all subjects completing the double blind-period fulfilled the criteria or wished to enter the open-label period, therefore the number of subjects completing the double blind-period is more than the number entering the open-label period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Double-Blind Period
    Reporting group description
    		 -

    Reporting group values
    		 Double-Blind Period Total
    Number of subjects
    		 62 62
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 16 16
        From 65-84 years
    		 45 45
        85 years and over
    		 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 69.4 ( 7.45 ) -
    Gender categorical
    Units: Subjects
        Female
    		 21 21
        Male
    		 41 41
    Subject analysis sets

    Subject analysis set title
    Randomised population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised subjects

    Subject analysis set title
    Full Analysis Population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomised subjects who received at least one dose of double-blind core phase study medication

    Subject analysis set title
    Per Protocol Population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All Full Analysis population subjects without major protocol violations. Major protocol violations were agreed at the determination of subject evaluability meeting prior to unblinding.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who received at least one dose of study medication.

    Subject analysis sets values
    		 Randomised population Full Analysis Population Per Protocol Population Safety Population
    Number of subjects
    62
    62
    48
    62
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
    16
    16
    12
    16
        From 65-84 years
    45
    45
    35
    45
        85 years and over
    1
    1
    1
    1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    69.4 ( 7.45 )
    69.4 ( 7.45 )
    69.6 ( 7.31 )
    69.4 ( 7.45 )
    Gender categorical
    Units: Subjects
        Female
        Male

    End points

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    End points reporting groups
    Reporting group title
    Prednisone
    Reporting group description
    		 Prednisone (immediate-release tablets) 15 mg daily dose administered orally in the morning and placebo Lodotra(R) administered in the evening, both with a light meal.

    Reporting group title
    Lodotra(R)
    Reporting group description
    		 Lodotra(R) tablets (modified-release) 15 mg daily dose administered in the evening and placebo prednisone tablets administered in the morning, both administered with a light meal.
    Reporting group title
    Open-Label
    Reporting group description
    		 Lodotra(R) (modified-release) at a starting dose of 12 mg daily or prednisone (immediate-release) at a starting dose of 12 mg daily.

    Subject analysis set title
    Randomised population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised subjects

    Subject analysis set title
    Full Analysis Population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomised subjects who received at least one dose of double-blind core phase study medication

    Subject analysis set title
    Per Protocol Population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All Full Analysis population subjects without major protocol violations. Major protocol violations were agreed at the determination of subject evaluability meeting prior to unblinding.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who received at least one dose of study medication.

    Primary: Percentage of complete responders at the end of the double-blind period.

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    End point title
    		 Percentage of complete responders at the end of the double-blind period.
    End point description
    The percentage of complete responders (CR) at the end of the 4-week double-blind period comparing Lodotra(R) with prednisone IR. CR was defined as all three of the following: 1. ≥ 70% improvement in PMR visual analogue scale (VAS) 2. ≥ 70% reduction in the duration of morning stiffness (MST) 3. ≥ 70% reduction in C-Reactive Protein (CRP) value or CRP value < 2 times Upper Limit of Normal (ULN) The primary analysis was performed on the Per Protocol (PP) population.
    End point type
    Primary
    End point timeframe
    4-week double-blind period.
    End point values
    		 Prednisone Lodotra(R) Full Analysis Population Per Protocol Population
    Number of subjects analysed
    26 [1]
    22 [2]
    62
    48
    Units: percentage
    14
    9
    27
    23
    Notes
    [1] - Per Protocol Population
    [2] - Per Protocol Population
    Statistical analysis title
    		 Lodotra(R) is non-inferior to prednisone IR wrt CR
    Statistical analysis description
    The primary endpoint was the percentage of complete responders at the end of the 4-week double-blind core phase, comparing Lodotra(R) with Prednisone IR. The comparison was used to test, in a confirmatory manner, the hypothesis that Lodotra(R) is non-inferior to Prednisone IR with respect to the percentage of complete responders at Week 4 of the double-blind core phase.
    Comparison groups
    Lodotra(R) v Prednisone
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Adjusted Difference in proportions
    Point estimate
    12.22
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -15
         upper limit
    		 -

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) were recorded from the point at which the Informed Consent was signed until 7-10 days after the subject left the study. This included new AEs that were reported in the 7-10 days following the subject's completion/discontinuation visit
    Adverse event reporting additional description
    Any AE that was still ongoing 7-10 days after the completion/discontinuation visit had an outcome of ‘ongoing’ in the CRF. SAEs were followed until the event resolved or the event or sequelae stabilised. A treatment-emergent AE was any AE with an onset date on or after the first dose of study medication, or that worsened after the first dose.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Prednisone IR
    Reporting group description
    		 -

    Reporting group title
    Lodotra(R)
    Reporting group description
    		 -

    Serious adverse events
    		 Prednisone IR Lodotra(R)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 32 (3.13%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Temporal arteritis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Pancytopenia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 32 (3.13%)
         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
    		 Prednisone IR Lodotra(R)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 30 (30.00%)
    6 / 32 (18.75%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    3
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    4
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    2
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jan 2013
    Protocol amendment 2 (30 January 2013) was a global amendment that reflected the change in the duration of morning stiffness, indicating that patients can be classified as having PMR to >45 minutes according to the 2012 Provisional Classification Criteria for PMR (Dasgupta et al., 2012). The amendment also required the measurement of Rheumatoid Factor and Anti-Citrullinated Protein Antibodies. Elevated results for these tests indicated that a subject had underlying RA. Underlying RA would have excluded the subject from the Per Protocol population.

    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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