This study has been transitioned to CTIS with ID 2023-508363-79-00 check the CTIS register for the current data. Part AMain objectives: • To evaluate the safety and tolerability of single intrathecal (IT) doses of ALN-APP in adult patients with…
ID
Source
Brief title
Condition
- Structural brain disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Part A - Single-dose Period:
To evaluate frequency of adverse events. Safety will also be evaluated through
vital signs, physical exams, neurological assessment, cognitive and suicide
severity assessment, neuroimaging, electrocardiograms (ECGs), and clinical
laboratory assessments.
Part B - Multi-dose Period:
To evaluate frequency of adverse events. Safety will also be evaluated through
vital signs, physical exams, neurological assessment, cognitive and suicide
severity assessment, and clinical laboratory assessments.
Secondary outcome
Part A - Single-dose Period:
Change from baseline in levels of CSF sAPPα and sAPPβ and evaluate PK
parameters of ALN-APP and of potential metabolites in plasma (area under the
concentration-time curve [AUC], maximum plasma concentration [Cmax]), urine
(fraction excreted in the urine [fe]) and CSF (concentration at time 't' [Ct]).
Part B - Multi-dose Period:
Change from baseline in levels of CSF sAPPα and sAPPβ and evaluate PK
parameters of ALN-APP and of potential metabolites in plasma (area under the
concentration-time curve [AUC], maximum plasma concentration [Cmax]), and CSF
(concentration at time 't' [Ct]).
Background summary
This Phase 1 randomized, double-blind, placebo-controlled, single ascending
dose and open-label multi-dose study is designed to evaluate the
safety, tolerability, pharmacokinetics and pharmacodynamics of intrathecally
administered ALN-APP in adult patients with Early-Onset Alzheimer*s Disease
(EOAD).
Study objective
This study has been transitioned to CTIS with ID 2023-508363-79-00 check the CTIS register for the current data.
Part A
Main objectives:
• To evaluate the safety and tolerability of single intrathecal (IT) doses of
ALN-APP in adult patients with EOAD
Part B
Main objectives:
• To evaluate the safety and tolerability of multiple IT doses of ALN-APP in
adult patients with EOAD.
Study design
This is a 2-part first-in-human Phase 1 study to evaluate the safety,
tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of intrathecally
administered ALN-APP in adult patients with EOAD. Part A will be a randomized,
double-blind, placebo-controlled single-ascending dose (SAD) period and Part B
will be a multi-dose open-label period including patients previously enrolled
in Part A or their replacement who are allowed to enter Part B.
A single dose of study drug (ALN-APP or placebo) will be administered to each
patient in Part A. Initially, 2 sentinel patients will be monitored for adverse
events for at least 15 days prior to study drug administration to the remaining
patients in the respective dose cohort. The decision to proceed to dosing the
next cohort and the actual dose to be administered will be determined by the
Safety Review Committee (SRC) based on postdose safety and tolerability data
through at least Month 1 in addition to available PD and other data.
In Part B, up to 3 ALN-APP dosing regimens may be evaluated. Dosing regimen
includes: (1) the dose level administered and (2) the dosing frequency. Dosing
in Part B may begin when the SRC recommends the dosing regimen for the first
cohort based on review of cumulative safety data and available PD data from at
least 3 Part A cohorts through at least the Month 3 visit. Part B may start
while the follow-up and/or dosing of certain Part A cohort(s) is ongoing.
The SRC will perform ongoing reviews of safety, tolerability, and available PK
and PD data collected throughout the study.
Intervention
In Part A of the study four dose level cohorts will be enrolled sequentially,
with each subject receiving a single dose of the study drug or a placebo.
Subjects enrolled in group 1 and 2 will be randomized 4:2 to ALN-APP versus
placebo. Subjects in group 3 and 4 will be randomized 6:2 to ALN-APP versus
placebo. Each subject will receive a single dose.
Group: 1
Planned Dose of Study Drug (mg): 25
Ratio Study drugs:Placebo: 4:2
Total number of patients within group worldwide: 6
Group: 2
Planned Dose of Study Drug (mg): 75
Ratio Study drugs:Placebo: 4:2
Total number of patients within group worldwide: 6
Group: 3
Planned Dose of Study Drug (mg): 225
Ratio Study drugs:Placebo: 6:2
Total number of patients within group worldwide: 8
Group: 4
Planned Dose of Study Drug (mg): 600
Ratio Study drugs:Placebo: 6:2
Total number of patients within group worldwide: 8
Group: Optional
Planned Dose of Study Drug (mg): 900
Ratio Study drugs:Placebo: 6:2
Total number of patients within group worldwide: 8
Group: Optional
Planned Dose of Study Drug (mg): 1200
Ratio Study drugs:Placebo: 6:2
Total number of patients within group worldwide: 8
Group: Optional
Planned Dose of Study Drug (mg): <1200
Ratio Study drugs:Placebo: 6:2
Total number of patients within group worldwide: 8
For each dose escalation, the decision to proceed to dosing the next cohort and
the actual dose to be administered will be determined by the SRC
based on the review of postdose safety and tolerability data through at least
Month 1, as well as RBANS score at Month 1, CBC with differential and CSF sAPPα
and sAPPβ levels through Day 15, from at least 5 patients for Cohorts 1 and 2
(6 patients/cohort) and at least 6 patients for the remaining cohorts (8
patients/cohort), cumulative safety data (eg, if a safety signal is observed,
then upon SRC recommendation, a de-escalation cohort may be initiated), and
available PK and PD data.
The actual dose to be administered may be modified (higher, lower, or the same,
but no more than 3-fold higher than the previous dose) from planned doses based
on emerging safety, PK, and PD data from preceding cohorts. The actual dose of
the optional cohorts will not exceed a 1.5-fold increment from the highest dose
previously tested, and no dose will exceed the maximum dose of 1200 mg.
During part B subject will receive repeat doses over a 12-month period. The
dose level and frequency will be based on review of part A data. No dose in
Part B will exceed the highest dose in Part A. Informed consent for part B will
be obtained separately.
Study burden and risks
Subjects will participate in Part A of the study for the duration of 14 months.
Subjects will need to come to the hospital more often than they normally would
and they undergo additional tests. These include physical and neurological
examination, ECG*s, pregnancy tests, urine/blood tests and questionnaires.
Subjects will receive medication via intrathecal injection and subjects cannot
be pregnant at the start or during the study.
Aside from these interventions, participation in this study involves blood
draws (venapunction) and in the course of 14 months, during 10 visits, 181ml
blood will be taken. Additionally cerebrospinal fluid (CSF) samples collection
of 20ml will be collected.
The study medication, ALN-APP, has not been previously administered in humans.
Therefore, it is not known which risks are associated. However as with any
study medication, the subject might experience an allergic reaction. These
include the following symptoms: Hives, Rash, Itching, Flushing, Swelling of the
lips, tongue or throat, Sudden shortness of breath, Decreased consciousness,
Nausea, Vomiting, Decrease in blood pressure.
The study medication is administered via a needle inserted between two lumbar
bones into the subjects lower spine: While this is a relatively safe procedure
there are possible minor and major complications which can occur even when
standard procedures are followed, and proper technique are used. These
complications include: Headache, Back discomfort or pain, Radicular symptoms,
Bleeding, Infection, In rare cases bleeding in the brain and development of
tumors beneath the skin.
There may be other risks depending on the subjects specific medical condition,
these include:
• Allergy-related reactions
• ECG risks: skin irritation is rare but could occur from the electrodes or gel
that is used.
• PET-scan risks: we use radioactive materials which may cause damage to the
subjects health
• MRI Risks
• Lumbar puncture risk
Scientific evidence generated over the last 3 decades implicates amyloid beta
(Aβ) aggregation as an early event in the pathogenesis of Alzheimer*s disease
(AD). Evidence suggests that reducing the production of APP and thereby
reducing downstream APP cleavage products such as Aβ may be an effective
therapeutic strategy for AD.
Third Street 300
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US
Listed location countries
Age
Inclusion criteria
Inclusion Criteria for Participants in Part A and Replacement Patients in Parts
A and B:
1. Male or female, aged 18 years or older at the time of informed consent
2. Individuals with mild cognitive impairment or mild dementia due to EOAD,
where disease onset occurred at age <65 years, and AD diagnosis confirmed by
CSF biomarkers or positive PET amyloid imaging
3. CDR global score 0.5 or 1.0 and Mini Mental State Examination (MMSE) >20
4. Able and willing to meet all study requirements: adequately supportive
psychosocial circumstances, able to undergo Magnetic Resonance Imaging (MRI)
scans and able to tolerate them, body Mass Index (BMI) >=18 and <=34 kg/m2 at
Screening visit, able to tolerate LP and undergo PET
5. Patient is able to understand and is willing and able to comply with the
study requirements and to provide written informed consent
Inclusion Criteria for Participants Who Transition from Part A to Part B:
1. Able and willing to meet all study requirements in the opinion of the
Investigator, including travel to study center, procedures, measurements and
visits, including adequately supportive psychosocial circumstances, able to
undergo Magnetic Resonance Imaging (MRI) scans and able to tolerate them, able
to tolerate LP and undergo PET
2. Patient is able to understand and is willing and able to comply with the
study requirements and to provide written informed consent
Exclusion criteria
Exclusion Criteria for Participants in Part A and Replacement Patients in Parts
A and B:
1. Non-Alzheimer's disease dementia
2. Has any of the following laboratory parameter assessments at Screening:
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2×upper
limit of normal (ULN), total bilirubin >1.5×ULN, international normalized ratio
(INR) >1.4, platelet count <100,000/microliter (µL), absolute neutrophil count
normal (LLN) cells/µL or absolute lymphocyte count glomerular filtration rate (eGFR) <45 mL/min/1.73m2
3. Clinically significant ECG abnormalities at Screening
4. Has systolic blood pressure >150 mmHg and/or a diastolic blood pressure >90
mmHg after 10 minutes of rest at screening
5. Has known active human immunodeficiency virus (HIV) infection
6. Has active severe acute respiratory syndrome coronavirus 2 (SARSCoV-2)
infection
7. Treatment with another investigational drug, biological agent, or device
within 6 months of Screening, or 5 half-lives of investigational agent
8. Use of the following medications is prohibited unless the dose has been
stable for at least 12 weeks prior to Screening and the dose regimen is not
anticipated to change during the study: antidepressants, antipsychotics,
anxiolytics, benzodiazepines, acetylcholinesterase inhibitors, memantine
9. Supplement use (eg, coenzyme Q10, vitamins, creatine), unless stable dose
for 6 weeks prior to Screening
10. Antiplatelet or anticoagulant therapy within the 28 days prior to Screening
or anticipated use during the study
11. Oral carbonic anhydrase inhibitors
12. Treatment with amyloid-targeting antibody within the last 3 years prior to
Screening
13. Treatment with another IT administered medication within the last 1 year
prior to Screening
14. Active infection requiring systemic antiviral or antimicrobial therapy
15. Prior treatment with an siRNA or antisense oligonucleotide (ASO)
16. Any history of gene therapy or cell transplantation or experimental brain
surgery
17. Presence of an implanted shunt for the drainage of CSF or an implanted CNS
catheter
18. Any condition, including EOAD-related symptoms, that would prevent either
writing or performing assessments
19. Attempted suicide, suicidal ideation with a plan that required hospital
admission and/or change in level of care within 12 months prior to Screening
20. Any condition that increases risk of meningitis (eg, immunodeficient state)
21. History of bleeding diathesis or coagulopathy
22. A medical history of brain or spinal disease that would interfere with the
LP process, CSF circulation or safety assessment
23. History of uncontrolled seizures within the last 6 months prior to Screening
24. Hospitalization for any major medical or surgical procedure
25. Clinically relevant hematological, hepatic, cardiac or renal disease or
event
26. History of intolerance to IT injection(s)
27. Is not willing to comply with the contraceptive requirements during the
study period
28. Female patient is pregnant, planning a pregnancy, or breast-feeding and
history of drug/chemical or alcohol abuse
Exclusion Criteria for Participants Who Transition from Part A to Part B:
1. Has any of the following laboratory parameter assessments at Screening:
international normalized ratio (INR) >1.4, platelet count <100,000/microliter
(µL), absolute neutrophil count absolute lymphocyte count 2. Clinically significant ECG abnormalities at Screening
3. Has systolic blood pressure >150 mmHg and/or a diastolic blood pressure >90
mmHg after 10 minutes of rest
4. Has known active human immunodeficiency virus (HIV) infection
5. Has active severe acute respiratory syndrome coronavirus 2 (SARSCoV-2)
infection
6. Treatment with another investigational drug, biological agent, or device
within 6 months of Screening, or 5 half-lives of investigational agent
7. Use of the following medications is prohibited unless the dose has been
stable for at least 12 weeks prior to Screening and the dose regimen is not
anticipated to change during the study: antidepressants, antipsychotics,
anxiolytics, benzodiazepines, acetylcholinesterase inhibitors, memantine
8. Supplement use (eg, coenzyme Q10, vitamins, creatine), unless stable dose
for 6 weeks prior to Screening
9. Antiplatelet or anticoagulant therapy within the 28 days prior to Screening
10. Attempted suicide, suicidal ideation with a plan that required hospital
admission and/or change in level of care within 12 months prior to Screening,
risk of meningitis, bleeding diathesis or coagulopathy, history of brain or
spinal disease, uncontrolled seizures within the last 6 months, hospitalization
for any major medical or surgical procedure, not willing to comply with the
contraceptive requirements, Female patient is pregnant, planning a pregnancy,
or breast-feeding and drug/chemical or alcohol abuse.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-508363-79-00 |
| EudraCT | EUCTR2021-003198-74-NL |
| CCMO | NL79863.000.22 |