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    Clinical Trial Results:
    A randomized controlled trial of alendronate as preventive treatment against the development of gluco-corticoid-induced osteoporosis in patients being treated for malignant lymphoma

    Summary
    EudraCT number
    		 2015-005688-18
    Trial protocol
    		 DK  
    Global end of trial date
    28 Feb 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Jun 2022
    First version publication date
    26 Jun 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Paw1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aalborg University Hospital
    Sponsor organisation address
    Moelleparkvej 4, Aalborg, Denmark, 9000
    Public contact
    Paw Jensen, Department of Hematology, 0045 97663860, paje@rn.dk
    Scientific contact
    Paw Jensen, Department of Hematology, 0045 97663860, paje@rn.dk
    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
    29 Apr 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Feb 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Feb 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The study has as main purpose to investigate whether bisphosphonate treatment alendronate can prevent the development of osteoporosis expressed as low T-score by DXA and / or the identity of the spine in patients Glucocortikoidholdig chemotherapy treatment for malignant lymphoma
    Protection of trial subjects
    Subjects were fully informed of all aspects of the clinical trial as well as the possibility to discontinue at any time appropriate for the subject. At the end of the trial all subjects received the results of the last DEXA scan including a recommendation regarding the action neded to be taken according the result (ex. if T-score<2,5 the recommendation was start medication for osteoporosis)
    Background therapy
    		 calcium and vitamin-D
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Dec 2016
    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
    Denmark: 59
    Worldwide total number of subjects
    59
    EEA total number of subjects
    59
    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)
    18
    From 65 to 84 years
    41
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 In total, 59 (30 in the ALN arm and 29 in the placebo arm) patients were enrolled in the study during the preplanned recruitment period (December 2016 until February 2020)

    Pre-assignment
    Screening details
    		 Additional glucocorticoid treatment for a maximum of four weeks at the time of screening was allowed.

    Period 1
    Period 1 title
    Interventional (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Randomization in blocks of 2-8 patients was performed by the hospital pharmacy. Only the pharmacy had access to the randomization key. Unblinding was performed after the last patient had last study visit and all DXA scan results had been reported. All analyses were pre-specified in the statistical analysis plan with final version signed prior to study unblinding.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Alendronate
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alendronate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    70 mg once weekly for 12 months

    Arm title
    		 placebo
    Arm description
    		 -
    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
    one tablet once weekly for 12 months

    Number of subjects in period 1
    		Alendronate placebo
    Started
    30
    29
    Completed
    22
    23
    Not completed
    8
    6
         Consent withdrawn by subject
    5
    1
         Adverse event, non-fatal
    1
    1
         Lost to follow-up
    1
    -
         discontinuing glucocorticoid containing chemothera
    1
    3
         lack of compliance
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Interventional
    Reporting group description
    		 -

    Reporting group values
    		 Interventional Total
    Number of subjects
    		 59 59
    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)
    		 18 18
        From 65-84 years
    		 41 41
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 66 (40 to 80) -
    Gender categorical
    Units: Subjects
        Female
    		 15 15
        Male
    		 44 44
    Subject analysis sets

    Subject analysis set title
    Analysis
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The efficacy population for primary and secondary endpoints was patients with baseline BMD assessment and at least one follow-up BMD assessment. The safety population was all patients who received at least one dose of study medication. All P-values ≤5% were considered statistically significant.

    Subject analysis sets values
    		 Analysis
    Number of subjects
    47
    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)
    15
        From 65-84 years
    32
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    66 (40 to 80)
    Gender categorical
    Units: Subjects
        Female
    12
        Male
    35

    End points

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

    Reporting group title
    placebo
    Reporting group description
    		 -

    Subject analysis set title
    Analysis
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The efficacy population for primary and secondary endpoints was patients with baseline BMD assessment and at least one follow-up BMD assessment. The safety population was all patients who received at least one dose of study medication. All P-values ≤5% were considered statistically significant.

    Primary: T-score lumbar spine 12 months

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    End point title
    		 T-score lumbar spine 12 months
    End point description
    Primary endpoint of the study was change in T-score from baseline to EOS after 12 months, ∆T_EOS=T_1y-T_baseline, measured by dual-energy X-ray absorptiometry scan (DXA) at lumbar spine L3 level.
    End point type
    Primary
    End point timeframe
    Primary endpoint of the study was change in T-score from baseline to EOS after 12 months, ∆T_EOS=T_1y-T_baseline, measured by dual-energy X-ray absorptiometry scan (DXA) at lumbar spine L3 level.
    End point values
    		 Alendronate placebo
    Number of subjects analysed
    23
    24
    Units: T-score
        number (not applicable)
    0.15
    -0.12
    Statistical analysis title
    		 2-sided t-test
    Statistical analysis description
    Differences in delta T(eos) and delta T(eot) between treatment groups were tested using a 2-sided t test assuming equal variance. For details se article.
    Comparison groups
    placebo v Alendronate
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.04
         upper limit
    		 0.51

    Secondary: Number of fractures

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    End point title
    		 Number of fractures
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Alendronate placebo
    Number of subjects analysed
    30
    29
    Units: numbers
    0
    1
    No statistical analyses for this end point

    Secondary: T-score End ot treatment 4-6 months lumbar spine

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    End point title
    		 T-score End ot treatment 4-6 months lumbar spine
    End point description
    End point type
    Secondary
    End point timeframe
    4 to 6 months
    End point values
    		 Alendronate placebo
    Number of subjects analysed
    23
    24
    Units: T-score
        number (not applicable)
    0.01
    0.00
    No statistical analyses for this end point

    Secondary: T-score Total hip 12 months

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    End point title
    		 T-score Total hip 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Alendronate placebo
    Number of subjects analysed
    23
    24
    Units: T-score
        number (not applicable)
    -0.05
    -0.10
    No statistical analyses for this end point

    Secondary: T-score femoral neck 12 months

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    End point title
    		 T-score femoral neck 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Alendronate placebo
    Number of subjects analysed
    23
    24
    Units: T-score
        number (not applicable)
    -0.07
    -0.10
    No statistical analyses for this end point

    Secondary: T-score EOT 4-6 months total hip

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    End point title
    		 T-score EOT 4-6 months total hip
    End point description
    End point type
    Secondary
    End point timeframe
    4-6 months
    End point values
    		 Alendronate placebo
    Number of subjects analysed
    23
    24
    Units: T-score
        number (not applicable)
    -0.05
    -0.05
    No statistical analyses for this end point

    Secondary: T-score ETO 4-6 months femoral neck

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    End point title
    		 T-score ETO 4-6 months femoral neck
    End point description
    End point type
    Secondary
    End point timeframe
    4-6 months
    End point values
    		 Alendronate placebo
    Number of subjects analysed
    23
    24
    Units: T-score
        number (not applicable)
    -0.11
    -0.02
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    12 months
    Adverse event reporting additional description
    Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. Grade 1-4 AEs were registered for the gastrointestinal canal, as these were of special interest, and registrations for other AEs were limited to Grade 3 and 4. A potential relationship of AE`s to study med
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    Alendronate arm
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Alendronate arm Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 30 (50.00%)
    14 / 29 (48.28%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    venous tromboembolism
         subjects affected / exposed
    2 / 30 (6.67%)
    2 / 29 (6.90%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    anemia
         subjects affected / exposed
    2 / 30 (6.67%)
    3 / 29 (10.34%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    retinal rupture
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    low performance
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    upper GI
         subjects affected / exposed
    3 / 30 (10.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lower GI
         subjects affected / exposed
    3 / 30 (10.00%)
    4 / 29 (13.79%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    hematuria
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Diabetes mellitus
         subjects affected / exposed
    3 / 30 (10.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    neutropene febrile
         subjects affected / exposed
    5 / 30 (16.67%)
    8 / 29 (27.59%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Alendronate arm Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 30 (33.33%)
    3 / 29 (10.34%)
    Vascular disorders
    venous embolism
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    upper
         subjects affected / exposed
    8 / 30 (26.67%)
    1 / 29 (3.45%)
         occurrences all number
    8
    1
    Musculoskeletal and connective tissue disorders
    Pain
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    infektion
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1

    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.
    no

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/35045567
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