| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Early Alzheimer’s Disease |
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| E.1.1.1 | Medical condition in easily understood language |
| Early 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001896 |
| E.1.2 | Term | Alzheimer's disease |
| E.1.2 | System Organ Class | 100000004852 |
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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 |
• Assess the safety and tolerability of Trappsol® Cyclo™ over 24 weeks in patients with early Alzheimer’s disease (EAD)
• Explore the potential efficacy (defined clinical effects and/or effects on biomarkers) of Trappsol® Cyclo™ over 24 weeks in patients with EAD
• Determine the pharmacokinetics (PK) of Trappsol® Cyclo™ over 24 weeks in patients with EAD
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female ≥50 to ≤80 years of age, at the time of consent.
a. Able to review and understand the clinical trial info and to give self-competent informed consent
b. Have at least an eighth-grade education.
c. Primary language for Austria based patients must be German and patients should be able to understand and read German at a level that will ensure adequate completion of study procedures including informed consent and all cognitive tests.
2. MCI due to AD (Stage 3) according to the FDA Guidance for Industry on EAD: Developing Drugs for Treatment:68
a. Meet the NIA-AA criteria for MCI due to AD.12,30
b. Have a global Clinical Dementia Rating (CDR) scale score of 0.5 and a CDR Memory Box score of 0.5 or greater at both Screening and Baseline.
c. History of memory complaint/decline reported by patient or partner/caregiver with gradual onset and slow progression over the last 1 year before Screening.
d. In the opinion of the Investigator based on patient and caregiver review, relatively preserved functional abilities and activities of daily living.
OR
Mild AD dementia (Stage 4)
a. Meet the NIA-AA criteria for mild AD dementia.
b. Have a global CDR score of 0.5 to 1.0 and a CDR Memory Box score of 0.5 or greater at both Screening and Baseline.
3. All patients should have an MMSE2:SV score ≥20 and ≤28 at both Screening and Baseline with no more than a 3 point change between visits.
4. CSF biomarker for supporting the diagnosis of AD. The test result to determine cerebral Aβ pathology must be known prior to enrollment at Baseline.
5. MRI of the brain performed during the screening period or within the prior 12 months that is not contradictory of AD diagnosis upon local read.
6. Locally or centrally read MRI of ARIA suggesting less than 4 microhemorrhages.
7. Have a primary caregiver who has sufficient contact with the patient, is able to provide assessment of cognitive and functional changes and is willing to accept primary responsibility for supervising the patient and assessing the condition of the patient throughout the study in accordance with protocol requirements. The primary caregiver must meet the following criteria:
a. Be able and willing to provide information needed for efficacy assessments such as CDR-SB.
b. Willing to sign the caregiver informed consent.
8. Not likely to experience a change in living conditions or change in primary caregiver during participation in the trial.
9. Standard of care therapy for AD with acetylcholine esterase inhibitors and/or memantine are allowed as long as the dose has been stable for at least 60 days prior to Screening and is expected to remain stable for the study duration. NOTE: Treatment-naïve patients desiring starting on standard of care, can start such treatment. In this case they can be re-screened after 60 days of stable treatment.
10. Background medications used for other stable chronic illnesses that are not expressly prohibited are also allowed provided that they remain stable for the study duration:
a. Psychotropics, such as antidepressants and antipsychotics, must be at a stable dose for at least 30 days prior to Screening and remain stable throughout the study duration within the framework and regimen in Section 6.7.
b. Short-acting benzodiazepines for sleep can be used up to 3/week but not within 24 hours of cognitive assessments.
11. All patients must pass a brief audiologic examination including pure tone audiometry (see also exclusion criteria 17).
12. Body mass index between 17 and ≤35 kg/m2 at Screening, with upper weight limit of 125 kg.
13. Females participating in the study must meet 1 of the following criteria:
a. Surgically sterilized (eg, hysterectomy, bilateral oophorectomy, or tubal ligation) for at least 6 months or postmenopausal (postmenopausal females must have no menstrual bleeding for at least 1 year) or
b. If not postmenopausal, agree to use highly effective birth control methods including combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal); progestogen only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable); intrauterine device; intrauterine hormone releasing system; or vasectomized partner, and have negative urine pregnancy test at Screening. Highly effective contraception must be used during the study and until 3 months after the last dose of study treatment.
14. All sexually active male patients with WOCBP partners (post menarche) must use a condom with or without spermicide in addition to the birth control used by their partners during the study and until 3 months after the last dose of study treatment.
15. Age-appropriate estimate glomerular filtration rate calculated by the Modification of Diet in Renal Disease Study.
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| E.4 | Principal exclusion criteria |
1. Not able to give informed consent based on their cognitive abilities
2. Clinically significant renal disease that in the opinion of the Investigator precludes the patient from participating in the study.
3. Evidence of a neurodegenerative disease other than AD or any medical history or brain imaging abnormality that might cause the dementia in the opinion of the Investigator.
4. Severe hypothyroidism that is refractory to standard of care and with no or inadequate response to clinically relevant dosage of levothyroxine as determined by thyroid-stimulating hormone, T3 and T4, and presentation of clinical signs and symptoms.
5. Abnormally low levels of serum Vitamin B12.
6. Imaging should be generally supportive of the diagnosis of EAD and, importantly, not consistent with other neurodegenerative disorder or differential dementia diagnoses. For example, any suggestion of vascular disease, including multiple infarction involving large blood vessels or localized single infarction, multiple lacunae of the basal nuclei or white matter or extensive lesions of the periventricular white matter or combination of several lesions are considered exclusionary. Additionally, any single lacuna in an area known to impact cognition such as the hippocampus will also be exclusionary.
a. In cases of prior MRI scans used for inclusion, should there be any evidence of new neurological symptoms between that scanning and Screening, rescanning is necessary.
b. Vascular dementia as defined by a HIS of ≥4 is exclusionary.
7. Lacks visual, auditory acuity and/or language abilities adequate to perform cognitive assessments.
8. History of any medical illness, such as cancer, requiring systemic therapy in the last 5 years, except for localized basal cell carcinoma of the skin and in-situ cervical cancer successfully treated with surgical excision; history of severe heart failure, major stroke, uncontrolled seizure disorder, or other medical illnesses that in the Investigator’s opinion will increase the patient’s risk of participation in the study or confound study assessments.
9. Patients with the following measurements identified during Screening:
a. Platelet count <50,000/μL.
b. International normalized ratio >1.5
c. Patients with a hemorrhagic trend.
10. Positive blood screen for HIV1 and HIV2, hepatitis B surface antigen, or hepatitis C virus antibodies at Screening unless successful curative treatment for hepatitis C has been received and there is documentation that there is no hepatitis B/C virus detected 3 months after completion of treatment.
11. Any planned surgery that requires a general anesthesia that would take place during the study. Local anesthesia during outpatient surgery is permitted if, in the opinion of the Investigator, this operation does not interfere with study procedures and patient safety.
12. History or current evidence of major psychiatric illness such as schizophrenia, bipolar disorder, or MDD; or if a patient has a GDS-SF score >8 at Screening and thereby meeting criteria for MDD, then the patient will be excluded.
13. History of violent or aggressive behavior that requires medication to control.
14. Suicidal thoughts, intentions, or actions captured during screening by C-SSRS or history of suicidal attempt in 2 years prior to Screening.
15. History of alcohol or drug abuse or dependence within 12 months of screening as defined by the DSM-5.
16. Previous or ongoing treatment with Aduhelm, donanemab, or active or passive investigational immunotherapy therapy for amyloid or tau; or participation in a clinical study involving monoclonal antibodies, or derivatives, or immunoglobulins (related to AD treatment) within 12 months before Screening unless it can be documented that the patient was randomized to placebo.
17. Has been treated with any known drugs that are moderate or strong inhibitors/inducers of cytochrome P450 enzymes within 30 days before the first dose of study medication.
18. Has any of the otologic-related exclusion criteria listed in protocol.
19. QT prolongation risk such as a history of additional risk factors for TdP or sudden death (eg, heart failure, hypokalemia, family history of Long QT Syndrome, unexplained syncope, concurrent medications including anti-depressant agents known to prolong QT/QTc.
20. Patients on high doses of anticoagulants and/or at increased risk of bleeding need to discuss with their doctor, if they should stop or delay intake of anticoagulants prior to the lumbar puncture procedure. The needs to discontinue prior to the procedure and the time window required will be guided by the investigator’s medical assessment. Prior to lumbar puncture, blood coagulation tests (prothrombin time [PT]/INR and aPTT) will be performed. Platelet measurements are included among clinical laboratory safety tests for the Screening.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety endpoints
• Incidence and severity of TEAEs
• Adverse events of special interest (AESIs):
- MRI assessments of ARIA-H or ARIA-E
- Hearing loss based audiological examination
- Infusion reactions
• Vital signs and/or physical examinations
• Safety clinical laboratory values (hematology, clinical chemistry, and urinalysis) including C-terminal telopeptide
• 12-lead ECGs. Triplicate ECGs will be time-matched with PK samples at Week 0 (Baseline), Week 4, and Week 8.
• C-SSRS
PK Endpoints
PK parameters including but not limited to Cmax, Tmax, AUClast, AUCinf, T½, Clast, and Tlast (see Table 10.1 in main protocol) will be calculated. Plasma levels will be measured prior to the start of the study drug infusion, 1 and 3 hours into the infusion, upon completion of infusion, 50 to 60 minutes post infusion, and 2 hours post infusion at Baseline (Week 0, V2), Week 4 (V3), Week 8 (V4), Plasma sample will be collected for potential analysis of PK trough levels will be measured prior to start of study drug infusion at Week 12 (V5) and Week 24 (V8). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
AEs, vital signs and C-SSRS will be evaluated at every visit
MRI (ARIA) will be done at Screening, Week 8, 16 and 24
Physical examination is will be done at Screening and EoT
Safety clinical lab will be done at Screening, Baseline, Week 12 and EoT
ECGs will be done at Screening, Baseline, Weeks 4, 8, 12 and EoT
PK assessments will be done at Baseline, Week 4, 8, 12 and EoT |
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| E.5.2 | Secondary end point(s) |
• Mean change in total ADAS-Cog 14 score from Baseline (V2) to Weeks 12 (V5) and 24 (V8)
• Change in CDR-SB from Baseline (V2) to Weeks 12 (V5) and 24 (V8)
• Change in MMSE-2:SV total score from Baseline (V2) to Weeks 12 (V5) and 24 (V8)
• Change in ADCS-CGIC from Baseline (V2) to Weeks 12 (V5) and 24 (V8)
• Change in ADCS-ADL from Baseline (V2) to Weeks 12 (V5) and 24 (V8) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
ADAS-Cog will be done at Baseline, Weeks 12 and 24
CDR-SB, MMSE-2, ADCS-CGIC, ADCS-ADL will be done at Screening, Baseline, Weeks 12 and 24 |
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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 | Yes |
| 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 | 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 | 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 | 3 |
| 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 | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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