Safety, Tolerability and Immunogenicity of ACI-24 Vaccine in Adults With Down Syndrome (3-Star)

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

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

Study Overview

• Status: Completed
• Conditions: Down Syndrome
• Intervention / Treatment: Biological: ACI-24 low dose; Biological: ACI-24 high dose; Biological: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • St. Joseph's Hospital and Medical Center - Barrow Neurology Clinics
  • California
    • La Jolla, California, United States, 92037-1712
      • UCSD Adult Down Syndrome Program
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Johns Hopkins University
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: AC Immune SA
• Collaborators: National Institute on Aging (NIA); Alzheimer's Disease Cooperative Study (ADCS); LuMind IDSC Foundation
• Investigators: Study Director: Michael S. Rafii, MD, PhD, USC Keck School of Medicine of the University of Southern California, San Diego

Publications and helpful links

General Publications

• Rafii MS, Sol O, Mobley WC, Delpretti S, Skotko BG, Burke AD, Sabbagh MN, Yuan SH, Rissman RA, Pulsifer M, Evans C, Evans AC, Beth G, Fournier N, Gray JA, Dos Santos AM, Hliva V, Vukicevic M, Kosco-Vilbois M, Streffer J, Pfeifer A, Feldman HH. Safety, Tolerability, and Immunogenicity of the ACI-24 Vaccine in Adults With Down Syndrome: A Phase 1b Randomized Clinical Trial. JAMA Neurol. 2022 Jun 1;79(6):565-574. doi: 10.1001/jamaneurol.2022.0983.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2016
• Primary Completion (Actual): June 1, 2020
• Study Completion (Actual): June 1, 2020

Study Registration Dates

• First Submitted: April 1, 2016
• First Submitted That Met QC Criteria: April 11, 2016
• First Posted (Estimate): April 14, 2016

Study Record Updates

• Last Update Posted (Actual): October 15, 2021
• Last Update Submitted That Met QC Criteria: September 21, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: cognitive decline
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Disease; Congenital Abnormalities; Genetic Diseases, Inborn; Intellectual Disability; Abnormalities, Multiple; Chromosome Disorders; Syndrome; Down Syndrome
• Other Study ID Numbers: ACI-24-1301; 1R01AG047922-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Access to de-identified, individual and trial -level data (analysis datasets), and other information (e.g., protocols) will be provided.
• IPD Sharing Access Criteria: These clinical trial data can be requested by any qualified researchers who engage in rigorous independent scientific research and will be provided after review and approval of their research proposal, their Statistical Analysis Plan (SAP) and execution of a Data Use Agreement (DUA). Data sharing shall be in accordance with ADCS' data sharing plan in its grant application and applicable NIH policy in effect at the time of the NIH award.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP)