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    Clinical Trial Results:
    A randomized, double blind, placebo controlled trial to evaluate the safety and efficacy of Apovir for treatment of patients with Alzheimer’s disease

    Summary
    EudraCT number
    		 2013-002126-23
    Trial protocol
    		 SE  
    Global end of trial date
    23 Jun 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Jul 2017
    First version publication date
    08 Jul 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    APOCT-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Apodemus AB
    Sponsor organisation address
    Nobels väg 2, Solna, Sweden, 171 65
    Public contact
    Clinical trials, Apodemus AB, 46 708 681368, info@apodemus.se
    Scientific contact
    Clinical trials, Apodemus AB, 46 708 681368, info@apodemus.se
    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
    23 Aug 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Jun 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Jun 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Main efficacy objective: To investigate the effect of Apovir on disease progression of Alzheimer's Disease as assessed by the Alzheimer’s Disease Assessment Scale-Cognitive Subscale [ADAS-cog] compared to placebo. The change in score Before and after 9 months of treatment with Apovir or placebo respectively was assessed. Main safety objective: To investigate the safety and tolerability of the combination therapy of Apovir in patients with AD
    Protection of trial subjects
    The trial was in compliance with the ethical principles derived from the Declaration of Helsinki, the International Conference of Harmonisation (ICH) Good Clinical Practice (GCP) guidelines and local regulatory requirements.
    Background therapy
    		 Acethylcholinesterase inhibitor or memantine
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Oct 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Scientific research
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 69
    Worldwide total number of subjects
    69
    EEA total number of subjects
    69
    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)
    6
    From 65 to 84 years
    61
    85 years and over
    2

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Patients were recruited via advertising in local newspaper and via medical record searches at memory clinics in the Stockholm area. Patients were prescreened for main eligibility criteria by the Clinical trial site personnel before a screening visit was scheduled.

    Pre-assignment
    Screening details
    		 Eligible patients were 60-85 years old, had an Alzheimer's Disease diagnosis and a MMSE score 27-21. Patients could be on treatment with other Alzheimer's Disease medication (acetylcholinesterase inhibitors or memantine) if drug and dose had been stable for at least 3 months prior to inclusion. Out of 169 patients screened 69 were randomized.

    Period 1
    Period 1 title
    Baseline
    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
    All patients and study staff were blinded during the entire trial. DSMB received unblinded safety data during the safety reporting period of the trial. From 2015-04-21 and onwards, the Sponsor CEO was given access to unblinded data required for strategic decisions. In order to minimize bias, the Sponsor CEO was from this time-point not involved in any discussions or decisions regarding individual patients e.g. participation in the Clean file meeting was not allowed.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Apovir
    Arm description
    		 Patients were randomised 1:1 to receive Apovir or Placebo. Patients were to be stratified based on presence/absence of treatment with AChEI/Memantine at baseline. However, all patients received treatment with AChEI/Memantine and stratification was therefore not relevant. Patients randomised to Apovir before first administration of IMP.
    Arm type
    		 Experimental

    Investigational medicinal product name
    APO-P001
    Investigational medicinal product code
    Other name
    pleconaril, picovir
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    APO-P001 600 mg/day (200 mg in the morning and 400 mg in the evening) was to be taken by the patients Daily for 9 months. IMP was to be taken together with food.

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Ribavirin was to be taken twice daily in the morning and in the evening for 9 months. The daily dose, 600 mg was decreased for all patients to 400 mg during the trial. Ribavirin was to be taken together with food.

    Arm title
    		 Placebo
    Arm description
    		 Patients were randomised 1:1 to receive Apovir or Placebo. Patients were to be stratified based on presence/absence of treatment with AChEI/Memantine at baseline. However, all patients received treatment with AChEI/Memantine and stratification was therefore not relevant. Patients randomised to placebo before first administration of IMP.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo APO-P001
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo APO-P001 capsules were to be taken in the same manner as the Apovir APO-P001 capsules.

    Investigational medicinal product name
    Placebo Ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Ribavirin placebo capsules were to be taken in the same manner as the Apovir ribavirin capsules.

    Number of subjects in period 1
    		Apovir Placebo
    Started
    35
    34
    Completed
    35
    34
    Period 2
    Period 2 title
    Main period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    All patients and study staff were blinded during the entire trial. DSMB received unblinded safety data during the safety reporting period of the trial. From 2015-04-21 and onwards, the Sponsor CEO was given access to unblinded data required for strategic decisions. In order to minimize bias, the Sponsor CEO was from this time-point not involved in any discussions or decisions regarding individual patients e.g. participation in the Clean file meeting was not allowed.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Apovir
    Arm description
    		 Patients randomised to Apovir, a combination of APO-P001 and ribavirin. Apovir was taken orally, together with food twice Daily for 9 months. A daily dose of 600 mg APO-P001 and 600 mg ribavirin (decreased to 400 mg for all patients during the trial) were administered by the patients at home.
    Arm type
    		 Experimental

    Investigational medicinal product name
    APO-P001
    Investigational medicinal product code
    Other name
    pleconaril, picovir
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    APO-P001 600 mg/day (200 mg in the morning and 400 mg in the evening) was to be taken by the patients Daily for 9 months. IMP was to be taken together with food.

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Ribavirin was to be taken twice daily in the morning and in the evening for 9 months. The daily dose, 600 mg was decreased for all patients to 400 mg during the trial. Ribavirin was to be taken together with food.

    Arm title
    		 Placebo
    Arm description
    		 Patints randomised to placebo. Placebo capsules for APO-P001 and ribavirin respectively were administered twice Daily for 9 months in the same manner as the Apovir capsules.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo Ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Ribavirin placebo capsules were to be taken in the same manner as the Apovir ribavirin capsules.

    Investigational medicinal product name
    Placebo APO-P001
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo APO-P001 capsules were to be taken in the same manner as the Apovir APO-P001 capsules.

    Number of subjects in period 2
    		Apovir Placebo
    Started
    35
    34
    Completed
    17
    30
    Not completed
    18
    4
         Adverse event, serious fatal
    1
    -
         Patient discontinued treatment
    1
    -
         Consent withdrawn by subject
    4
    1
         Adverse event, non-fatal
    10
    3
         Hb lower than 105 g/L for women and 110 g/L for me
    1
    -
         Patient relative got sick
    1
    -
    Period 3
    Period 3 title
    Long-term follow up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor
    Blinding implementation details
    Patients and site staff remained blinded throughout the entire trial. From 2015-04-21 and onwards, the Sponsor CEO was given access to unblinded data required for strategic decisions. The CRO, including statistician and other Sponsor associates were unblinded after the first clean file meeting held on the 16SEP2015. At this time-point all patients had completed the 1 month post treatment follow-up visit. 35 visits were still to be performed at this time-point.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Apovir
    Arm description
    		 Patients randomised to Apovir. Follow-up period assessing effect of treatment 6 and 12 months after end of treatment in the Apovir treatment Group.
    Arm type
    		 Experimental

    Investigational medicinal product name
    APO-P001
    Investigational medicinal product code
    Other name
    pleconaril, picovir
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    This is the post treatment follow-up period of the trial, IMP was not adminsitered.

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    This is the post treatment follow-up period of the trial, IMP was not adminsitered.

    Arm title
    		 Placebo
    Arm description
    		 Patients randomised to Placebo. Follow-up period assessing effect of treatment 6 and 12 months after end of treatment in the Placebo treatment Group.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo APO-P001
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    This is the post treatment follow-up period of the trial, IMP was not adminsitered.

    Investigational medicinal product name
    Placebo Ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    This is the post treatment follow-up period of the trial, IMP was not adminsitered.

    Number of subjects in period 3 [1]
    		Apovir Placebo
    Started
    13
    28
    Completed
    12
    25
    Not completed
    1
    3
         Lost to follow-up
    1
    3
    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: All patients who completed the 1 month follow-up visit were invited to take part in the follow-up part of the trial both subjects who were included in the PPAS and those who were only included in the FAS.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Apovir
    Reporting group description
    		 Patients were randomised 1:1 to receive Apovir or Placebo. Patients were to be stratified based on presence/absence of treatment with AChEI/Memantine at baseline. However, all patients received treatment with AChEI/Memantine and stratification was therefore not relevant. Patients randomised to Apovir before first administration of IMP.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients were randomised 1:1 to receive Apovir or Placebo. Patients were to be stratified based on presence/absence of treatment with AChEI/Memantine at baseline. However, all patients received treatment with AChEI/Memantine and stratification was therefore not relevant. Patients randomised to placebo before first administration of IMP.

    Reporting group values
    		 Apovir Placebo Total
    Number of subjects
    		 35 34 69
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 2 4 6
        From 65-84 years
    		 32 29 61
        85 years and over
    		 1 1 2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 73.8 ± 5.3 71.7 ± 5.9 -
    Gender categorical
    Units: Subjects
        Female
    		 19 15 34
        Male
    		 16 19 35
    Ethnic origin
    Units: Subjects
        Caucasian
    		 35 34 69
        African descent
    		 0 0 0
        Asian or Pacific Islander
    		 0 0 0
        Mixed / Multi-racial
    		 0 0 0
        Other
    		 0 0 0
    Any medical/Surgical history
    Units: Subjects
        Medical/Surgical history reported
    		 17 22 39
        No medical/Surgical history reported
    		 18 12 30
    Any concurrent disease
    Units: Subjects
        Concurrent disease reported
    		 35 34 69
        No concurrent disease reported
    		 0 0 0
    Subject analysis sets

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis set was defined as all patients who received at least one dose of the IMP. Patients were analysed as treated.

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The FAS is defined as all randomised patients who received at least 1 dose of the IMP and have at least 1 post-baseline assessment of efficacy data. In analyses performed on the FAS, patients have been analysed as randomised.

    Subject analysis set title
    Per protocol analysis set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PPAS is a subset of the FAS fulfilling the following additional criteria: 1. All important inclusion criteria and none of the important exclusion criteria were fulfilled (which criteria were to be considered as important was to be defined and documented at the clean file meeting, prior to code breaking). 2. An assessment of the primary efficacy variable, ADAS-cog, at 9 months and baseline. 3. Complied with the trial medication (i.e., have taken at least 75% of the anticipated amount of each component of the IMP). 4. No other major protocol deviations during the period up to 9 months. In analyses performed on the PPAS, patients have been analysed as treated.

    Subject analysis set title
    Follow up analysis set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The FUAS is a subset of the FAS and consists of patients who were eligible and consented to participate in the follow-up part of the trial (6 and 12 months’ follow-up [Visits 9 and 10]) and have attended at least 1 of the Follow-up Visits at 6 and 12 months. Patients have been analysed as randomised.

    Subject analysis sets values
    		 Safety analysis set Full analysis set Per protocol analysis set Follow up analysis set
    Number of subjects
    69
    62
    35
    41
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
        Adults (18-64 years)
    6
    6
    4
    4
        From 65-84 years
    61
    54
    30
    36
        85 years and over
    2
    2
    1
    1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    72.7 ± 5.6
    72.6 ± 5.8
    71.8 ± 5.7
    71.8 ± 5.4
    Gender categorical
    Units: Subjects
        Female
    34
    28
    16
    19
        Male
    35
    34
    19
    22
    Ethnic origin
    Units: Subjects
        Caucasian
    69
    62
    35
    41
        African descent
    0
    0
    0
    0
        Asian or Pacific Islander
    0
    0
    0
    0
        Mixed / Multi-racial
    0
    0
    0
    0
        Other
    0
    0
    0
    0
    Any medical/Surgical history
    Units: Subjects
        Medical/Surgical history reported
    39
        No medical/Surgical history reported
    30
    Any concurrent disease
    Units: Subjects
        Concurrent disease reported
    69
        No concurrent disease reported
    0

    End points

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    End points reporting groups
    Reporting group title
    Apovir
    Reporting group description
    		 Patients were randomised 1:1 to receive Apovir or Placebo. Patients were to be stratified based on presence/absence of treatment with AChEI/Memantine at baseline. However, all patients received treatment with AChEI/Memantine and stratification was therefore not relevant. Patients randomised to Apovir before first administration of IMP.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients were randomised 1:1 to receive Apovir or Placebo. Patients were to be stratified based on presence/absence of treatment with AChEI/Memantine at baseline. However, all patients received treatment with AChEI/Memantine and stratification was therefore not relevant. Patients randomised to placebo before first administration of IMP.
    Reporting group title
    Apovir
    Reporting group description
    		 Patients randomised to Apovir, a combination of APO-P001 and ribavirin. Apovir was taken orally, together with food twice Daily for 9 months. A daily dose of 600 mg APO-P001 and 600 mg ribavirin (decreased to 400 mg for all patients during the trial) were administered by the patients at home.

    Reporting group title
    Placebo
    Reporting group description
    		 Patints randomised to placebo. Placebo capsules for APO-P001 and ribavirin respectively were administered twice Daily for 9 months in the same manner as the Apovir capsules.
    Reporting group title
    Apovir
    Reporting group description
    		 Patients randomised to Apovir. Follow-up period assessing effect of treatment 6 and 12 months after end of treatment in the Apovir treatment Group.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients randomised to Placebo. Follow-up period assessing effect of treatment 6 and 12 months after end of treatment in the Placebo treatment Group.

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis set was defined as all patients who received at least one dose of the IMP. Patients were analysed as treated.

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The FAS is defined as all randomised patients who received at least 1 dose of the IMP and have at least 1 post-baseline assessment of efficacy data. In analyses performed on the FAS, patients have been analysed as randomised.

    Subject analysis set title
    Per protocol analysis set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PPAS is a subset of the FAS fulfilling the following additional criteria: 1. All important inclusion criteria and none of the important exclusion criteria were fulfilled (which criteria were to be considered as important was to be defined and documented at the clean file meeting, prior to code breaking). 2. An assessment of the primary efficacy variable, ADAS-cog, at 9 months and baseline. 3. Complied with the trial medication (i.e., have taken at least 75% of the anticipated amount of each component of the IMP). 4. No other major protocol deviations during the period up to 9 months. In analyses performed on the PPAS, patients have been analysed as treated.

    Subject analysis set title
    Follow up analysis set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The FUAS is a subset of the FAS and consists of patients who were eligible and consented to participate in the follow-up part of the trial (6 and 12 months’ follow-up [Visits 9 and 10]) and have attended at least 1 of the Follow-up Visits at 6 and 12 months. Patients have been analysed as randomised.

    Primary: Change from baseline to 9 months in ADAS-cog total score

    		 Close Top of page
    End point title
    		 Change from baseline to 9 months in ADAS-cog total score
    End point description
    The ADAS-cog test consists of 11 tasks performed by the patient under supervision and measures the disturbances of memory, language, praxis, attention and other cognitive abilities which are often referred to as the core symptoms of Alzheimer's disease. The maximum total score is 70. An increase in score indicates a worsening of disease wheras a decrease indicates an improvement. Sensitivity analyses were performed and are reported as separate endpoints.
    End point type
    Primary
    End point timeframe
    Change from baseline to 9 months
    End point values
    		 Apovir Placebo Full analysis set
    Number of subjects analysed
    18
    31
    49
    Units: ADAS-cog total score
        arithmetic mean (standard deviation)
    -1.963 ± 4.398
    1.817 ± 8.623
    0.429 ± 7.531
    Statistical analysis title
    		 Change from baseline to 9 months in ADAS-cog
    Statistical analysis description
    The primary efficacy endpoint is the ADAS-cog score at 9 months post baseline. In order to compensate for different baseline ADAS-cog scores, the change from baseline until 9 months post baseline has been used as the primary variable. No imputations of missing data have been done. The hypothesis that the change in ADAS-cog is equal among patients randomised to placebo and patients randomised to Apovir has been tested by means of the exact Wilcoxon rank sum test. The 2-sided p-value is presented
    Comparison groups
    Apovir v Placebo
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1809 [1]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [1] - The corresponding analysis was done at 3 months p=0.7110, 6 months p=0.1120 and 1 month follow-up p=0.0545
    Statistical analysis title
    		 Sensitivity analysis- imputation of data with LOCF
    Statistical analysis description
    Sensitivity analyses were performed for the primary efficacy endpoint. The difference between treatment Groups in change from baseline to 9 months in ADAS-cog total score was tested using the Wilcoxon rank sum test imputing missing observations by means of Last Observation Carried Forward (LOCF) princíple.
    Comparison groups
    Apovir v Placebo
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.7556
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [2] - Sensitivity analysi-imputation of missing data was done with LOCF. Analysis based on data from the 62 patients in the FAS.
    Statistical analysis title
    		 Sensitivity analysis- responder analysis ADAS-cog
    Statistical analysis description
    Sensitivity analyses were performed for the primary efficacy endpoint. A responder was defined as having a decrease in ADAS-cog score of at least 4 Points from baseline to 9 months. 3 responder definition criteria were defined for handling of missing data: 1: as non-responders 2: as responders 3: as non-responders in the Apovir Group and as responders in the placebo group
    Comparison groups
    Apovir v Placebo
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 1 [4]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [3] - A responder analysis without imputed data had not been pre-specified and is therefore not reported. Analysis based on data from the 62 patients in the FAS.
    [4] - Responder definition 1 p=1.0000 Responder definition 2 p= 0.0092 Responder definition 3 p=0.7707
    Statistical analysis title
    		 Sensitivity analysis- responder analysis mean
    Statistical analysis description
    Sensitivity analysis were performed for the primary efficacy endpoint. A responder was defined as having a mean decrease in ADAS-cog score of at least 4 Points from baseline across visits at 6 and 9 months and 1 month follow-up. 3 responder definition criteria were defined for handling of missing data: 1: as non-responders 2: as responders 3: as non-responders in the Apovir Group and as responders in the placebo group
    Comparison groups
    Placebo v Apovir
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.1672 [6]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [5] - Analysis based on data from the 62 patients in the FAS.
    [6] - Responder definition 1 p= 0.1672 Responder definition 2 p= 0.0028 Responder definition 3 p= 0.5216

    Secondary: Change in ADAS-cog total score - PPAS

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    End point title
    		 Change in ADAS-cog total score - PPAS
    End point description
    The ADAS-cog test consists of 11 tasks performed by the patient under supervision and measures the disturbances of memory, language, praxis, attention and other cognitive abilities which are often referred to as the core symptoms of Alzheimer's disease. The maximum total score is 70. An increase in score indicates a worsening of disease wheras a decrease indicates an improvement.
    End point type
    Secondary
    End point timeframe
    From baseline to 9 months
    End point values
    		 Apovir Placebo
    Number of subjects analysed
    10
    25
    Units: ADAS-cog total score
        arithmetic mean (standard deviation)
    -2.8 ± 3.94
    0.094 ± 4.836
    Statistical analysis title
    		 Change from baseline to 9 months in ADAS-cog
    Comparison groups
    Apovir v Placebo
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1197 [7]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [7] - Corresponding analyses were done for 3 months p=0.4545, 6 months p=0.0579 and 1 month follow-up p=0.2019

    Secondary: Change from baseline in MMSE score 9 months

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    End point title
    		 Change from baseline in MMSE score 9 months
    End point description
    MMSE is used to test for complaints of memory problems, and to diagnose progresion and severity of dementia. It consists of 30 questions and simple tasks in 6 categories: orientation, registration, attention/calculation, recall, language and coping and gives a maximum total score of 30. A decrease in score indicates a worsening and an increased score indicates an improvement of the condition. The test was performed by the patient under supervision of a physician. No statistical analysis has been specified for this secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Change from baseline to 9 months
    End point values
    		 Apovir Placebo
    Number of subjects analysed
    18
    31
    Units: MMSE score
    arithmetic mean (standard deviation)
        MMSE score
    -1.7 ± 2.4
    -1.3 ± 3.4
    No statistical analyses for this end point

    Secondary: Change fom baseline in MMSE score 6 months

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    End point title
    		 Change fom baseline in MMSE score 6 months
    End point description
    MMSE is used to test for complaints of memory problems, and to diagnose progresion and severity of dementia. It consists of 30 questions and simple tasks in 6 categories: orientation, registration, attention/calculation, recall, language and coping and gives a maximum total score of 30. A decrease in score indicates a worsening and an increased score indicates an improvement of the condition. The test was performed by the patient under supervision of a physician. No statistical analysis has been specified for this secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Change from baseline to 6 months
    End point values
    		 Apovir Placebo
    Number of subjects analysed
    21
    30
    Units: MMSE score
    arithmetic mean (standard deviation)
        MMSE score
    -1.1 ± 2.5
    -0.8 ± 2.4
    No statistical analyses for this end point

    Secondary: Change from baseline in MMSE score 1 month FU

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    End point title
    		 Change from baseline in MMSE score 1 month FU
    End point description
    MMSE is used to test for complaints of memory problems, and to diagnose progresion and severity of dementia. It consists of 30 questions and simple tasks in 6 categories: orientation, registration, attention/calculation, recall, language and coping and gives a maximum total score of 30. A decrease in score indicates a worsening and an increased score indicates an improvement of the condition. The test was performed by the patient under supervision of a physician. No statistical analysis has been specified for this secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Change from baseline to 1 month after end of treatment
    End point values
    		 Apovir Placebo
    Number of subjects analysed
    16
    30
    Units: MMSE score
    arithmetic mean (standard deviation)
        MMSE score
    -0.2 ± 2.3
    -1.7 ± 3
    No statistical analyses for this end point

    Secondary: Change in CDR-SB - 9 months

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    End point title
    		 Change in CDR-SB - 9 months
    End point description
    The CDR consistis of 6 items (boxes) and is a global scale developed to clinically denote the presence of dementia of Alzheimer type and stage its severity. The test was performed by an investigator, nurse or psychologist. Each item was rated 0 to 3 with the score 3 indicating the severest stage. The sum of boxes (CDR-SB) was calculated as the sum of the 6 individual items (0-18). No statistical analysis has been specified for this secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Change from baseline to 9 months
    End point values
    		 Apovir Placebo
    Number of subjects analysed
    17
    28
    Units: CDR-SB
        arithmetic mean (standard deviation)
    0.5 ± 1.98
    1.36 ± 2.48
    No statistical analyses for this end point

    Secondary: Change in ADAS-cog total score - 3 months

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    End point title
    		 Change in ADAS-cog total score - 3 months
    End point description
    The ADAS-cog test consists of 11 tasks performed by the patient under supervision and measures the disturbances of memory, language, praxis, attention and other cognitive abilities which are often referred to as the core symptoms of Alzheimer's disease. The maximum total score is 70. An increase in score indicates a worsening of disease wheras a decrease indicates an improvement.
    End point type
    Secondary
    End point timeframe
    Change from baseline to 3 months
    End point values
    		 Apovir Placebo
    Number of subjects analysed
    28
    32
    Units: ADAS-cog total score
        arithmetic mean (standard deviation)
    0.475 ± 8.206
    -0.094 ± 5.577
    No statistical analyses for this end point

    Secondary: Change in ADAS-cog total score - 6 months

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    End point title
    		 Change in ADAS-cog total score - 6 months
    End point description
    The ADAS-cog test consists of 11 tasks performed by the patient under supervision and measures the disturbances of memory, language, praxis, attention and other cognitive abilities which are often referred to as the core symptoms of Alzheimer's disease. The maximum total score is 70. An increase in score indicates a worsening of disease wheras a decrease indicates an improvement.
    End point type
    Secondary
    End point timeframe
    Baseline to 6 months
    End point values
    		 Apovir Placebo
    Number of subjects analysed
    21
    31
    Units: ADAS-cog total score
        arithmetic mean (standard deviation)
    -1.81 ± 5.403
    0.43 ± 5.798
    No statistical analyses for this end point

    Secondary: Change in ADAS-cog total score - 1 month FU

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    End point title
    		 Change in ADAS-cog total score - 1 month FU
    End point description
    The ADAS-cog test consists of 11 tasks performed by the patient under supervision and measures the disturbances of memory, language, praxis, attention and other cognitive abilities which are often referred to as the core symptoms of Alzheimer's disease. The maximum total score is 70. An increase in score indicates a worsening of disease wheras a decrease indicates an improvement.
    End point type
    Secondary
    End point timeframe
    Baseline to 1 month follow-up
    End point values
    		 Apovir Placebo
    Number of subjects analysed
    16
    30
    Units: ADAS-cog total score
        arithmetic mean (standard deviation)
    -2.876 ± 3.551
    1.012 ± 8.291
    No statistical analyses for this end point

    Secondary: Change in CDR-SB - 1 month FU

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    End point title
    		 Change in CDR-SB - 1 month FU
    End point description
    The CDR consistis of 6 items (boxes) and is a global scale developed to clinically denote the presence of dementia of Alzheimer type and stage its severity. The test was performed by an investigator, nurse or psychologist. Each item was rated 0 to 3 with the score 3 indicating the severest stage. The sum of boxes (CDR-SB) was calculated as the sum of the 6 individual items (0-18). No statistical analysis has been specified for this secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to 1 month follow-up
    End point values
    		 Apovir Placebo
    Number of subjects analysed
    16
    29
    Units: CDR-SB
        arithmetic mean (standard deviation)
    0.5 ± 2.03
    1.24 ± 3.04
    No statistical analyses for this end point

    Secondary: Change in AQT color and form -3 months

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    End point title
    		 Change in AQT color and form -3 months
    End point description
    Alzheimer Quick Test (AQT) is a timed test where patients are asked to name 1) color, 2) form and 3) color + form for a series of figures. The total naming time in seconds are recorded. Change from baseline in time for completing the test is presented. No statistical analysis has been specified for this secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to 3 months
    End point values
    		 Apovir Placebo
    Number of subjects analysed
    28
    32
    Units: AQT color and form naming
        arithmetic mean (standard error)
    12.2 ± 47.8
    0.9 ± 26.9
    No statistical analyses for this end point

    Secondary: Change in AQT color and form - 6 months

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    End point title
    		 Change in AQT color and form - 6 months
    End point description
    Alzheimer Quick Test (AQT) is a timed test where patients are asked to name 1) color, 2) form and 3) color + form for a series of figures. The total naming time in seconds are recorded. Change from baseline in time for completing the test is presented. No statistical analysis has been specified for this secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to 6 months
    End point values
    		 Apovir Placebo
    Number of subjects analysed
    21
    31
    Units: AQT color and form naming
        arithmetic mean (standard deviation)
    8.6 ± 41.8
    6.8 ± 32
    No statistical analyses for this end point

    Secondary: Change in AQT color and form - 9 months

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    End point title
    		 Change in AQT color and form - 9 months
    End point description
    Alzheimer Quick Test (AQT) is a timed test where patients are asked to name 1) color, 2) form and 3) color + form for a series of figures. The total naming time in seconds are recorded. Change from baseline in time for completing the test is presented. No statistical analysis has been specified for this secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to 9 months
    End point values
    		 Apovir Placebo
    Number of subjects analysed
    18
    31
    Units: AQT color and form naming
        arithmetic mean (standard deviation)
    -3.9 ± 28.2
    4.8 ± 34.7
    No statistical analyses for this end point

    Secondary: Change in AQT color and form -1 month FU

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    End point title
    		 Change in AQT color and form -1 month FU
    End point description
    Alzheimer Quick Test (AQT) is a timed test where patients are asked to name 1) color, 2) form and 3) color + form for a series of figures. The total naming time in seconds are recorded. Change from baseline in time for completing the test is presented. No statistical analysis has been specified for this secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to 1 month follow-up
    End point values
    		 Apovir Placebo
    Number of subjects analysed
    16
    30
    Units: AQT color and form naming
        arithmetic mean (standard deviation)
    -1.9 ± 38.1
    1.7 ± 29.3
    No statistical analyses for this end point

    Secondary: Plasma concentration APO-P001 - 1 month

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    End point title
    		 Plasma concentration APO-P001 - 1 month
    End point description
    Plasma samples collected before first IMP dose for the day of sampling.
    End point type
    Secondary
    End point timeframe
    1 month
    End point values
    		 Apovir
    Number of subjects analysed
    29
    Units: APO-P001 ng/ml
        arithmetic mean (full range (min-max))
    1362.9 (684 to 2730)
    No statistical analyses for this end point

    Secondary: Plasma concentration APO-P001 - 3 months

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    End point title
    		 Plasma concentration APO-P001 - 3 months
    End point description
    Plasma samples collected before first IMP dose for the day of sampling.
    End point type
    Secondary
    End point timeframe
    3 months
    End point values
    		 Apovir
    Number of subjects analysed
    28
    Units: APO-P001 ng/mL
        arithmetic mean (full range (min-max))
    1916.3 (792 to 3170)
    No statistical analyses for this end point

    Secondary: Plasma concentration APO-P001 - 6 months

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    End point title
    		 Plasma concentration APO-P001 - 6 months
    End point description
    Plasma samples collected before first IMP dose for the day of sampling.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Apovir
    Number of subjects analysed
    21
    Units: APO-P001 ng/mL
        arithmetic mean (full range (min-max))
    2284.8 (1320 to 4830)
    No statistical analyses for this end point

    Secondary: Plasma concentration APO-P001 - 9 months

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    End point title
    		 Plasma concentration APO-P001 - 9 months
    End point description
    Plasma samples collected before first IMP dose for the day of sampling.
    End point type
    Secondary
    End point timeframe
    9 months
    End point values
    		 Apovir
    Number of subjects analysed
    18
    Units: APO-P001 ng/mL
        arithmetic mean (full range (min-max))
    2315.6 (1120 to 4310)
    No statistical analyses for this end point

    Secondary: Plasma concentration Ribavirin - 1 month

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    End point title
    		 Plasma concentration Ribavirin - 1 month
    End point description
    Plasma samples collected before first IMP dose for the day of sampling.
    End point type
    Secondary
    End point timeframe
    1 month
    End point values
    		 Apovir
    Number of subjects analysed
    29
    Units: Ribavirin micromol/L
        arithmetic mean (full range (min-max))
    6.56 (2.4 to 11.5)
    No statistical analyses for this end point

    Secondary: Plasma concentration Ribavirin - 3 months

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    End point title
    		 Plasma concentration Ribavirin - 3 months
    End point description
    Plasma samples collected before first IMP dose for the day of sampling.
    End point type
    Secondary
    End point timeframe
    3 months
    End point values
    		 Apovir
    Number of subjects analysed
    24
    Units: Ribavirin micromol/L
        arithmetic mean (full range (min-max))
    6.84 (2.8 to 13.7)
    No statistical analyses for this end point

    Secondary: Plasma concentration Ribavirin - 6 months

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    End point title
    		 Plasma concentration Ribavirin - 6 months
    End point description
    Plasma samples collected before first IMP dose for the day of sampling.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Apovir
    Number of subjects analysed
    18
    Units: Ribavirin micromol/L
        arithmetic mean (full range (min-max))
    6.2 (0.3 to 16.8)
    No statistical analyses for this end point

    Secondary: Plasma concentration Ribavirin - 9 months

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    End point title
    		 Plasma concentration Ribavirin - 9 months
    End point description
    Plasma samples collected before first IMP dose for the day of sampling.
    End point type
    Secondary
    End point timeframe
    9 months
    End point values
    		 Apovir
    Number of subjects analysed
    15
    Units: Ribavirin micromol/L
        arithmetic mean (full range (min-max))
    5.27 (0.3 to 14.3)
    No statistical analyses for this end point

    Secondary: CSF concentration APO-P001

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    End point title
    		 CSF concentration APO-P001
    End point description
    CSF samples were collected before first IMP dose for the day of sampling.
    End point type
    Secondary
    End point timeframe
    9 months
    End point values
    		 Apovir
    Number of subjects analysed
    14
    Units: APO-P001 ng/mL
        arithmetic mean (full range (min-max))
    6.576 (2.7 to 17.5)
    No statistical analyses for this end point

    Secondary: CSF concentration Ribavirin

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    End point title
    		 CSF concentration Ribavirin
    End point description
    CSF samples were collected before first IMP dose for the day of sampling.
    End point type
    Secondary
    End point timeframe
    9 months
    End point values
    		 Apovir
    Number of subjects analysed
    14
    Units: Ribavirin micromol/L
        arithmetic mean (full range (min-max))
    3.605 (0.41 to 6.81)
    No statistical analyses for this end point

    Secondary: Responder and clinically relevant worsening in ADAS-cog- 9 months

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    End point title
    		 Responder and clinically relevant worsening in ADAS-cog- 9 months
    End point description
    A responder was defined as having a decrease of at least 4 Points compared to baseline. A patient who had an increase in ADAS-cog of at least 4 Points compared to baseline was considered to have a worsening of symptoms.
    End point type
    Secondary
    End point timeframe
    From baseline to 9 months
    End point values
    		 Apovir Placebo
    Number of subjects analysed
    18
    31
    Units: At least 4 point change in ADAS-cog
        Responder
    6
    6
        Clinically relevant worsening
    1
    7
    No statistical analyses for this end point

    Secondary: Responder and clinically relevant worsening in ADAS-cog - 3 months

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    End point title
    		 Responder and clinically relevant worsening in ADAS-cog - 3 months
    End point description
    A responder was defined as having a decrease of at least 4 Points compared to baseline. A patient who had an increase in ADAS-cog of at least 4 Points compared to baseline was considered to have a worsening of symptoms.
    End point type
    Secondary
    End point timeframe
    Baseline to 3 months
    End point values
    		 Apovir Placebo
    Number of subjects analysed
    28
    32
    Units: At least 4 point change in ADAS-cog
        Responder
    7
    6
        Clinically relevant worsening
    6
    4
    No statistical analyses for this end point

    Secondary: Responder and clinically relevant worsening in ADAS-cog - 6 months

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    End point title
    		 Responder and clinically relevant worsening in ADAS-cog - 6 months
    End point description
    A responder was defined as having a decrease of at least 4 Points compared to baseline. A patient who had an increase in ADAS-cog of at least 4 Points compared to baseline was considered to have a clinically relevant worsening of symptoms.
    End point type
    Secondary
    End point timeframe
    Baseline to 6 months
    End point values
    		 Apovir Placebo
    Number of subjects analysed
    21
    31
    Units: At leats 4 point change in ADAS-cog
        Responder
    8
    5
        Clinically relevant worsening
    3
    6
    No statistical analyses for this end point

    Secondary: Responder and clinically relevant worsening in ADAS-cog - 1 month FU

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    End point title
    		 Responder and clinically relevant worsening in ADAS-cog - 1 month FU
    End point description
    A responder was defined as having a decrease of at least 4 Points compared to baseline. A patient who had an increase in ADAS-cog of at least 4 Points compared to baseline was considered to have a clinically relevant worsening of symptoms.
    End point type
    Secondary
    End point timeframe
    Baseline to 1 month follow-up
    End point values
    		 Apovir Placebo
    Number of subjects analysed
    16
    30
    Units: At least 4 point change in ADAS-cog
        Responder
    8
    6
        Clinically relevant worsening
    1
    6
    No statistical analyses for this end point

    Secondary: Tolerability of Apovir (APO-P001 and Ribavirin)

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    End point title
    		 Tolerability of Apovir (APO-P001 and Ribavirin)
    End point description
    Tolerability was assessed as the number of patients discontinuing both APO-P001/placebo and Ribavirin/placebo during the treatment period of the trial.
    End point type
    Secondary
    End point timeframe
    Treatment period
    End point values
    		 Apovir Placebo
    Number of subjects analysed
    35
    34
    Units: Patients
        Dose disconinuation
    17
    3
    No statistical analyses for this end point

    Secondary: Tolerability APO-P001

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    End point title
    		 Tolerability APO-P001
    End point description
    Tolerability was assessed as the number of patients with any tolerability issue with APO-P001, dose interruption initiated by patient, dose interuption initiated by Investigator and discontinuation of treatment with APO-P001.
    End point type
    Secondary
    End point timeframe
    Treatment period
    End point values
    		 Apovir Placebo
    Number of subjects analysed
    35
    34
    Units: Patients
        Any tolerability
    19
    3
        Dose interruption initiated by patient
    5
    2
        Dose interruption initiated by Investigator
    1
    1
        Dose discontinuation
    17
    3
    No statistical analyses for this end point

    Secondary: Tolerability Ribavirin

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    End point title
    		 Tolerability Ribavirin
    End point description
    Tolerability was assessed as the number of patients with any tolerability issue with Ribavirin, dose interruption initiated by patient, dose interuption initiated by Investigator and discontinuation of treatment with Ribavirin and Ribavirin dose adjustment.
    End point type
    Secondary
    End point timeframe
    Treatment period
    End point values
    		 Apovir Placebo
    Number of subjects analysed
    35
    34
    Units: Patients
        Any tolerability
    24
    5
        Dose interruption initiated by patient
    4
    1
        Dose interruption initiated by Investigator
    0
    0
        Dose discontinuation
    20
    4
        Dose adjustment
    9
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The safety reporting period started at administration of the first dose of IMP and ended at the 1 month after end of treatment, ie visit 8.
    Adverse event reporting additional description
    Safety was assessed at all visits during the safety reporting period of the trial. A DMC reviewed unblinded safety data continuously during the safety reporting period of the trial.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1E
    Reporting groups
    Reporting group title
    Apovir
    Reporting group description
    		 Patients randomised to the Apovir Group received Apovir, a combination of APO-P001 and ribavirin, twice Daily for a period of 9 months. Apovir was administered orally and was to be taken together with food.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients randomised to the Placebo Group received Placebo capsules corresponding to the Apovir capsules. Placebo treatment was administered twice Daily for a period of 9 months as for Apovir. Placebo capsules were administered orally and was to be taken together with food.

    Serious adverse events
    		 Apovir Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 35 (22.86%)
    3 / 34 (8.82%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder neoplasm
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Depressed level of consciousness
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 34 (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
    Medical device complication
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 34 (2.94%)
         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
    Anaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Apovir Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    34 / 35 (97.14%)
    32 / 34 (94.12%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Melanocytic naevus
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    2
    Vascular disorders
    Hypertension
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 34 (2.94%)
         occurrences all number
    2
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    12 / 35 (34.29%)
    6 / 34 (17.65%)
         occurrences all number
    13
    7
    Back pain
         subjects affected / exposed
    4 / 35 (11.43%)
    3 / 34 (8.82%)
         occurrences all number
    4
    3
    Pyrexia
         subjects affected / exposed
    1 / 35 (2.86%)
    2 / 34 (5.88%)
         occurrences all number
    1
    2
    Discomfort
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 34 (2.94%)
         occurrences all number
    2
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 35 (2.86%)
    2 / 34 (5.88%)
         occurrences all number
    1
    2
    Investigations
    Weight decreased
    alternative assessment type: Systematic
         subjects affected / exposed
    8 / 35 (22.86%)
    1 / 34 (2.94%)
         occurrences all number
    8
    1
    Amylase increased
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 35 (8.57%)
    3 / 34 (8.82%)
         occurrences all number
    3
    3
    Fibrin D dimer increased
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 35 (8.57%)
    1 / 34 (2.94%)
         occurrences all number
    3
    1
    C-reactive protein increased
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 35 (2.86%)
    2 / 34 (5.88%)
         occurrences all number
    1
    2
    Blood creatine increased
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 35 (2.86%)
    5 / 34 (14.71%)
         occurrences all number
    1
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 35 (20.00%)
    9 / 34 (26.47%)
         occurrences all number
    11
    11
    Syncope
         subjects affected / exposed
    4 / 35 (11.43%)
    1 / 34 (2.94%)
         occurrences all number
    6
    1
    Blood and lymphatic system disorders
    Haemoglobin decreased
    alternative assessment type: Systematic
         subjects affected / exposed
    16 / 35 (45.71%)
    2 / 34 (5.88%)
         occurrences all number
    16
    2
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 35 (2.86%)
    3 / 34 (8.82%)
         occurrences all number
    2
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    9 / 35 (25.71%)
    4 / 34 (11.76%)
         occurrences all number
    11
    7
    Vomiting
         subjects affected / exposed
    5 / 35 (14.29%)
    4 / 34 (11.76%)
         occurrences all number
    7
    4
    Nausea
         subjects affected / exposed
    6 / 35 (17.14%)
    3 / 34 (8.82%)
         occurrences all number
    6
    4
    Abdominal pain upper
         subjects affected / exposed
    2 / 35 (5.71%)
    2 / 34 (5.88%)
         occurrences all number
    3
    3
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    4 / 35 (11.43%)
    1 / 34 (2.94%)
         occurrences all number
    4
    1
    Hyperhidrosis
         subjects affected / exposed
    3 / 35 (8.57%)
    0 / 34 (0.00%)
         occurrences all number
    3
    0
    Musculoskeletal and connective tissue disorders
    Neck pain
         subjects affected / exposed
    0 / 35 (0.00%)
    3 / 34 (8.82%)
         occurrences all number
    0
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 35 (5.71%)
    2 / 34 (5.88%)
         occurrences all number
    3
    3
    Influenza
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    2
    Pneumonia
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Dec 2013
    The estimated number of patients to be screened was changed from 80 to 120. A possibility for re-screen patients with based on MMSE was introduced for patients with an MMSE score 1-2 Points outisde the acceptable range for inclusion was added to the protocol and a possibility to perform home visits was described.
    28 Jul 2014
    The MMSE inclusion criterion was changed from 21-26 to 21-27. The reason for the change was A general dose reduction for ribavirin from 600 mg/day to 400 mg/day was described. The change had been implemented on 03MAR2014 as it was judged that the change was supported by the writing of the clinical trial protocol. The change was implemented because adverse eventsleading to a compromised tolerability in the trial were judged largely to be related to ribavirin had Cognitive tests added at the 1 month follow-up visit. The reason for the change was that adverse events had been reported during the trial that were suspected to interfere with the performance of the cognitive tests The option to temporarily discontinue treatment with ribavirin and/or APO-P001 was introduced. The authority of the DSMB to withdraw patients from the trial or decrease the initial ribavirin dose was extended to include also to temporary or permanently withdraw the ribavirin/placebo treatment also for other reasons
    20 Nov 2014
    A long-term post treatment follow-up part consisting of two visits (6 and 12 months after end of treatment) was added to the trial. The reason for adding the visits was to assess the effect of the treatment A clarification of planned statistical analyses was made

    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.
    A large proportion of the patients in the Apovir Group discontinued the trial prematuerly. 48.6% of the patients in the Apovir group completed the original part of the trial (1 month after end of treatment) and 34.2% completed the entire trial.
    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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