| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Early Stage Alzheimer's Disease |
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| E.1.1.1 | Medical condition in easily understood language |
| Early Stage Alzheimer's Disease |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001896 |
| E.1.2 | Term | Alzheimer's disease |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10074616 |
| E.1.2 | Term | Prodromal Alzheimer's disease |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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| 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 |
| The primary objective of this study is to assess the safety and tolerability of multiple doses of PQ912 compared with placebo in subjects with early stage AD. |
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| E.2.2 | Secondary objectives of the trial |
• To explore the efficacy of PQ912 from baseline to week 12 on cognitive function, as measured by a neuropsychological test battery.
• To assess the pharmacodynamics of PQ912 and to identify therapeutic markers as measured by a panel of concept- and AD-related biomarkers in CSF.
• To investigate the effect of PQ912 on brain functional connectivity as assessed by RSfMRI.
• To provide biological support for the hypothesized PQ912 efficacy in counter-acting disruption of the functional network organization in MCI due to AD or mild dementia due to AD, using functional connectivity and network analysis in EEG.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed and dated written informed consent obtained from the subject in accordance with local regulations.
2. Male or surgically sterile or postmenopausal female, aged ≥50 to ≤89 years. Male subjects with childbearing potential partners are willing to and should use condoms during study medication treatment and until 28 days after the last dose of study medication.
3. Diagnosis of MCI due to AD or mild dementia due to AD with amnestic presentation, according to Alzheimer Association – National Institute on Aging (AA-NIA) criteria [Albert et al 2011; McKhann et al 2011].
4. MMSE score of 21 to 30 inclusive at screening.
5. Screening visit brain MRI scan consistent with the diagnosis of MCI due to AD or mild dementia due to AD, as judged by central rater.
6. A positive AD signature showing one of the following (either a, b, c, OR d):
a. Screening CSF sample with an A-beta 42 concentration of less than 638 ng/L AND total tau >375 ng/L, as assessed by central laboratory.
b. Screening CSF sample with an A-beta 42 concentration of less than 638 ng/L AND p-tau > 52 ng/L, as assessed by central laboratory.
c. Tau/A-beta ratio > 0.52, as assessed by central laboratory.
d. Positive amyloid PET if available prior to screening.
7. Treatment naïve, this means not having received any prior established specific treatment for MCI due to AD or mild dementia due to AD including no (prior) use of an acetylcholinesterase inhibitor, or memantine. A maximum of two months of prior cumulative treatment with an acetylcholinesterase inhibitor or memantine is allowed if the acetylcholinesterase inhibitor or memantine was discontinued due to intolerance and if this was done at least two months prior to baseline. Use of Souvenaid will be allowed if Souvenaid was discontinued at least two months prior to baseline, or if the subject is on stable dose for at least six months prior to baseline and is willing to continue during the study on the same dose and frequency.
8. Fluency in local language and evidence of adequate premorbid intellectual functioning in the opinion of the investigator.
9. Adequate visual and auditory abilities to perform the cognitive and functional assessments in the opinion of the investigator.
10. Outpatient with study partner (age 18 years or older) capable of accompanying the subject on all clinic visits. In accordance to Swedish regulations the availability of a study partner is not applicable for Sweden.
11. The subject and study partner are likely to be able to participate in all scheduled evaluations. In accordance to Swedish regulations the availability of a study partner is not applicable for Sweden.
12. In the opinion of the investigator, the subject and study partner can be compliant and have a high probability of completing the study. In accordance to Swedish regulations the availability of a study partner is not applicable for Sweden. |
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| E.4 | Principal exclusion criteria |
1. Significant neurologic disease, other than AD, that may affect cognition.
2. Atypical clinical presentations of MCI due to AD or mild dementia due to AD, such as the visual variant of AD (including posterior cortical atrophy) or the language variant (including logopenic aphasia).
Concomitant disorders:
3. History of or screening visit brain MRI scan indicative of any other significant abnormality, including but not limited to multiple microhaemorrhages (4 or more, defined as 10 mm or less at the greatest diameter), severe white matter hyper intensities (Fazekas score 3), history or evidence of a single prior haemorrhage >1 cm3, multiple lacunar infarcts or evidence of a single prior infarct >1 cm3, evidence of a cerebral contusion, encephalomalacia, aneurysms, vascular malformations, subdural hematoma, or space-occupying lesions (e.g. brain tumours).
4. Current presence of a clinically important major psychiatric disorder (e.g. major depressive disorder) as defined by DSM-5 criteria, or symptom(s) (e.g. hallucinations) that could affect the subject’s ability to complete the study.
5. Current clinically important systemic illness that is likely to result in clinically relevant deterioration of the subject’s condition or might affect the subject’s safety during the study.
6. History of clinically evident stroke or history of clinically important and symptomatic carotid or vertebrobasilar stenosis or plaque.
7. History of seizures within the last two years prior to the screening visit.
8. Weight > 120 kg (264 lb) at screening.
9. Myocardial infarction within the last six months prior to screening.
10. History of cancer within the last two years prior to screening, with the exception of any of the following conditions: non-metastatic basal cell carcinoma, and squamous cell carcinoma of the skin or any other cancer if evidence of no residual cancer has been clinically confirmed within the last six months before baseline.
11. History of uncontrolled hypertension (in the opinion of the investigator) within six months prior to screening.
12. Other clinically important diseases or conditions or abnormalities of vital signs, physical examination, neurologic examination, laboratory results, or ECG examination (e.g. atrial fibrillation) that could compromise the study or the safety of the subject.
13. Haemoglobin level less than 11 g/dL (6.8 mmol/L) at screening.
14. Clinically important infection within 30 days prior to screening (e.g. chronic persistent or acute infection, such as bronchitis or urinary tract infection.
15. Any known hypersensitivity to any of the excipients contained in the test article formulation.
16. Severe hepatic failure (Child-Pugh C) or kidney failure (creatinine clearance (eGFR) ≤ 30 ml/min/1.73m2) or serum creatinine above 1.5 fold of ULN or AST or ALT above 3 fold of ULN at screening.
17. The following therapies are not permitted for the given intervals prior to baseline and until V5/EOT:
Anticoagulants (e.g. heparin and vitamin K antagonists) within 30 days
Use of experimental medications for AD or any other investigational medications or devices for treatment of indications other than AD within 60 days.
Treatment with an acetylcholinesterase inhibitor or memantine or Souvenaid, except for an acetylcholinesterase inhibitor or memantine in case of clinically relevant worsening of cognitive performance during the double blind study period, and for Souvenaid if only on stable dose for at least six weeks prior to baseline.
Treatment with immunosuppressive medications (e.g. systemic corticosteroids in a dose of more than 10 mg/day) within the last 90 days (topical and nasal corticosteroids and inhaled corticosteroids for asthma are permitted).
Treatment with chemotherapeutic agents for malignancy within the last year.
Concomitant treatment with strong inhibitors or moderate inducers of the metabolic enzyme CYP 2C19 or substrates with narrow therapeutic margin: fluconazole, fluvoxamin, ticlopidin, rifampicin, S-mephenytoin, repaglinide, phenytoin, phenobarbital and indometacin. A washout phase of at least two weeks before baseline is required for subjects having been treated with any of the above medicinal products.
Concomitant treatment with St. John’s Wort (a wash out phase of at least two weeks prior to baseline is required).
Any concomitant treatment which impairs cognitive function and cannot be washed out at least four weeks prior to baseline.
Other
18. Blood donation (routine blood donation) in the 90 days prior to screening.
19. History of alcohol or drug dependence or abuse as defined by DSM-5 criteria within the last 2 years prior to screening.
20. Presence of pacemakers, aneurysm clips, artificial heart valves, ear implants, CSF shunts, claustrophobia, or metal fragments or foreign objects in the eyes, skin, or body that would contraindicate a brain MRI scan.
21. Inadequate venous access to allow multiple blood draws. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Three primary safety endpoints are defined: time to dose adjustment (as an indication of tolerability), number of (S)AEs (as an indication of safety) and compliance as measured by adherence to prescribed investigational product compared to placebo (as an indication of feasibility).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Additionally the following safety endpoints will be assessed throughout the study: spontaneously reported adverse events (AEs), vital signs (heart rate, blood pressure), ECG measurements, clinical laboratory tests, changes on brain MRI scans as judged by central rating (ARIA-E, ARIA-H, infarcts etc.), physical and neurologic examinations.
Secondary study endpoints are:
Neuropsychological endpoints:
An exploratory endpoint is efficacy of PQ912 versus placebo on cognitive function as measured by a neuropsychological test battery between baseline (V2) and End-of-treatment visit (V5/EOT).
CSF endpoints:
The levels of and correlation between at least a choice of the following biomarkers will be assessed in CSF at screening (V1) and End-of-treatment visit (V5/EOT):
1. Individual tests for diagnosis:
A-beta 1-42.
Tau.
P- tau.
2. Exploratory biomarkers as clusters:
QC enzyme.
Panel of A-beta peptide versions of various length (X-40/42).
Panel measuring pGluAbeta and its substrates A-beta 3-40/42 and 11-40/42.
Panel of A-beta oligomer assays using different technologies, each likely detecting A-beta-Oligomers of different a length.
Panel of inflammatory markers.
Neuronal network endpoints:
The functional connectivity of the neuronal network will be evaluated with EEG and resting-state fMRI.
The following endpoints will be calculated from the EEG:
Mean peak frequency in the parieto-occipital region.
Mean global Phase Lag Index in the alpha band.
Minimum Spanning Tree analyses:
o Leaf fraction in the alpha band.
o Tree hierarchy in the alpha band.
The following endpoints will be calculated from the RSfMRI:
Eigenvector centrality values.
Average path length and clustering. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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 | Yes |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 | 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
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| End of trial will be when last patient completed follow up phase. 28 days after End of treatment visit a Follow up visit will take place. No study drug will be given during this phase. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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