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    Summary
    EudraCT Number:2013-002126-23
    Sponsor's Protocol Code Number:APOCT-002
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-07-12
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSweden - MPA
    A.2EudraCT number2013-002126-23
    A.3Full title of the trial
    A randomized, double blind, placebo controlled trial to evaluate the safety and efficacy of Apovir for treatment of patients with Alzheimer’s disease
    En randomiserad, dubbelblind, placebokontrollerad studie för att utvärdera säkerhet och effekt av Apovir vid behandling av patienter med Alzheimers sjukdom
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Safety and efficacy of Apovir for treatment of patients with Alzheimer's disease
    Säkerhet och effekt av Apovir vid behandling av patienter med Alzheimers sjukdom
    A.4.1Sponsor's protocol code numberAPOCT-002
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorApodemus AB
    B.1.3.4CountrySweden
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportApodemus AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationApodemus AB
    B.5.2Functional name of contact pointClinical trials
    B.5.3 Address:
    B.5.3.1Street AddressNobels Väg 3
    B.5.3.2Town/ citySolna
    B.5.3.3Post code171 65
    B.5.3.4CountrySweden
    B.5.4Telephone number4686197171
    B.5.6E-mailbo.niklasson@apodemus.se
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Copegus
    D.2.1.1.2Name of the Marketing Authorisation holderRoche
    D.2.1.2Country which granted the Marketing AuthorisationSweden
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameribavirin
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INN1-beta-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide
    D.3.9.1CAS number 36791-04-5
    D.3.9.3Other descriptive nameRIBAVIRIN
    D.3.9.4EV Substance CodeSUB10297MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namepleconaril
    D.3.2Product code APO-P001
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPLECONARIL
    D.3.9.1CAS number 153168-05-9
    D.3.9.2Current sponsor codeAPO-P001
    D.3.9.4EV Substance CodeSUB09957MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Alzheimer's disease
    E.1.1.1Medical condition in easily understood language
    Alzheimer's disease
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    E.1.2Level LLT
    E.1.2Classification code 10001896
    E.1.2Term Alzheimer's disease
    E.1.2System Organ Class 100000004852
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Main efficacy objective:• To investigate the effect of Apovir on disease progression of AD as assessed by the Alzheimer’s Disease Assessment Scale-Cognitive Subscale [ADAS-cog] compared to placebo
    Main safety objective: • To investigate the safety and tolerability of the combination therapy of Apovir in patients with AD
    E.2.2Secondary objectives of the trial
    • To investigate the effect of Apovir on disease progression of AD assessed by cognitive tests – (Mini Mental State Examination [MMSE], ADAS-cog, Alzheimer’s Quick Test [AQT] and Clinical Dementia Rating [CDR])
    • To investigate the plasma and cerebrospinal fluid concentrations of Apovir (APO-P001 and ribavirin) in patients with AD
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female patients diagnosed with AD according to ICD-10
    2. 60–85 years at the time of screening
    3. Mini Mental State Exam score 21–27 and judged by the Investigator to be able to give informed consent
    4. Patients have adequate hearing, vision, and language skills to perform neuropsychiatric testing and interviews as specified in the protocol, as judged by the Investigator
    5. 12-lead ECG with normal tracings; or changes that are not clinically significant and do not require medical intervention, as judged by the Investigator
    6. Patient has a relative or caregiver, judged to be reliable by the Investigator, who has signed informed consent. The relative or caregiver should participate in the patient’s visits at the clinic and assist the patient with drug compliance.
    7. Willingness to participate after signing informed consent
    E.4Principal exclusion criteria
    1. Active hepatitis B, active hepatitis C, or HIV infection
    2. Serious cardiac disease including unstable or uncontrolled cardiac disease during the last 6 months and/or previous history of deep vein thrombosis or clinical signs of deep venous thrombosis
    3. Major surgical procedure within 4 weeks prior to inclusion
    4. Patients on unstable treatment with AChI and / or Memantine for dementia. Unstable treatment is defined as initiated treatment or changed treatment or dose within 3 months prior to the baseline visit (i.e. patients on stable AChI / Memantine treatment and patients without AChI / Memantine treatment can be included in the trial) If patients receive treatment with AChI for dementia this treatment should have been unchanged regarding drug(s) and dose(s) for at least 3 months prior to the baseline visit (patients on an unchanged AChI dose/medication and patients without AChI treatment can be included in the trial)
    5. Men without reliable contraceptive method if sexually active with WOCBP. For purposes of this trial, WOCBP include any female who has experienced menarche, who has not undergone tubal ligation, and who is not postmenopausal. Post menopause is defined as: amenorrhea ≥ 12 consecutive months without another cause.
    6. Participation in any other clinical trial within 30 days of inclusion (randomisation) in the trial or patients with unresolved investigational treatment-related adverse events
    7. Other chronic disease or previous organ transplantation judged by the Investigator to interfere with the assessment of treatment success and/or ability to fully participate in the trial
    8. Impaired kidney function with a glomerular filtration rate (GFR) calculated from cystatin C <60 mL/min
    9. Calculated ribavirin dose at screening is <600 mg/day* according to the following formula:
    0.244 x 10ax 24b x (0.122 x GFR + 0.0414 x body weight in kg)
    when a Target concentration=10 mmol/L and b Dosing frequency=24 hours
    * If the ribavirin/placebo starting dose is adjusted to 400mg/day the calculated ribavirin dose may be <600mg/day, but must not be <400mg/day at screening.
    10. Known blood disease or Anaemia Haemoglobin < 120g/L for women and <130 g/L for men
    11. Known haemoglobinopathy (e.g. thalassemia and sickle cell anaemia)
    12. Patients that require immunosuppressive treatments including azathioprin, ciclosporin, systemic steroid treatment (e.g. prednisolone at doses of ≥10 mg/day or hydrocortisone) or has received such treatment within the last 6 months prior to randomization
    13. Patients that are treated with drugs that can interact significantly with APO-P001; ethinylestradiol and/or ribavirin; azathiopin, didanosine, zidovudine, mercaptopurine, stavudine
    14. Lack of suitability for participation in the trial, for any reason, as judged by the Investigator
    E.5 End points
    E.5.1Primary end point(s)
    Main efficacy endpoint:• ADAS-cog at 9 months (visit 7)
    Main safety endpoint: • Frequency and intensity of adverse events
    E.5.1.1Timepoint(s) of evaluation of this end point
    Efficacy endpoint: at 9 months
    Safety endpoint: total duration of the original part of the trial (visits 1 to 8)
    E.5.2Secondary end point(s)
    • Tolerability of Apovir as assessed by dose adjustments, interruption- or discontinuation of treatment
    • Vital signs, laboratory parameters and weight
    Change in disease progression of AD as assessed by:
    • ADAS-cog at 3 months (visit 5), and 6 months (visit 6) and the 1-month follow-up visit (visit 8)
    • AQT at 3 months (visit 5), 6 months (visit 6), and 9 months (visit 7) and the follow-up visit
    • MMSE at 6 months (visit 6), and 9 months (visit 7) and the follow-up visit
    • CDR sum of boxes at 9 months (visit 7) and the follow-up visit
    Plasma concentrations of Apovir:
    • Plasma concentrations Cpre dose of Apovir (APO-P001 and ribavirin respectively) on day 28 (visit 4) and at 3 months (visit 5), 6 months (visit 6) and 9 months (visit 7) (concentrations at 3 months will be compared to published data [Rhodes and Liu 2001; Khakoo et al 1998])
    Cerebrospinal fluid concentrations of Apovir:
    • Cerebrospinal fluid concentrations of Apovir (APO-P001 and ribavirin respectively) at 9 months (visit 7)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Timepoints of evaluation of all safety endpoints is total duration of the original part of the trial (visits 1 to 8).
    Timepoints for evaluation of efficacý endpoints is listed in the respective endpoint
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    randomisation will be stratified based on treatment with acetylcholine esterase inhibitors.
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Last patient last visit in the trial
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 5
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 55
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others Yes
    F.3.3.7.1Details of other specific vulnerable populations
    Patients with dementia of mild severity will be included in the trial.
    F.4 Planned number of subjects to be included
    F.4.1In the member state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 60
    F.4.2.2In the whole clinical trial 60
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    No treatment will be provided to the patients after the end of the trial
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-09-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-09-04
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-06-23
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