Title

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

    Phase 1
  • Study Type

    Interventional
  • Intervention/Treatment

    aci-24 ...
  • Study Participants

    20
The purpose of this study is to test in adults with Down Syndrome the safety, tolerability and immunogenicity of a vaccine, ACI-24.
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 Started
Mar 31
2016
Primary Completion
Jun 30
2020
Study Completion
Jun 30
2020
Results Posted
Sep 21
2021
Last Update
Oct 15
2021

Biological ACI-24 low dose

ACI-24 administered as a sterile suspension in PBS via s.c. injection.

Biological ACI-24 high dose

ACI-24 administered as a sterile suspension in PBS via s.c. injection.

Biological Placebo

Placebo is a standard PBS sterile solution administrated via s.c. injection.

  • Other names: PBS

ACI-24 low dose Active Comparator

Vaccine formulation will be administrated s.c. 7 times.

ACI-24 high dose Active Comparator

Vaccine formulation will be administrated s.c. 7 times.

Placebo Placebo Comparator

The placebo is ready-to-use solution for injection, administrated s.c. 7 times.

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.

Summary

ACI-24 1000µg

Placebo Cohort 1

Placebo Cohort 2

ACI-24 300µg

All Events

Event Type Organ System Event Term ACI-24 300µg ACI-24 1000µg Placebo Cohort 1 Placebo Cohort 2

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.

ACI-24 300µg

Week 0

632.3
AU/mL (AU: Arbitrary Unit) (Mean)
Standard Deviation: 570.9

Week 50

751.5
AU/mL (AU: Arbitrary Unit) (Mean)
Standard Deviation: 825.6

ACI-24 1000µg

Week 0

335.4
AU/mL (AU: Arbitrary Unit) (Mean)
Standard Deviation: 157.4

Week 50

434.3
AU/mL (AU: Arbitrary Unit) (Mean)
Standard Deviation: 224.3

Placebo

Week 0

162.8
AU/mL (AU: Arbitrary Unit) (Mean)
Standard Deviation: 84.5

Week 50

153.3
AU/mL (AU: Arbitrary Unit) (Mean)
Standard Deviation: 140.7

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.

ACI-24 300µg

Week 0

81.7
ng/L (Mean)
Standard Deviation: 56.6

Week 50

183.8
ng/L (Mean)
Standard Deviation: 18.7

ACI-24 1000µg

Week 0

138.5
ng/L (Mean)
Standard Deviation: 41.1

Week 50

186.2
ng/L (Mean)
Standard Deviation: 37.8

Placebo

Week 0

169.5
ng/L (Mean)
Standard Deviation: 43.5

Week 50

181.3
ng/L (Mean)
Standard Deviation: 11.2

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

ACI-24 300µg

week 0

1784.5
score on a scale (Mean)
Standard Deviation: 904.4

Week 50

1781.2
score on a scale (Mean)
Standard Deviation: 960.4

ACI-24 1000µg

week 0

997.1
score on a scale (Mean)
Standard Deviation: 271.8

Week 50

1046.3
score on a scale (Mean)
Standard Deviation: 152.1

Placebo

week 0

1024.3
score on a scale (Mean)
Standard Deviation: 193.9

Week 50

1002.1
score on a scale (Mean)
Standard Deviation: 138.5

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

ACI-24 300µg

week 0

8.0
score on a scale (Mean)
Standard Deviation: 5.1

Week 50

7.5
score on a scale (Mean)
Standard Deviation: 4.1

ACI-24 1000µg

week 0

9.2
score on a scale (Mean)
Standard Deviation: 5.1

Week 50

6.7
score on a scale (Mean)
Standard Deviation: 4.3

Placebo

week 0

7.8
score on a scale (Mean)
Standard Deviation: 5.3

Week 50

9.8
score on a scale (Mean)
Standard Deviation: 4.6

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

ACI-24 300µg

Week 0

72.0
score on a scale (Mean)
Standard Deviation: 5.8

Week 50

75.5
score on a scale (Mean)
Standard Deviation: 4.8

ACI-24 1000µg

Week 0

73.7
score on a scale (Mean)
Standard Deviation: 3.2

Week 50

77.5
score on a scale (Mean)
Standard Deviation: 2.5

Placebo

Week 0

73.8
score on a scale (Mean)
Standard Deviation: 5.6

Week 50

76.5
score on a scale (Mean)
Standard Deviation: 2.5

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

ACI-24 300µg

Week 0

47.7
score on a scale (Mean)
Standard Deviation: 10.2

Week 50

52.2
score on a scale (Mean)
Standard Deviation: 11.3

ACI-24 1000µg

Week 0

59.3
score on a scale (Mean)
Standard Deviation: 8.5

Week 50

65.2
score on a scale (Mean)
Standard Deviation: 9.4

Placebo

Week 0

59.0
score on a scale (Mean)
Standard Deviation: 5.3

Week 50

61.0
score on a scale (Mean)
Standard Deviation: 6.8

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

ACI-24 300µg

Week 0

54.2
score on a scale (Mean)
Standard Deviation: 9.9

Week 50

55.8
score on a scale (Mean)
Standard Deviation: 11.4

ACI-24 1000µg

Week 0

68.3
score on a scale (Mean)
Standard Deviation: 4.1

Week 50

72.8
score on a scale (Mean)
Standard Deviation: 4.1

Placebo

Week 0

58.0
score on a scale (Mean)
Standard Deviation: 9.3

Week 50

61.5
score on a scale (Mean)
Standard Deviation: 13.5

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

ACI-24 300µg

Week 0

64.3
score on a scale (Mean)
Standard Deviation: 17.2

Week 50

66.7
score on a scale (Mean)
Standard Deviation: 16.1

ACI-24 1000µg

Week 0

77.0
score on a scale (Mean)
Standard Deviation: 9.1

Week 50

83.0
score on a scale (Mean)
Standard Deviation: 10.4

Placebo

Week 0

59.0
score on a scale (Mean)
Standard Deviation: 15.1

Week 50

70.3
score on a scale (Mean)
Standard Deviation: 9.7

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

ACI-24 300µg

Week 0

4.5
score on a scale (Mean)
Standard Deviation: 3.6

Week 50

1.5
score on a scale (Mean)
Standard Deviation: 2.5

ACI-24 1000µg

Week 0

0.3
score on a scale (Mean)
Standard Deviation: 0.8

Week 50

0.3
score on a scale (Mean)
Standard Deviation: 0.8

Placebo

Week 0

8.5
score on a scale (Mean)
Standard Deviation: 10.0

Week 50

4.0
score on a scale (Mean)
Standard Deviation: 8.0

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.

ACI-24 300µg

Marked improvement

Moderate improvement

no change

ACI-24 1000µg

Marked improvement

Moderate improvement

no change

Placebo

Marked improvement

Moderate improvement

no change

Total

20
Participants

Age, Continuous

32.9
Years (Mean)
Standard Deviation: 4.1

BMI

40.2
kg/m^2 (Mean)
Standard Deviation: 10.1

KBIT 2: IQ Composite

47.8
IQ score (Mean)
Standard Deviation: 10.4

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Region of Enrollment

Sex: Female, Male

Overall Study

ACI-24 300µg

ACI-24 1000µg

Placebo

Drop/Withdrawal Reasons

ACI-24 1000µg