Safety, Tolerability and Immunogenicity of ACI-24 Vaccine in Adults With Down Syndrome

Study Overview
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Brief Summary
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The purpose of this study is to test in adults with Down Syndrome the safety, tolerability and immunogenicity of a vaccine, ACI-24.

Detailed Description
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This is a prospective multi-center, placebo controlled, double-blind and randomized dose escalation study of 2 doses of ACI-24 versus Placebo over 24 months with a total of 21 visits. All subjects will receive the study medication (ACI-24 or Placebo) 7 times via s.c. injection (12 months) and will be followed up for 12 months after the last dose with a final safety and efficacy assessment.

Official Title
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A Phase Ib Multi-Center, Double-Blind, Randomized, Placebo-Controlled Dose Escalation Study of the Safety, Tolerability and Immunogenicity of ACI-24 in Adults With Down Syndrome

Conditions
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Down Syndrome

Intervention / Treatment
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* Biological: ACI-24 low dose
* Biological: ACI-24 high dose
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females with Down Syndrome aged ≥25 to ≤45 years, with a cytogenetic diagnosis being either Trisomy 21 or Complete Unbalanced Translocation of the Chromosome 21. Subjects and their study partner/legal representative in the opinion of the investigator able to understand and to provide written informed consent. Written informed consent obtained from subjects and their study partner/legal representative before any trial-related activities. In the opinion of the investigator able to fully participate in the trial and sufficiently proficient in English to be capable of reliably completing study assessments. Subjects have a study partner/legal representative who have direct contact with the subjects at least 10 hours per week and who can be asked questions about the subjects. Exclusion Criteria: Subjects weighing less than 40 kg. IQ less than 40 (as assessed by Kaufman Brief Intelligence Test, Second Edition (KBIT-2). In the investigators opinion, any clinically significant current psychiatric or neurologic illness, including a past illness with a risk of recurrence, other than Down syndrome. Any medical condition likely to significantly hamper the evaluation of safety of the study drug. DSM-IV criteria for drug or alcohol abuse or dependence currently met within the past five years. History or presence of uncontrolled seizures. If history of seizures, they must be well controlled with no occurrence of seizures in the past 2 years prior to study screening. The use of anti-epileptic medications is permitted. History of meningitis or meningoencephalitis. History of malignant neoplasms within 3 years prior to study screening or where there is current evidence of recurrent or metastatic disease. History of persistent cognitive deficits immediately following head trauma. History of inflammatory neurology disorders. History of autoimmune disease with potential for CNS involvement. MRI scan at screening showing a single area of cerebral vasogenic edema, superficial siderosis, or evidence of a prior macrohemorrhage, or showing more than four cerebral microhemorrhages (regardless of their anatomical location or diagnostic characterization as possible or definite). MRI examination cannot be done for any reason, including metal implants contraindicated for MRI studies and/or severe claustrophobia. Significant hearing or visual impairment or other issues judged relevant by the investigator preventing to comply with the protocol and to perform the outcome measures. Severe infections or a major surgical operation within 3 months prior to screening. History of chronic or recurrent infections judged to be clinically significant by the investigator. History or presence of immunological or inflammatory conditions which are judged to be clinically significant by the investigator. Celiac disease not on a gluten free diet for at least 3 months prior to study screening. Chronic benign skin pathologies, unless viewed as clinically insignificant in the investigator's opinion. Any vaccine received within the past 2 months before baseline, except influenza vaccine which if indicated must be given at least 2 weeks prior to baseline. Clinically significant arrhythmias or other abnormalities on ECG at screening. (Minor abnormalities documented as clinically insignificant by the investigator will be allowed.) Clinically significant abnormal vital signs including sustained sitting blood pressure greater than 160/90 mmHg. In the opinion of the site investigator, deviations from normal values for hematologic parameters, liver function tests, and other biochemical measures, that are judged to be clinically significant. Subjects with treated hypothyroidism not on a stable dose of medication for at least 3 months prior to screening and having clinically significant abnormal serum T-4 and TSH at screening. Subjects with diabetes mellitus with an HbA1c of ≥ 8.0%. Subjects who have been receiving any experimental drug for Down Syndrome with a washout less than 30 days or less than five halflives of the drug, whichever is longer. Female subjects being pregnant as confirmed by serum testing at screening or planning to be pregnant or lactating. Female subjects not using a reliable method of contraception (unless abstaining). Patient receiving any anticoagulant drug, or aspirin at doses greater than 100 mg daily in the 7 days prior to lumbar puncture (in order to avoid risk of bleeding during scheduled or unscheduled lumbar puncture) Use of antidepressants other than SSRI/SNRIs at stable dose, antipsychotics (typical or atypical), GABA agonists (e.g. gabapentin), or stimulants (e.g. methylphenidate, modafinil). In exceptional cases, low doses of atypical antipsychotics (e.g. risperidone up to 0.5 mg/day or quetiapine up to 50 mg/day) or benzodiazepines are only allowed after review by the site principal investigator, in consultation with the project director and/or medical monitors. Current use of immunosuppressant or immunomodulating drugs or their use within the past 6 months prior to study screening. Current use of steroids or their use within the past 3 months prior to study screening. Use of Cholinesterase Inhibitor or use of Glutamatergic drugs (Topiramate, Memantine, Lamotrigine) if not on stable dose for at least 3 months prior to screening. Subjects who have donated blood or blood products during the 30 days prior to screening who plan to donate blood while participating in the study or within four weeks after completion of the study.

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ACI-24 low dose<br>Vaccine formulation will be administrated s.c. 7 times. | Biological: ACI-24 low dose<br>* ACI-24 administered as a sterile suspension in PBS via s.c. injection.<br>|
| Active Comparator: ACI-24 high dose<br>Vaccine formulation will be administrated s.c. 7 times. | Biological: ACI-24 high dose<br>* ACI-24 administered as a sterile suspension in PBS via s.c. injection.<br>|
| Placebo Comparator: Placebo<br>The placebo is ready-to-use solution for injection, administrated s.c. 7 times. | Biological: Placebo<br>* Placebo is a standard PBS sterile solution administrated via s.c. injection.<br>* Other names: PBS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antibody Titer (Serum Anti-Aβ1-42 Free IgG) - Mean Absolute Value | All subjects who received at least 1 dose of the study treatment of either ACI-24 300 μg, ACI-24 1000 μg or placebo are considered. The measure is expressed in Arbitrary Units per mL (AU/mL). AU/mL in a sample is obtained by back-calculation towards the standard curve. | Values at baseline (week 0) and week 50 are reported | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Amyloid Beta 1-40 in Blood - Mean Absolute Value | All subjects who received at least 1 dose of the study treatment of either ACI-24 300 μg, ACI-24 1000 μg or placebo are considered. | Values at baseline (week 0) and week 50 are reported | 
| CANTAB - MOT Latency Score | All subjects who received at least 1 dose of the study treatment of either ACI-24 300 μg, ACI-24 1000 μg or placebo are considered. Cambridge Neuropsychological Test Automated Battery (CANTAB), Motor Screening Task (MOT) is a cognitive scale to be completed by the subject. Range score from 0 to ∞, lower score means a better outcome | Values at baseline (week 0) and week 50 are reported | 
| CANTAB - PAL First Attempt Memory Score | All subjects who received at least 1 dose of the study treatment of either ACI-24 300 μg, ACI-24 1000 μg or placebo are considered. Cambridge Neuropsychological Test Automated Battery (CANTAB), Paired Associate Learning (PAL) is a cognitive scale to be completed by the subject. Range score from 0 to 20, higher score means a better outcome | Values at baseline (week 0) and week 50 are reported | 
| Brief Praxis Test (BPT) - Total Score | All subjects who received at least 1 dose of the study treatment of either ACI-24 300 μg, ACI-24 1000 μg or placebo are considered. Brief Praxis Test (BPT) is a cognitive scale to be completed by the subject. Range score from 0 to 80, higher score means better outcome | Values at baseline (week 0) and week 50 are reported | 
| Vineland II - Communication Domain Standard Score | All subjects who received at least 1 dose of the study treatment of either ACI-24 300 μg, ACI-24 1000 μg or placebo are considered. Vineland II is a behavioral questionnaire to be completed by the study partner of the subject. Range score from 0 to 113, higher score means a better outcome | Values at baseline (week 0) and week 50 are reported | 
| Vineland II - Daily Living Skill - Domain Standard Score | All subjects who received at least 1 dose of the study treatment of either ACI-24 300 μg, ACI-24 1000 μg or placebo are considered. Vineland II is a behavioral questionnaire to be completed by the study partner of the subject. Range score from 0 to 114, higher score means a better outcome | Values at baseline (week 0) and week 50 are reported | 
| Vineland II - Socialisation - Domain Standard Score | All subjects who received at least 1 dose of the study treatment of either ACI-24 300 μg, ACI-24 1000 μg or placebo are considered. Vineland II is a behavioral questionnaire to be completed by the study partner of the subject. Range score from 0 to 115, higher score means a better outcome | Values at baseline (week 0) and week 50 are reported | 
| NPI - Total Score | All subjects who received at least 1 dose of the study treatment of either ACI-24 300 μg, ACI-24 1000 μg or placebo are considered. Neuropsychiatric Inventory (NPI) is a behavioral questionnaire to be completed by the study partner of the subject. Range score from 0 to 144, higher score means a worse outcome | Values at baseline (week 0) and week 50 are reported. | 
| Clinical Global Impression of Change (CGIC) - Change From Baseline at Week 50 | All subjects who received at least 1 dose of the study treatment of either ACI-24 300 μg, ACI-24 1000 μg or placebo are considered. Clinical Global Impression of Change (CGIC) is a global assessment to be completed by the investigator. | Values at baseline (week 0) and week 50 are reported | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cognitive decline