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    Clinical Trial Results:
    A multi-centre, prospective, randomised trial of short course alendronate therapy or placebo combined with vitamin D and calcium to prevent loss of bone mineral density in antiretroviral-naïve, HIV-1 infected subjects initiating antiretroviral therapy.

    Summary
    EudraCT number
    		 2014-004819-37
    Trial protocol
    		 IE   DK   GB  
    Global end of trial date
    07 Sep 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Apr 2022
    First version publication date
    18 Apr 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    APART_2014
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02322099
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University College Dublin
    Sponsor organisation address
    Belfield Campus, Dublin, Ireland, Dublin 4
    Public contact
    Prof Patrick Mallon, Centre for Experimental Pathogen Host Research, +353 17164542, cephr@ucd.ie
    Scientific contact
    Prof Patrick Mallon, Centre for Experimental Pathogen Host Research, +353 17164542, cephr@ucd.ie
    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
    24 Nov 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Sep 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Sep 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    In antiretroviral-naïve, HIV1-infected adults, to compare the effect of a short (14 week) course of oral alendronate 70mg weekly versus placebo combined with calcium and vitamin D, initiated 2 weeks prior to start of antiretroviral therapy (ART) for HIV1 infection on ART-induced bone mineral density (BMD) loss over 48 weeks of follow-up post ART initiation.
    Protection of trial subjects
    This trial was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. All subjects provided written informed consent before undergoing any trial related procedures. The trial was reviewed and approved by the Competent Authorities and the local Research Ethics Committees (REC). An independent data safety monitoring board (DSMB) was established to oversee the conduct of the study. The DSMB comprised an expert in osteoporosis, two experts in HIV with clinical trial experience, and a representative of the sponsor (UCD). All participants attended a total of 7 study visits over the 50 weeks (48 weeks post-ART initiation) follow-up period. All visits included medical/clinical review including assessments of safety and oral hygiene as well as pregnancy tests in women of childbearing potential. If pregnancy was reported during the study the woman was discontinued from the IMP but offered to remain in the study and the outcome of the pregnancy was recorded. Also, any abnormality identified on DXA scans was followed up through referral from the study team to the Rheumatology specialist in liaison with the Radiologist specialist. In addition, a Clinical Endpoint Review Committee composed of the principal investigator and a rheumatology specialist was established to review those subjects with abnormal DXA scans at week 14 (completion of Alendronate course). Any subject with BMD<-1 at week 14 was reviewed by this committee and a decision was made as to whether calcium/vitamin D supplementation should continue for these subjects after week 14.
    Background therapy
    		 All participants received calcium / vitamin D3 supplementation combined with either generic, oral Alendronate 70mg weekly or placebo, commenced 2 weeks prior to ART initiation and continued for a total of 14 weeks. The ART regimen comprised tenofovir disproxil fumarate / emtricitabine and a third agent. Randomisation was stratified by gender and use of protease inhibitors in the ART regimen.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 May 2016
    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
    Ireland: 53
    Worldwide total number of subjects
    53
    EEA total number of subjects
    53
    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)
    53
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment started in Ireland in April 2016. 53 subjects were recruited, the first on 15/06/2016 and the last on 03/10/2018. A total of 50 subjects were randomised. Of the 3 subjects who withdrew before randomisation, one initiated ART before randomisation and two were lost to follow after screening.

    Pre-assignment
    Screening details
    		 Study population comprised HIV-1 positive, antiretroviral-naïve adults requiring initiation of antiretroviral therapy (ART). In order to ensure that the study population had achieved peak-bone mass, we recruited males over 25 and women over 30 years old. There were no CD4+ T-cell count or HIV RNA restrictions for study entry.

    Pre-assignment period milestones
    Number of subjects started
    		 53
    Number of subjects completed
    		 50

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Lost of follow-up after screening: 2
    Reason: Number of subjects
    		 Physician decision: 1
    Period 1
    Period 1 title
    Intention to treat (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst
    Blinding implementation details
    A double-blind technique will be used. Alendronate and matched placebo will be packaged identically so that blind/masking is maintained. The subject, the investigator and the Sponsor personnel or delegate(s) who are involved in the treatment or clinical evaluation of the subjects are unaware of the group assignments.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Alendronate
    Arm description
    		 Alendronate 70mg oral tablets administered once weekly for a period of 12 weeks starting 2 weeks prior to ART initiation
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alendronate 70 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Each tablet contains 70 mg alendronic acid (as sodium alendronate trihydrate). The dosage is one 70 mg tablet once weekly for a period of 12 weeks. Alendronate tablet must be taken at least 30 minutes before the first food, beverage or medicinal product of the day with plain water only. Other beverages (including mineral water), food and some medicinal products are likely to reduce the absorption of alendronate.

    Arm title
    		 Placebo
    Arm description
    		 Placebo tablets to match sodium alendronate 70 mg. Oral tablets administered once weekly for a period of 12 weeks starting 2 weeks prior to ART initiation.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to match Alendronate 70 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablets are identical in appearance and composition apart from the active substance). The dosage is one tablet once weekly for a period of 12 weeks. Each placebo tablet contains: Cellactose 80 (lactose monohydrated and cellulose powdered), Croscarmellose sodium, Colloidal Anhydrous silica (Aerosil 200), Magnesium stearate. Administration instructions are in line with those for alendronate in order to maintain the blinding. The IMP tablet must be taken at least 30 minutes before the first food, beverage or medicinal product of the day with plain water only. Other beverages (including mineral water), food and some medicinal products are likely to reduce the absorption of alendronate.

    Number of subjects in period 1 [1]
    		Alendronate Placebo
    Started
    24
    26
    Completed
    22
    22
    Not completed
    2
    4
         Consent withdrawn by subject
    1
    -
         Pregnancy
    -
    1
         Lost to follow-up
    1
    3
    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: A total of 53 subjects were enrolled in the study/signed the informed consent. Three of these subjects withdrew the study before randomisation, one initiated ART before randomisation (physician decision) and two were lost of follow-up after screening

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Alendronate
    Reporting group description
    		 Alendronate 70mg oral tablets administered once weekly for a period of 12 weeks starting 2 weeks prior to ART initiation

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablets to match sodium alendronate 70 mg. Oral tablets administered once weekly for a period of 12 weeks starting 2 weeks prior to ART initiation.

    Reporting group values
    		 Alendronate Placebo Total
    Number of subjects
    		 24 26 50
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 36 (32 to 39) 34 (31 to 41) -
    Gender categorical
    Units: Subjects
        Female
    		 4 3 7
        Male
    		 20 23 43
    Ethnicity
    Units: Subjects
        African
    		 10 7 17
        South American
    		 7 3 10
        Caucasian
    		 7 16 23
    HIV transmission risk group
    Units: Subjects
        Heterosexual contact
    		 12 6 18
        Homosexual contact
    		 9 13 22
        Injecting drug use
    		 0 2 2
        Unknown
    		 3 5 8
    Smoking status
    Units: Subjects
        Current smoker
    		 7 11 18
        Ex-smoker
    		 2 6 8
        Never smoked
    		 14 8 22
        Unknown
    		 1 1 2
    Prior falls
    Units: Subjects
        Yes
    		 0 2 2
        No
    		 24 24 48
    History of fractures
    Units: Subjects
        Yes
    		 8 2 10
        No
    		 16 24 40
    Type of ART regimen
    Units: Subjects
        PI-based ART
    		 0 2 2
        NNRTI-based ART
    		 1 1 2
        InSTI-based ART
    		 23 23 46
    BMI
    Body mass index at baseline
    Units: Kg/m2
        median (inter-quartile range (Q1-Q3))
    		 24.5 (22.9 to 29.0) 23.2 (22.1 to 25.7) -
    Absolute CD4+ T-cell count
    Units: cells/mm3
        median (inter-quartile range (Q1-Q3))
    		 348 (176 to 492) 428 (256 to 598) -
    Absolute CD8+ T-cell count
    Units: cells/mm3
        median (inter-quartile range (Q1-Q3))
    		 742 (606 to 984) 1139 (726 to 1408) -
    CD4+ T-cell count (%)
    Units: percentage
        median (inter-quartile range (Q1-Q3))
    		 24 (14 to 31) 23 (14 to 29) -
    CD8+ T-cell count (%)
    Units: percentage
        median (inter-quartile range (Q1-Q3))
    		 46 (42 to 59) 54 (46 to 60) -

    End points

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    End points reporting groups
    Reporting group title
    Alendronate
    Reporting group description
    		 Alendronate 70mg oral tablets administered once weekly for a period of 12 weeks starting 2 weeks prior to ART initiation

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablets to match sodium alendronate 70 mg. Oral tablets administered once weekly for a period of 12 weeks starting 2 weeks prior to ART initiation.

    Primary: Percentage change in total hip BMD at week 50

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    End point title
    		 Percentage change in total hip BMD at week 50
    End point description
    BMD determined by dual energy X-ray Absorptiometry (DXA) performed prior to and 48 weeks after ART initiation. Missing values/subjects excluded from analysis due to DXA scan not done/scan not done properly
    End point type
    Primary
    End point timeframe
    Baseline to week 50
    End point values
    		 Alendronate Placebo
    Number of subjects analysed
    22
    20
    Units: g/cm2
        median (inter-quartile range (Q1-Q3))
    0.50 (-3.10 to 1.80)
    -2.70 (-4.30 to -2.05)
    Attachments
    		 Primary outcome analysis
    Statistical analysis title
    		 Difference in % change from baseline to week 50
    Statistical analysis description
    Between-group differences in percentage change in total hip BMD compared using Wilcoxon rank tests.
    Comparison groups
    Placebo v Alendronate
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    3.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 5.05

    Secondary: Percentage change in lumbar spine BMD at week 50

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    End point title
    		 Percentage change in lumbar spine BMD at week 50
    End point description
    Missing values/subjects excluded from analysis due to DXA scan not done/scan not done properly
    End point type
    Secondary
    End point timeframe
    Baseline to week 50
    End point values
    		 Alendronate Placebo
    Number of subjects analysed
    22
    20
    Units: g/cm2
        median (inter-quartile range (Q1-Q3))
    -1.40 (-4.10 to 3.13)
    -3.69 (-4.82 to -1.70)
    Statistical analysis title
    		 Difference in % change from baseline to week 50
    Statistical analysis description
    Between-group differences in percentage change in lumbar spine BMD compared using Wilcoxon rank tests.
    Comparison groups
    Alendronate v Placebo
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    2.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.28
         upper limit
    		 5.16

    Secondary: Percentage change in femoral neck BMD at week 50

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    End point title
    		 Percentage change in femoral neck BMD at week 50
    End point description
    Missing values/subjects excluded from analysis due to DXA scan not done/scan not done properly
    End point type
    Secondary
    End point timeframe
    Baseline to week 50
    End point values
    		 Alendronate Placebo
    Number of subjects analysed
    22
    20
    Units: g/cm2
        median (inter-quartile range (Q1-Q3))
    0.62 (-3.68 to 2.10)
    -4.00 (-6.75 to 0.23)
    Statistical analysis title
    		 Difference in % change from baseline to week 50
    Statistical analysis description
    Between-group differences in percentage change in femoral neck BMD compared using Wilcoxon rank tests.
    Comparison groups
    Alendronate v Placebo
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    3.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.05
         upper limit
    		 6.51

    Secondary: Percentage change in total hip BMD to week 14

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    End point title
    		 Percentage change in total hip BMD to week 14
    End point description
    Missing values/subjects excluded from analysis due to DXA scan not done/scan not done properly
    End point type
    Secondary
    End point timeframe
    Baseline to week 14
    End point values
    		 Alendronate Placebo
    Number of subjects analysed
    17
    25
    Units: g/cm2
        median (inter-quartile range (Q1-Q3))
    1.88 (-0.70 to 2.81)
    -0.65 (-2.65 to 1.13)
    Statistical analysis title
    		 Difference in % change from baseline to week 14
    Statistical analysis description
    Between-group differences in percentage change in total hip BMD compared using Wilcoxon rank tests.
    Comparison groups
    Alendronate v Placebo
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    2.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.17
         upper limit
    		 4.22

    Secondary: Percentage change in total hip BMD to week 26

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    End point title
    		 Percentage change in total hip BMD to week 26
    End point description
    Missing values/subjects excluded from analysis due to DXA scan not done/scan not done properly
    End point type
    Secondary
    End point timeframe
    Baseline to week 26
    End point values
    		 Alendronate Placebo
    Number of subjects analysed
    18
    23
    Units: g/cm2
        median (inter-quartile range (Q1-Q3))
    1.05 (-2.05 to 2.23)
    -2.03 (-2.97 to 0.63)
    Statistical analysis title
    		 Difference in % change from baseline to week 26
    Statistical analysis description
    Between-group differences in percentage change in total hip BMD compared using Wilcoxon rank tests.
    Comparison groups
    Alendronate v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    1.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.06
         upper limit
    		 3.87

    Secondary: Percentage change in lumbar spine BMD to week 14

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    End point title
    		 Percentage change in lumbar spine BMD to week 14
    End point description
    Missing values/subjects excluded from analysis due to DXA scan not done/scan not done properly
    End point type
    Secondary
    End point timeframe
    Baseline to week 14
    End point values
    		 Alendronate Placebo
    Number of subjects analysed
    18
    25
    Units: g/cm2
        median (inter-quartile range (Q1-Q3))
    1.24 (-0.04 to 3.02)
    -0.96 (-3.10 to 0.78)
    Statistical analysis title
    		 Difference in % change from baseline to week 14
    Statistical analysis description
    Between-group differences in percentage change in lumbar spine BMD compared using Wilcoxon rank tests.
    Comparison groups
    Alendronate v Placebo
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    2.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 4.97

    Secondary: Percentage change in lumbar spine BMD to week 26

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    End point title
    		 Percentage change in lumbar spine BMD to week 26
    End point description
    Missing values/subjects excluded from analysis due to DXA scan not done/scan not done properly
    End point type
    Secondary
    End point timeframe
    Baseline to week 26
    End point values
    		 Alendronate Placebo
    Number of subjects analysed
    18
    23
    Units: g/cm2
        median (inter-quartile range (Q1-Q3))
    0.05 (-3.04 to 3.30)
    -2.48 (-4.65 to -0.24)
    Statistical analysis title
    		 Difference in % change from baseline to week 26
    Statistical analysis description
    Between-group differences in percentage change in lumbar spine BMD compared using Wilcoxon rank tests.
    Comparison groups
    Alendronate v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    3.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.12
         upper limit
    		 6.17

    Secondary: Percentage change in femoral neck BMD to week 14

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    End point title
    		 Percentage change in femoral neck BMD to week 14
    End point description
    Missing values/subjects excluded from analysis due to DXA scan not done/scan not done properly
    End point type
    Secondary
    End point timeframe
    Baseline to week 14
    End point values
    		 Alendronate Placebo
    Number of subjects analysed
    17
    25
    Units: g/cm2
        median (inter-quartile range (Q1-Q3))
    -0.48 (-2.77 to 4.26)
    0.07 (-4.27 to 2.90)
    Statistical analysis title
    		 Difference in % change from baseline to week 14
    Statistical analysis description
    Between-group differences in percentage change in femoral neck BMD compared using Wilcoxon rank tests.
    Comparison groups
    Alendronate v Placebo
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.08
         upper limit
    		 4.94

    Secondary: Percentage change in femoral neck BMD to week 26

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    End point title
    		 Percentage change in femoral neck BMD to week 26
    End point description
    Missing values/subjects excluded from analysis due to DXA scan not done/scan not done properly
    End point type
    Secondary
    End point timeframe
    Baseline to week 26
    End point values
    		 Alendronate Placebo
    Number of subjects analysed
    18
    23
    Units: g/cm2
        median (inter-quartile range (Q1-Q3))
    -1.94 (-3.36 to 2.42)
    -0.86 (-4.48 to 0.13)
    Statistical analysis title
    		 Difference in % change from baseline to week 26
    Statistical analysis description
    Between-group differences in percentage change in femoral neck BMD compared using Wilcoxon rank tests.
    Comparison groups
    Alendronate v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.62
         upper limit
    		 4.16

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Signing of Informed Consent through End of Study (Up to 50 weeks)
    Adverse event reporting additional description
    Safety population included all randomized subjects who either received study treatment Alendronate or placebo. Subjects were analyzed according to their actual treatment received
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Alendronate
    Reporting group description
    		 Alendronate 70mg oral tablets administered once weekly for a period of 12 weeks starting 2 weeks prior to ART initiation

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablets to match sodium alendronate 70 mg. Oral tablets administered once weekly for a period of 12 weeks starting 2 weeks prior to ART initiation.

    Serious adverse events
    		 Alendronate Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 23 (8.70%)
    5 / 26 (19.23%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Post herpetic neuralgia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Eosinophilic folliculitis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Cachexia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Folliculitis
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Pyelonephritis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Folliculitis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Incorrect self-administration of IMP
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bilateral epididymorchitys
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 26 (3.85%)
         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
    		 Alendronate Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 23 (78.26%)
    18 / 26 (69.23%)
    Vascular disorders
    Syncope
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    General disorders and administration site conditions
    Incorrect self-administration of IMP
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    2
    Fatigue
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Immune system disorders
    Psoriasis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Allergic reactions to antibiotics
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Reproductive system and breast disorders
    Genital rash
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Pharyngeal hyperaemia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Sinusitis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Nightmares
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Bone density decreased
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 26 (3.85%)
         occurrences all number
    2
    1
    Elevated creatinine
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Elevated ALT
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    2
    Elevated GGT
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Elevated Glucose
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Elevated creatinine kinase
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Elevated liver enzymes
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Congenital, familial and genetic disorders
    Dry cough
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Headache
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Pain in arm
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 26 (3.85%)
         occurrences all number
    2
    1
    Lymphogramuloma venereum
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Nausea and vomiting
         subjects affected / exposed
    4 / 23 (17.39%)
    0 / 26 (0.00%)
         occurrences all number
    4
    0
    Abdominal pain
         subjects affected / exposed
    3 / 23 (13.04%)
    0 / 26 (0.00%)
         occurrences all number
    3
    0
    Diarrhoea
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 26 (3.85%)
         occurrences all number
    2
    1
    Abdominal cramps
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Dental pain
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Heartburn
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Oral candidiasis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Gum Bleeding
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Itching
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Facial rash
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Rash
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Seborreheic dermatitis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Skin changes
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Polyuria
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    0 / 23 (0.00%)
    3 / 26 (11.54%)
         occurrences all number
    0
    3
    Back pain
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Arthralgia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Joint pain
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Muscle pain
         subjects affected / exposed
    1 / 23 (4.35%)
    2 / 26 (7.69%)
         occurrences all number
    1
    2
    Knee pain
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Ankle pain
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Chlamydial infection
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Pustular blisters
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Tooth abscess
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Leg ulcer
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Appetite lost
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Jul 2019
    Extension of placebo shelf-life (manufactured in January 2015) to match the shelf life of a new batch of active alendronate acquired in Nov 2018 (expiry date June 2020). The competent authorities had no objection to the proposal that the placebo shelf life matched the test product shelf life but advised that the sponsor remained fully responsible for quality of the placebo, including absence of microbial contamination, i.e. compliance with Ph. Eur. requirements. In order to comply with this requirement, an analytical testing on the placebo to confirm absence of contamination was performed in April 2019. This report was submitted to the HPRA and the MHRA. The MHRA required that the proposed placebo shelf life extension was submitted as a substantial amendment for assessment – submitted 18th July 2019. Notice of acceptance of amendment received in July 2019.
    20 Oct 2019
    Reduction on study sample size. The original sample size of 80 subjects had to be reduced to 64 due to lack of sufficient placebo that raised as a result of unplanned extra tests associated with packaging of new study drug in July 2019. A reduced sample size of 32 subjects per arm was the maxium possible target. With 32 subjects per arm, the study provides 80% power to detect slightly larger but clinically meaningful between-group differences in change in femoral neck BMD of 2.58% (assuming SD is 3.63%) at 48 weeks. Approval was obtained in Nov 2019.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    13 Mar 2020
    As of 13 March 2020, due to the COVID-19 pandemic, a directive was issued to halt all non-essential research activity at the participating sites. At this time, there were 53 subjects (49 randomised) recruited in Ireland and on follow-up. For participants already enrolled in the clinical trial all the visits were completed by 7th Sept 2020. The Sponsor notified the Regulatory Authorities that the study had been terminated prematurely in Nov 2020.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    - Reduction in sample size might affect the power of the study to detect differences between arms - Limited female representation - Third ART agent was almost exclusively INSTIs, unable to detect potential differential effects of alternative agents
    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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