| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects with a clinical diagnosis of Alzheimer's disease who are APOE 4 carriers (APOE4/4, APOE3/4) and at the Early stage of disease, ages 50-80 years |
|
| E.1.1.1 | Medical condition in easily understood language |
| Early stage Alzheimer’s disease |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Prim. Obj.
To evaluate the effects of oral ALZ-801 in subjects with Early AD who have the APOE4/4 or APOE3/4 genotype, on the plasma biomarkers of core AD pathology and brain volumes
Primary Plasma Biomarkers Outcome: p-tau181
Key Imaging Outcome: hippocampal volume on vMRI
Saf. Obj.
To evaluate the safety and tolerability of chronic treatment with ALZ-801 in subjects with Early AD who are APOE4 carriers
Expl. Fluid Biomarker Obj.
To evaluate the effects of oral ALZ-801 on other plasma and CSF biomarkers:
Plasma biomarker of astrocytic activation: GFAP
Plasma biomarker of neurodegeneration: NfL
CSF biomarkers of core AD pathology: p-tau181, p-tau217, Aβ40 and Aβ42
CSF biomarker of synaptic toxicity: neurogranin
CSF biomarkers of neurodegeneration: total tau (t-tau) and NfL
CSF neuroinflammation markers: TREM2 (microglia) and YKL-40 (astrocytes)
Clin. Obj.
To evaluate the efficacy of ALZ-801 on tests of cognition and function: RAVLT, DSST, A-IADL, MMSE and CDR-SB |
|
| E.2.2 | Secondary objectives of the trial |
Secondary Obj
•To evaluate the effects of oral ALZ-801 on other plasma biomarkers of core AD pathology and brain volumes
Sec. Plasma Biomarker Out: Aβ40, Aβ42, and p-tau217
Sec. Imaging Biomarker Out: cortical thickness and ventricular volume
Pharmacokinetic Obj
•To evaluate PK of ALZ-801 and its metabolites in AD subjects
•To evaluate extended PK profile over 8 hours in 24 subjects after 65 weeks of treatment
Add. Exploratory Obj
•To evaluate effect of ALZ-801 on other AD biomarkers as assays become available
•To evaluate the effect of ALZ-801 on other MRI imaging measures
LTE
Objectives of LTE periods of study are to evaluate long-term safety and efficacy of ALZ-801 over a total of 156 and 208 w or 3 and 4 years of treatment. This includes evaluation of safety parameters, fluid biomarkers, vMRI and clinical outcomes over an additional 104 w of treatment in LTE periods. Safety and tolerability of TID dosing in subjects who are eligible for dose escalation will be evaluated |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
PK Profile Substudy:
A total of 24 subjects (12 APOE4/4 homozygotes and 12 APOE3/4 heterozygotes) will be consented to participate in a substudy. These subjects will come to the site at Visit 9 (Week 65), and pre-dose and 8 post-dose plasma samples will be obtained for PK profile analyses. Twenty-four (24) subjects who agree to be part of the PK Profile Substudy will be consented using a separate ICF.
The PK substudy will enroll 24 subjects who will undergo extended PK sampling over 8 hours at the Week 65 visit.
Plasma PK samples will be used to evaluate the PK of ALZ-801 and its metabolites in all study subjects, as well as to evaluate the 8-hour PK profile in 24 subjects in the PK substudy.
LTE
PK Profile Substudy in LTE Year 2:
PK Substudy for the BID Dose
Approximately 12 subjects (6 APOE4/4 homozygotes and 6 APOE4 heterozygotes) will be consented to participate in a PK substudy in the LTE Year 2 at Week 168 (Visit 6E) or an additional visit between Week 168 and Week 182 (called Visit 6E-PK), and plasma samples will be obtained for PK analysis at a pre-dose timepoint, after 30 min, and 1, 2, 4, and 6 hours post-dose.
PK Substudy for the TID Dose
Approximately 6 subjects (3 APOE4/4 homozygotes and 3 APOE4 heterozygotes) from this group will be consented to participate in a PK substudy in the LTE Year 2, and plasma samples will be obtained for PK analysis at a pre-dose timepoint, after 30 min, and 1, 2, 4, and 6 hours
post-dose.
The PK Substudy will occur at the following visits:
•For subjects who escalate to TID dose at Week 168 (Visit 6E), this will occur at Week 182 (Visit 7E) or at an additional visit between Week 182 and Week 196 (called Visit 7E-PK).
•For subjects who escalate to TID dose at Week 182 (Visit 7E), this will occur at Week 196 (Visit 8E) or at an additional visit between Week 196 and Week 208 (called Visit 8E-PK) or at Week 208 (Visit 9E) for subjects who escalate at Week 196.
CSF PK Substudy
In the core study and LTE Year 1, at visits where CSF sampling occurs, a
sample for CSF drug levels will be obtained.
|
|
| E.3 | Principal inclusion criteria |
Main Inclusion Criteria - Core Study (Weeks 0-104)
1. Subjects aged 50 to 80 years who have a diagnosis of early AD according to the National Institute on Aging – Alzheimer’s Association criteria (Mild Cognitive Impairment due to AD or
Probable AD dementia).
2. Subjects are carriers of the APOE4 allele (APOE4/4 or APOE3/4 genotype).
3. Subjects with MMSE score 22 to 30 inclusive; Clinical Dementia Rating (CDR)-Global Score of 0.5 or 1.0 and CDR Memory Box Score of ≥ 0.5.
4. Subjects with documented confirmation of AD diagnosis by either positive amyloid positron emission tomography (PET) or positive CSF AD signature. Subjects without documented
positive AD biomarker status must have a positive CSF biomarker result from a sample provided at screening.
5. Subjects may be on stable doses of acetylcholinesterase for the duration of the study, but memantine is not allowed.
Long-Term Extension Year 1 (Weeks 104-160)
Inclusion Criteria
To be eligible for the LTE Year 1, the subject must:
1. Complete the last visit (Week 104) of the core study.
2. Be willing to sign an IRB/IEC-approved ICF indicating that he/she understands the purpose of the study and the procedures that are required for the study and that he/she is willing to participate in the study. Subjects are free to withdraw consent at any time. If a subject is
unable or deemed not competent to sign the consent form, the subject's legally authorized representative may sign the consent form with the subject's assent, except where local regulations and IRB/IEC approval do not allow subjects who are unable or deemed not competent to sign the consent form, to participate in the study.
3. Agree (subject and caregiver/study partner) to be compliant with study procedures and, in the opinion of the Investigator, have a high probability of completing the study.
4. Have stable medical conditions in the opinion of the Investigator.
Long-Term Extension Year 2 (Weeks 156-212)
Inclusion Criteria
To be eligible for the LTE Year 2, the subject must:
1. Complete the last visit (Week 156) of the LTE Year 1
2. Be willing to sign an IRB/IEC-approved ICF indicating that he/she understands the purpose of the study and the procedures that are required for the study and that he/she is willing to participate in the study. Subjects are free to withdraw consent at any time. If a subject is
unable or deemed not competent to sign the consent form, the subject's legally authorized representative may sign the consent form with the subject's assent, except where local regulations and IRB/IEC approval do not allow subjects who are unable or deemed not competent to sign the consent form, to participate in the study.
3. Agree (subject and caregiver/study partner) to be compliant with study procedures and, in the opinion of the Investigator, have a high probability of completing the study.
4. Have stable medical conditions in the opinion of the Investigator.
In addition, to be eligible for dose escalation to TID dosing, the subject
must:
5. Have MMSE score <22 at clinic visit between Weeks 156-196 (Visits 5E-8E).
6. When the MMSE score is <22, be willing to sign the TID dosing section of the IRB/IEC approved ICF indicating that he/she understands the TID dose escalation. Subjects are free to withdraw consent at any time. If a subject is unable or deemed not competent to sign the TID dosing section of the consent form, the subject's legally authorized representative may sign with the subject's assent, except where local regulations and IRB/IEC approval do not allow subjects who are unable or deemed not competent to sign the consent form, to participate in the study.
7. Have tolerated the BID dose for the last 3 months.
8. Deemed by the investigator to be likely to benefit from the TID dose and to complete the LTE Year 2. |
|
| E.4 | Principal exclusion criteria |
1.Has a brain MRI at screening indicative of significant abnormality, incl. but not limited to, prior hemorrhage (> 1 cm)or large infarct (> 1 cm), > 2 lacunar infarcts outside the brain stem, severe white matter changes (Fazekas grade 3), superficial hemosiderosis > 1 cm, aneurysm, vascular malformation, subdural hematoma, space-occupying lesion (e.g., abscess or brain tumor such as meningioma), or ventricular enlargement consistent with normal pressure hydrocephalus
2.Has a diagnosis of neurodegenerative disorder other than AD
3.Has a current diagnosis of MDD accord. to criteria of DSMMD-5th Ed. Subjects who do not meet current criteria for MDD and who are on stable doses of antidepressants or mood stabilizers may be included in the study at discretion of Inv
4.Has a history of suicidal behavior or has ongoing suicidal ideation
5.Has a history of seizures. Subjects with a history of one seizure, but without evidence of vascular or mixed dementia, or brain tumor on MRI, may be allowed into study at discretion of MM
6.Has a medically confirmed history of recent cerebral infarct or recent transient ischemic attack
7.Has a medically confirmed history of recent myocardial infarction or unstable, untreated coronary artery disease, or angina pectoris
8.Has a history of cancer, diagnosed and treated within last 3 years prior to Scr–P2V, with exception of following: (a) treated basal cell carcinoma of the skin, or (b) treated in situ or Stage 1 cancers of skin (squamous cell only), colon, prostate, breast, or colon
9.Has a hemoglobin level < 11 g/dL in male subjects or < 10 g/dL in female subjects, or a hemoglobin level > 16 g/dL
10.Has a prothrombin time as measured by INR ≥ 1.5 and a platelet count ≤ 50 x 10^9/L
11.Has donated blood within 8 weeks prior to Scr–P2V
12.Has clinically relevant abnormalities in serum TSH or calcium. If subject is taking replacement therapy, corresponding Screening test values must be clinically acceptable
13.Has serum vitamin B12 below lower limit of normal
14.Has any clinical chemistry laboratory value greater than or equal to CTCAE; v4.0; Gr2, unless considered not clinically relevant by Inv and MM
15.The subject at Screening has one or more of following
a.Alanine aminotransferase (ALT) ≥ 3 x upper limit of normal (ULN) OR
b.Aspartate aminotransferase (AST) ≥ 3 x ULN OR
c.Total bilirubin (TBL) ≥ 1.5 x ULN
16.Has an estimated glomerular filtration rate < 40 ml/min per 1.73 m2 accord. to Modif. of Diet in Renal Disease formula
17.Has a glycosylated hemoglobin (HbA1c) > 8% (NGSP) or 64 mmol/mol (IFCC) at Scr–P1V
18.Has a history of alcohol or drug dependence or abuse within 2 years of Scr–P2V or tests positive for drugs of abuse at Scr–P2V
19.Has a lifetime history of schizophrenia, schizoaffective disorder or bipolar disorder
20.Has any significant medical condition (e.g., uncontrolled cardiovascular, GI, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, renal, or other major disease or malignancy) that is unstable and that would either: (a) place the subject at undue risk from administration of study drug or from undergoing study procedures, or (b) interfere with interpretation of safety or efficacy evaluations obtained in course of study
21.Has participated in a clinical study of any potential disease-modifying AD treatment, and received active drug within 6 months prior to Scr–P2V
22.Has participated in a clinical study and received active treatment with an anti-amyloid or anti-tau vaccine
23.Has received any of treatments listed in Tab more recently than the indicated period before Scr–P2V
24.Anticipates receiving any of treatment listed in Tab, during current clinical study
25.Is unable to swallow ALZ-801 tablets or has a known intolerance or hypersensitivity to tramiprosate or any of excipients contained in ALZ-801 tablets
26.Has a history of, or currently has, any clinically significant ECG finding, or a QT interval corrected by Fridericia's method (QTcF) of > 450 msec for males and > 470 msec for females
27.Has positive serology for HIV or for hepatitis B or C virus
LTE Year1
1.Withdrew from core study before completing W104 visit
2.Were noncompliant (<70%) with the study medication or in Investigator’s or Sponsor’s opinion, with study procedures in core study
3.Had a clinically significant medical, surgical, laboratory, or other abnormality at the W104 visit of core study that would compromise their participation in the LTE or compromise their safety in opinion of Inv
LTE Year2
1.Withdrew from LTE Year 1 before completing W156 visit
2.Were noncompliant (<70%) with study medication or, in Investigator's or Sponsor's opinion, with study procedures in LTE Year 1
3.Had a clinically significant medical, surgical, laboratory, or other abnormality at Week156 visit of LTE Year 1 that would compromise their participation in the continued LTE or compromise their safety in opinion of Inv |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Endpoints - Core Study
Primary and Key Secondary Outcome
• Primary Plasma Biomarker Outcome: change from baseline to Week 104 in plasma biomarker of core AD pathology: p-tau181
• Key Imaging Outcome: change from baseline to Week 104 in hippocampal volume on vMRI
Safety Outcomes
• Incidence and nature of TEAE, serious TEAE, and TEAE leading to withdrawal
• Changes in laboratory parameters, vital signs, and physical examination
• Changes in 12-lead electrocardiogram (ECG) parameters
• MRI assessments for Amyloid-Related Imaging Abnormalities with edema (ARIA-E) or microhemorrhages (ARIA-H)
Long-Term Extension (Year 1)
Primary and Key Secondary Outcomes
• Primary Plasma Biomarker Outcome: change from study baseline to Week 156 in plasma biomarkers: p-tau181
Key Imaging Outcome: change from study baseline to Week 156 in
hippocampal volume on vMRI
Safety Outcomes
•Safety and tolerability over 156 weeks of study and over 52 weeks of
the LTE Year 1 as listed in Study Protocol V7.0 Section 2.2.2
LTE Year 2
Primary and Key Secondary Outcomes
•Primary Plasma Biomarker Outcome: change from study baseline to Week 208 in plasma biomarkers: p-tau181
•Key Imaging Outcome: change from baseline to Week 208 in hippocampal volume on vMRI
Safety Outcomes
•Safety and tolerability over 104 weeks of the LTE-assessments (and over 208 weeks in the overall study) as listed in Study Protocol V7.0 Section 2.2.2
Secondary Fluid Biomarker Outcome
•Change from baseline to Week 208 in plasma biomarkers: p-tau217, Aβ40, and Aβ42
Secondary Imaging Biomarker Outcome
•Change from baseline to Week 182 in hippocampal volume
•Change from baseline to Weeks 182 and 208 in cortical thickness, whole brain volume and ventricular volume on vMRI
Exploratory Fluid Biomarkers Outcomes
•Change from baseline to Week 208 in plasma GFAP
•Change from baseline to Week 208 in plasma NfL
Clinical Outcomes
•Change from baseline to Weeks 168, 182, 196, and 208 in the clinical outcomes: RAVLT, DSST, MMSE, A-IADL, and CDR-SB
•Change from baseline on the NPI: change from the first clinic assessment of the NPI to assessments at all later visits
Pharmacokinetic Outcomes
•PK assessments for ALZ-801 and its metabolites as in Study Protocol V7.0 Section 2.2.7
Additional Fluid and Imaging Biomarker Outcomes
•Change from baseline to Weeks 168, 182, 196 in plasma biomarkers: GFAP, NfL, p-tau181, p-tau217, Aβ40, and Aβ42
•Change from baseline to Weeks 182 and 208 in other exploratory MRI imaging outcomes (as described in the SAP)
•Change from LTE Year 1 baseline (Week 104) to Weeks 130, 156, 182, and 208 in MRI DTI measures. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Core Study
Prim. and Key Second. O
Prim. Plasma Biomarker, Key Imaging O
BSL to W104
LTE Y1
Prim. and Key Second. O
Prim. Plasma Biomarker, Key Imaging O
BLS to W156
Safety O
•Safety and tolerability over 156 w of study and over 52 w of LTE Y1 as
listed in Sec 2.2.2
LTE Y2
Prim. and Key Second. O
Prim. Plasma Biomarker, Key Imaging Outc
BLS to W208
Safety O
•Safety and tolerability over 104 w of study of LTE-assessments (and
over 208 w in overall study) as listed in Sec 2.2.2
Second. Fluid Biomarker O
BSL to W208
Second. Imaging Biomarker O
BSL to W182
BSL to W182, 208
Expl. Fluid Biomarkers O
BSL to W208
Clin. O
BSL to W168, 182, 196, 208
BSL on NPI
Add. Fluid and Imaging Biomarker O
BSL to W168, 182, 196
BSL to W182, 208
LTE BSL Y1 to W130, 156, 182, 208 |
|
| E.5.2 | Secondary end point(s) |
Core study
Secondary Fluid Biomarker Outcome
•Change from baseline to Week 104 in plasma biomarkers of other core AD pathologies: Aβ40, Aβ42, and p-tau217
Secondary Imaging Biomarker Outcome
•Change from baseline to Week 104 in cortical thickness and ventricular volume
Exploratory Fluid Biomarker Outcomes
•Change from baseline to Week 104 in biomarker of plasma GFAP
•Change from baseline to Week 104 in plasma NfL
•Change from baseline to Week 104 in CSF p-tau181, p-tau217, Aβ40, and Aβ42
•Change from baseline to Week 104 in CSF neurogranin
•Change from baseline to Week 104 in CSF t-tau and NfL
•Change from baseline to Week 104 in CSF TREM2 and YKL-40
Clinical Outcomes
•Change from baseline to Week 104 in RAVLT, DSST, A-IADL MMSE, CDRSB
Pharmacokinetic and Pharmacodynamic Outcomes
•Plasma and CSF levels of ALZ-801, tramiprosate, and its metabolite before and after first dose, at steady state, and at later time points in the study. PK non-compartmental analysis will be performed using Phoenix WinNonlin (version 7.0 or later).
•Correlation of PK levels to biomarker outcomes.
•Correlation of PK levels to efficacy and safety parameters.
•Extended PK profile over 8 hours on Week 65 will be evaluated in approximately 24 subjects (approximately 12 APOE4/4 homozygotes and 12 APOE3/4 heterozygotes) who have consented to participate in the PK Profile Substudy
Additional Fluid and Imaging Biomarker Outcomes
•Change from baseline to Weeks 6, 13, 26, 52, and 78 for plasma biomarkers
•Change from baseline to Week 52 in hippocampal volume, cortical thickness, and ventricular volume
•Change from baseline to Week 52 and 104 in other exploratory MRI imaging outcomes
•Change from baseline to Week 52 for CSF biomarkers
•Potential additional exploratory analyses of plasma and CSF biomarkers, including CSF Aβ oligomer assays may be performed using state of the art methods, if available
Additional Clinical Outcomes
•Change from baseline to Weeks 13, 26, 52, and 78 for RAVLT and DSST
•Change from baseline to Weeks 13, 26, 39, 52, 65, 78, and 91 for MMSE
•Change from baseline to Week 52 for A-IADL and CDR-SB,
LTE (Year 1)
Secondary Fluid Biomarker Outcome
•Change from study baseline to Week 156 in plasma biomarkers: p-tau217, Aβ40, and Aβ42
Secondary Imaging Biomarker Outcome
•Change from study baseline to Week 130 in hippocampal volume
•Change from baseline to Weeks 130 and 156 on cortical thickness, whole brain volume and ventricular volume on vMRI
Exploratory Fluid Biomarkers Outcomes
•Change from baseline to Week 156 in plasma GFAP
•Change from baseline to Week 156 in plasma NfL
•Change from baseline to Week 156 in CSF p-tau181, p-tau217, Aβ40, and Aβ42
•Change from baseline to Week 156 in CSF neurogranin
•Change from baseline to Week 156 in CSF t-tau and NfL
•Change from baseline to Week 156 in CSF sTREM2 and YKL-40
Clinical Outcomes
•Change from baseline to Weeks 130 and 156 in the clinical outcomes: RAVLT, DSST, MMSE, A-IADL, and CDR-SB
Pharmacokinetic Outcomes
•PK assessments for ALZ-801 and its metabolites as in Study Protocol V7.0 Section 2.2.7
Additional Fluid and Imaging Biomarker Outcomes
•Change from baseline to Week 130 in plasma biomarkers: GFAP, NfL, p-tau181, p-tau217, Aβ40, and Aβ42
•Change from baseline to Weeks 130 and 156 in other exploratory MRI imaging outcomes
•Change from LTE baseline (Week 104) to Weeks 130 and 156 in MRI diffusion tensor imaging (DTI) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Core Study
Second. Fluid Biomarker O.
from BSL to W104
Second. Imaging Biomarker O.
from BSL to W104
Exploratory Fluid Biomarker O.
from BSL to W104
Clin. O.
from BSL to W104
Additional Fluid and Imaging Biomarker O.
from BSL to W6, 13, 26, 52, 78
from BSL to W52
from BSL to W52, 104
from BSL to W52
Add. Clinical O.
from BSL to W13, 26, 52, 78 for RAVLT, DSST
from BSL to W13, 26, 39, 52, 65, 78, 91 for MMSE
from BSL to W52 for A-IADL, CDR-SB
LTE Year 1
Second. Fluid Biomarker O.
BSL to W156
Second. Imaging Biomarker O.
BSL to W130
BSL to W130, 156
Exploratory Fluid Biomarkers O.
BSL to W156
Clin. O.
from BSL to W130, 156
Add. Fluid and Imaging Biomarker O.
from BSL to W130
from BSL to W130, 156
from LTE BSL to W130, 156 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 59 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 59 |
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