Amyotrophic Lateral Sclerosis
Conditions
Keywords
ALS, Amyotrophic Lateral Sclerosis, MND, Motor Neurone Disease, 3K3A-APC
Brief summary
Phase 2 open label trial to investigate the safety and potentially efficacy of 3K3A-APC in patients with Amyotrophic Lateral Sclerosis (ALS).
Detailed description
This Phase 2 open label trial seeks to investigate whether a novel therapy named 3K3A-APC is safe and potentially effective in patients with Amyotrophic Lateral Sclerosis (ALS). A total of 16 patients with ALS will be enrolled into 2 dose cohorts with five doses of 15mg or 30mg doses given 12 hours apart in each cohort. The primary study outcomes are to ensure the safety and tolerability of 3K3AAPC in ALS patients, and to determine whether 3K3A-APC is able to reduce the pathological changes that might possibly cause ALS.
Interventions
DRUG3K3A-APC Protein
3K3A-APC with intravenous dosing of five doses of either 15mg or 30mg at 12 hourly interval. The first 8 patients will receive 15mg dose, and the next 8 patients will receive 30mg dose.
Sponsors
ZZ Biotech, LLC
Macquarie University, Australia
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Patients must have clinically definite ALS (Awaji Criteria) 2. Male or female age 18 years and less than 75 years at time of ALS study 3. Symptom onset less than 36 months before screening 4. Diagnosis of ALS less than 24 months before screening 5. Clinically definite Upper Motor Neuron signs
Exclusion criteria
1. Current treatment with anticoagulants (e.g., warfarin, novel oral anticoagulants, heparin) that might preclude safe completion of the lumbar puncture 2. Condition that precludes the safe performance of routine lumbar puncture, such as prohibitive lumbar spinal disease, bleeding diathesis, or clinically significant coagulopathy or thrombocytopenia 3. Use of investigational drugs or devices within 60 days prior to Baseline (dietary supplements taken outside of a clinical trial are not exclusionary, e.g., coenzyme Q10) 4. Prolonged prothrombin time or activated partial thromboplastin time \>2xULN 5. Severe hypertension or hypotension 6. Glomerular filtration rate (GFR) \<35 mL/min 7. Forced vital capacity (FVC) at screening of \<50% of predicted 8. Prior exposure to any exogenous form of APC 9. Inability to lie flat for procedures (MRI, PET, LP) 10. Pregnant or lactating during the study period
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Had Any Serious Adverse Events or Any Adverse Events With Severity Higher Than Moderate. | 15 Days | Number of participants who had any serious adverse events or any adverse events with severity higher than moderate, as determined by the Principal Investigator, using the composite safety assessment including clinical laboratory testing (full blood count, biochemistry, coagulation, iron study, CSF analysis and ECG), physical examination and self-reporting of adverse events. All clinical significant findings in the composite safety assessment were reported as adverse events. |
| Percentage of Change in PERSI Score in the Motor Cortex Before and After Dosing | 7 Days | PERSI (Parametric Estimation of Reference Signal Intensity) score is the measurement of microglial activation in the motor cortex utilising serial \[18F\]FEMPA PET imaging. The percentage of change in PERSI score before and after dosing in the two (2) dose cohorts is calculated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Monocyte Activation | 7 Days | Change in the level of monocyte activation in the peripheral blood utilising a novel method. |
| Cytokine Level | 7 Days | Change in cytokine level in serum, plasma and CSF. |
| Soluble CD14 Level | 7 Days | Change in soluble CD14 level in serum, plasma and CSF. |
| Neurofilament Level | 7 Days | Change in neurofilament level in serum, plasma and CSF. |
| Kynurenine Level | 7 Days | Change in kynurenine level in serum, plasma and CSF. |
| Chemokine Level | 7 Days | Change in chemokine level in serum, plasma and CSF. |
| Diffusion Kurtosis Using MRI Scan | 7 Days | Change in diffusion kurtosis using MRI scan of the brain to determine whether the blood brain barrier integrity can be measured in ALS by Magnetic Resonance Imaging, and whether 3K3A-APC is able to repair it |
Countries
Australia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 15mg Dose Group Participants will receive a fixed dose regimen of five doses of 15mg.
3K3A-APC Protein: 3K3A-APC with intravenous dosing of five doses of either 15mg or 30mg at 12 hourly interval. The first 8 patients will receive 15mg dose, and the next 8 patients will receive 30mg dose. | 8 |
| 30mg Dose Group Participants will receive a fixed dose regimen of five doses of 30mg.
3K3A-APC Protein: 3K3A-APC with intravenous dosing of five doses of either 15mg or 30mg at 12 hourly interval. The first 8 patients will receive 15mg dose, and the next 8 patients will receive 30mg dose. | 8 |
| Total | 16 |
Baseline characteristics
| Characteristic | 15mg Dose Group | 30mg Dose Group | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 3 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 5 Participants | 11 Participants |
| Age, Continuous | 59.5 years | 57.1 years | 58.3 years |
| ALSFRS-R Score | 30.875 units on a scale | 37.125 units on a scale | 34.0 units on a scale |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 8 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 8 Participants | 16 Participants |
| Region of Enrollment Australia | 8 participants | 8 participants | 16 participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Male | 6 Participants | 5 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 4 / 8 | 6 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 |
Outcome results
Primary
Number of Participants Who Had Any Serious Adverse Events or Any Adverse Events With Severity Higher Than Moderate.
Number of participants who had any serious adverse events or any adverse events with severity higher than moderate, as determined by the Principal Investigator, using the composite safety assessment including clinical laboratory testing (full blood count, biochemistry, coagulation, iron study, CSF analysis and ECG), physical examination and self-reporting of adverse events. All clinical significant findings in the composite safety assessment were reported as adverse events.
Time frame: 15 Days
Population: All dosed participants are included in the analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 15mg Dose Group | Number of Participants Who Had Any Serious Adverse Events or Any Adverse Events With Severity Higher Than Moderate. | 0 Participants |
| 30mg Dose Group | Number of Participants Who Had Any Serious Adverse Events or Any Adverse Events With Severity Higher Than Moderate. | 0 Participants |
Primary
Percentage of Change in PERSI Score in the Motor Cortex Before and After Dosing
PERSI (Parametric Estimation of Reference Signal Intensity) score is the measurement of microglial activation in the motor cortex utilising serial \[18F\]FEMPA PET imaging. The percentage of change in PERSI score before and after dosing in the two (2) dose cohorts is calculated.
Time frame: 7 Days
Population: In total, 8 participants were included in the data analysis, with 5 participants in the 15mg group and 3 participants in the 30mg group.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 15mg Dose Group | Percentage of Change in PERSI Score in the Motor Cortex Before and After Dosing | -0.14 Percentage of change |
| 30mg Dose Group | Percentage of Change in PERSI Score in the Motor Cortex Before and After Dosing | 0.53 Percentage of change |
Secondary
Chemokine Level
Change in chemokine level in serum, plasma and CSF.
Time frame: 7 Days
Secondary
Cytokine Level
Change in cytokine level in serum, plasma and CSF.
Time frame: 7 Days
Secondary
Diffusion Kurtosis Using MRI Scan
Change in diffusion kurtosis using MRI scan of the brain to determine whether the blood brain barrier integrity can be measured in ALS by Magnetic Resonance Imaging, and whether 3K3A-APC is able to repair it
Time frame: 7 Days
Secondary
Kynurenine Level
Change in kynurenine level in serum, plasma and CSF.
Time frame: 7 Days
Secondary
Monocyte Activation
Change in the level of monocyte activation in the peripheral blood utilising a novel method.
Time frame: 7 Days
Secondary
Neurofilament Level
Change in neurofilament level in serum, plasma and CSF.
Time frame: 7 Days
Secondary
Soluble CD14 Level
Change in soluble CD14 level in serum, plasma and CSF.
Time frame: 7 Days