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

• ClinicalTrials.gov Identifier: NCT02738450
• Recruitment Status: Completed
• First Posted: April 14, 2016
• Results First Posted: September 21, 2021
• Last Update Posted: October 15, 2021
• Sponsor: AC Immune SA
• Collaborators: National Institute on Aging (NIA); Alzheimer's Disease Cooperative Study (ADCS); LuMind IDSC Foundation
• Information provided by (Responsible Party): AC Immune SA

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Down Syndrome	Biological: ACI-24 low dose; Biological: ACI-24 high dose; Biological: Placebo	Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: March 2016
• Actual Primary Completion Date: June 2020
• Actual Study Completion Date: June 2020

Arms and Interventions

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 Name: PBS

Outcome Measures

Primary Outcome Measures :

1. Antibody Titer (Serum Anti-Aβ1-42 Free IgG) - Mean Absolute Value [ Time Frame: Values at baseline (week 0) and week 50 are reported ]

   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.

Secondary Outcome Measures :

1. Amyloid Beta 1-40 in Blood - Mean Absolute Value [ Time Frame: Values at baseline (week 0) and week 50 are reported ]
   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.
2. CANTAB - MOT Latency Score [ Time Frame: Values at baseline (week 0) and week 50 are reported ]

   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

3. CANTAB - PAL First Attempt Memory Score [ Time Frame: Values at baseline (week 0) and week 50 are reported ]

   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

4. Brief Praxis Test (BPT) - Total Score [ Time Frame: Values at baseline (week 0) and week 50 are reported ]

   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

5. Vineland II - Communication Domain Standard Score [ Time Frame: Values at baseline (week 0) and week 50 are reported ]

   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

6. Vineland II - Daily Living Skill - Domain Standard Score [ Time Frame: Values at baseline (week 0) and week 50 are reported ]

   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

7. Vineland II - Socialisation - Domain Standard Score [ Time Frame: Values at baseline (week 0) and week 50 are reported ]

   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

8. NPI - Total Score [ Time Frame: Values at baseline (week 0) and week 50 are reported. ]

   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

9. Clinical Global Impression of Change (CGIC) - Change From Baseline at Week 50 [ Time Frame: Values at baseline (week 0) and week 50 are reported ]

   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.

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, Arizona

St. Joseph's Hospital and Medical Center - Barrow Neurology Clinics

Phoenix, Arizona, United States, 85013

United States, California

UCSD Adult Down Syndrome Program

La Jolla, California, United States, 92037-1712

United States, Maryland

Johns Hopkins University

Baltimore, Maryland, United States, 21224

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

Sponsors and Collaborators

AC Immune SA

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

  Study Documents (Full-Text)

Documents provided by AC Immune SA:

Study Protocol  [PDF] January 28, 2020

Statistical Analysis Plan  [PDF] September 18, 2020

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: AC Immune SA
• ClinicalTrials.gov Identifier: NCT02738450
• Other Study ID Numbers: ACI-24-1301; 1R01AG047922-01 ( U.S. NIH Grant/Contract )
• First Posted: April 14, 2016
• Results First Posted: September 21, 2021
• Last Update Posted: October 15, 2021
• Last Verified: September 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Access to de-identified, individual and trial -level data (analysis datasets), and other information (e.g., protocols) will be provided.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• 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.
• URL: https://www.adcs.org/

Keywords provided by AC Immune SA:

cognitive decline

Additional relevant MeSH terms:

Down Syndrome; Syndrome; Disease; Pathologic Processes; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Abnormalities, Multiple; Congenital Abnormalities; Chromosome Disorders; Genetic Diseases, Inborn