Study to investigate the safety of VRG50635 in healthy volunteers and patients with motor neuron disease (amyotrophic lateral sclerosis)
| ISRCTN | ISRCTN14792372 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN14792372 |
| EudraCT/CTIS number | 2022-002747-22 |
| Secondary identifying numbers | CHDR2219 |
- Submission date
- 20/09/2022
- Registration date
- 26/09/2022
- Last edited
- 26/09/2022
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Nervous System Diseases
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Record updated in last year
Plain English Summary
Background and study aims
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder that results from the loss of motor neurons in the brain and spinal cord causing paralysis of voluntary muscles. Like most neurodegenerative disorders, ALS is thought to be caused by abnormal protein aggregation and the derailing of cell pathways that are protective and essential for the correct functioning, development, and formation of new neurons in the brain. Thus, repair and/or preservation of the integrity of the neuronal protein quality control system is an attractive and emerging therapeutic target. In this study, the safety and tolerability of PIKfyve inhibitor VRG50635 will be investigated.
Who can participate?
Healthy men and women and adult ALS patients
What does the study involve?
In part 1, participants will be given a single dose of VRG50635 or placebo. There will also be a food effect cohort who will receive single doses of VRG50635 or placebo. In part 2, participants will be given multiple doses of VRG50635 or a placebo and in part 3, VRG50635 and placebo for 28 days in a cross-over assignment. Participants will be monitored throughout the study for adverse events, vital signs, electrocardiography, physical signs, suicidal ideation and with laboratory safety tests.
What are the possible benefits and risks of participating?
No benefit from participating in this research is anticipated. There might be side effects or adverse effects of the study drug, for example, cases of anemia, weight loss and a rare case of acute myeloid leukemia have been encountered in preclinical studies.
Where is the study run from?
Centre for Human Drug Research (The Netherlands)
When is the study starting and how long is it expected to run for?
April 2022 to October 2023
Who is funding the study?
Verge Genomics (USA)
Who is the main contact?
Dr Lars Smits (Project Leader) (The Netherlands)
lsmits@chdr.nl
Contact information
Dr Lars Smit
Public
Public
Zernikedreef 8
Leiden
2333 CL
Netherlands
 ORCID ID |
0000-0001-7228-782X |
|---|---|
| Phone | +31 71 5246 400 |
| clintrials@chdr.nl |
Study information
| Study design | Three-part first-in-human single-centre randomized double-blind placebo-controlled parallel-group dose-ranging study with healthy subjects (parts 1 and 2) and a patient crossover cohort (part 3) |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised parallel trial |
| Study setting(s) | Other |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use contact details to request a participant information sheet |
| Scientific title | A randomised, double-blind, placebo-controlled, single- and multiple-, ascending-dose study of the safety, tolerability, and pharmacokinetics and pharmacodynamics of VRG50635 and food effect in healthy volunteers (phase Ia) and multiple-dose study in subjects with amyotrophic lateral sclerosis |
| Study hypothesis | VRG50635 is hypothesized in improving motor neuron health and survival, has exposures in the central nervous system (CNS), has effects on the relevant target, pathway, and disease biomarkers supporting translatability, and has a favorable safety profile in non-human models. Furthermore, the active metabolite VRG50468 can reduce amyotrophic lateral sclerosis (ALS) patient motor neuron death in vitro across multiple genetic subtypes with efficacy that surpasses current approved ALS drugs. |
| Ethics approval(s) | Approved 06/09/2022, Stichting Beoordeling Ethiek Biomedisch Onderzoek (stichting BEBO, Dr. Nassaulaan 109401 HK ASSEN, The Netherlands; +31592405871; info@stbebo.nl), ref: NL81735.056.22 |
| Condition | Amyotrophic lateral sclerosis |
| Intervention | VRG50635 is a PIKfyve inhibitor. In each cohort in part 1, 6 subjects will receive VRG50635 and 2 subjects will receive a placebo. In part 2, 8 subjects will receive VRG50635 and 2 subjects will receive a placebo. Part 3 is a crossover design; each subject will receive a placebo and VRG50635 for 28 days with a washout of 2 weeks in between. Dose range Part 1: Cohort 1: 60mg Cohort 2: 120mg Cohort 3: 240mg Cohort 4: 600mg Cohort 5: 1200mg Cohort 6: 1800mg Part 2 and 3: The dose levels will be determined based on results from parts 1 and 2. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase I |
| Drug / device / biological / vaccine name(s) | VRG50635 |
| Primary outcome measure | Part 1 Single ascending dose: 1. Assessment of: 1.1. Adverse events (AEs) measured by collecting the number of AEs, the intensity, relationship with the study drug and chronicity, continuously throughout the study 1.2. Vital signs, evaluations of systolic and diastolic blood pressure, pulse rate, respiratory rate (only predose, 0.5h, 1.5h, 24h) and temperature at screening, Day -1, predose and postdose at 0.5h, 1.5h, 2h, 24h, 48h and at follow-up (FU) 1.3. Electrocardiograms (ECGs) measured in triplicate at screening, predose and postdose at 0.5h, 1.5h, 4h, 7h, 24h, 48h and at FU. The ECG parameters assessed will include heart rate, PR, QRS, QT and QTcF. 1.4 Physical examinations, including neurological examination, at screening predose, 48h postdose and at FU 1.5. Suicidal ideation and behaviour measured using the Columbia Suicide Severity Rating Scale (C-SSRS) at screening, Day -1, and 48h postdose 1.6. Laboratory safety tests, including chemistry, hematology, coagulation and glucose at screening, Day-1, 24h (no Coagulation), 48h, at FU Part 2 Multiple ascending doses 2. Assessment of: 2.1. Adverse events (AEs) measured by collecting the number of AEs, the intensity, relationship with the study drug and chronicity, continuously throughout the study 2.2. Vital signs, evaluations of systolic and diastolic blood pressure, pulse rate, respiratory rate (only predose, Day 2 and Day 4) and temperature at screening, Day -1, predose and postdose on Day 1 (2h and 5h), Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Day 8, Day 9 and at FU 2.3. ECGs measured in triplicate at screening, Day -1, predose and postdose on Day 1 (2h and 5h), Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Day 9 and at FU. The ECG parameters assessed will include heart rate, PR, QRS, QT and QTcF. 2.4. Physical examinations, including neurological examination, screening, predose and postdose on Day 1, Day 3, Day 5, Day 7, Day 9 and FU 2.5. Suicidal ideation and behaviour measured using the Columbia Suicide Severity Rating Scale (C-SSRS) at screening, Day -1, and postdose on Day 9 2.6. Laboratory safety tests, including chemistry, hematology, coagulation and glucose at screening, Day -1 (no coagulation) and postdose on Day 1 (no coagulation), Day 3, Day 5 (no coagulation), Day 7 (no coagulation), Day 9 and at FU Part 3 ALS 3. Assessment of: 3.1. AEs measured by collecting the number of AEs, the intensity, relationship with the study drug and chronicity, continuously throughout the study 3.2. Vital signs, evaluations of systolic and diastolic blood pressure, pulse rate, respiratory rate (only predose, 0.5h, 1.5h, 24h) and temperature at screening, predose, and postdose on Day 1, Day 2, Day 7, Day 14, Day 28 (both occasions), and FU 3.3. ECGs measured in triplicate at screening, predose, and post-dose on Day 1, Day 2, Day 7, Day 14, Day 28 (both occasions) and FU. The ECG parameters assessed will include heart rate, PR, QRS, QT and QTcF. 3.4. Physical examinations, including neurological examination, at screening, predose, and postdose on Day 1, Day 7, Day 14, Day 28 and Day 29 (both occasions) and FU 3.5 Suicidal ideation and behaviour measured using the Columbia Suicide Severity Rating Scale (C-SSRS) at screening, predose and postdose on Day 1, Day 7, Day 14, and Day 28 (both occasions). 3.6. Laboratory safety tests, including chemistry, hematology, coagulation and glucose at screening, predose and postdose on Day 7 (no coagulation), Day 14, (no coagulation), Day 28 (both occasions) and FU (no coagulation) |
| Secondary outcome measures | Part 1 Single ascending dose: Characterize plasma and urine pharmacokinetics (PK) of VRG50635 and active metabolite VRG50648. PK parameters include Tmax, Tlag, Cmax AUC(0-last), AUC (0-inf) and T1/2. Urine PK parameters include cumulative total amount excreted in urine and cumulative percentage of dose in urine. Plasma PK timepoints: predose and postdose: 0.5h, 1h, 1,5h, 2h, 4h, 7h, 10h, 24h, 34h, 48h; Urine PK timepoints: Predose, 0-6h, 6-24h, 24-36 hours, 36-48 hours (cohorts 2, 3, 4, 5 and 6) Characterize plasma PK of VRG50635 and VRG50648 after high-fat meal. PK parameters include Tmax, Tlag, Cmax AUC(0-last), AUC (0-inf) and T1/2. Plasma PK timepoints: predose and postdose: 0.5h, 1h, 1,5h, 2h, 4h, 7h, 10h, 24h, 34h, 48h. Part 2 Multiple ascending doses Characterize plasma and cerebrospinal fluid (CSF) PK of VRG50635 and VRG50648. PK parameters include Tmax, Tlag, Cmax AUC(0-last), AUC (0-inf) and T1/2. CSF PK parameters include concentrations and plasma/CSF ratio. Plasma PK timepoints: pre-dose and 0.5, 1, 1.5, 2, 4, 7, 10 h post-dose; pre-dose sample on Days 2, 3, on Day 4 prior to CSF sample, 5; on Day 6 predose and on Day 7, pre-dose, 0.5, 1, 1.5, 2, 4, 7 and 10 h following the last dose; on Day 8, 24h after the last dose; on Days 9 and 10, 48 and 72 h after the last dose. CSF sample timepoint: Day 4, 2 hours post-dose. Part 3 ALS Characterize plasma and CSF PK of VRG50635 and VRG50648. PK parameters include Tmax, Tlag, Cmax AUC(0-last), AUC (0-inf) and T1/2. CSF PK parameters include concentrations and plasma/CSF ratio. Plasma PK timepoints: pre-dose and 0.5, 1, 1.5, 2, 4, 9, 12 h post-dose; predose on Day 2 (44); pre-dose sample on Days 7 (50), 14 (57) and 28 (71); and 0.5, 1, 1.5, 2, 4, 9, 12 hours post-dose on Day 28 (71) and a 24 hours post-dose sample on Day 29 (72). On days -1, 28 and 71 a PK sample will be taken directly after CSF sampling. CSF sample timepoints: Day -1, 28 and 71, 2 hours post-dose. |
| Overall study start date | 01/04/2022 |
| Overall study end date | 01/10/2023 |
Eligibility
| Participant type(s) | Mixed |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Upper age limit | 65 Years |
| Sex | Both |
| Target number of participants | 93 |
| Participant inclusion criteria | Inclusion criteria for Parts 1 and 2: 1. Healthy male or female aged between 18 to 65 years old at screening (inclusive) 2. For male and female subjects of childbearing potential: Subjects and their spouse/partners who are of childbearing potential must use highly effective contraception when engaging in sexual activity consisting of 2 forms of birth control (1 of which must be a barrier method such as latex or polyurethane condoms) starting at screening and continue throughout the clinical study period, and for 90 days after the final study drug administration. 3. For males: Subject must not donate sperm starting at screening and throughout the clinical study period, and for 90 days after the final study drug administration. Inclusion criteria for Part 3: 1. Diagnosis of laboratory-supported probable, probable, or definite (sporadic) amyotrophic lateral sclerosis (ALS) according to the El Escorial World Federation of Neurology revised research diagnostic criteria (Ludolph et al. 2015) 2. Aged between 18 and 80 years old 3. 5 years or less since the onset of ALS symptoms 4. Forced vital capacity (FVC) ≥50% predicted value 5. Able to swallow medication for the duration of the study (in the opinion of the investigator) |
| Participant exclusion criteria | Exclusion criteria for Parts 1 and 2: 1. History of clinically significant hematological, renal, neurologic, pancreatic, gastrointestinal, hepatic, cardiovascular, psychological, pulmonary, metabolic, endocrine, immunological, allergic disease, or other major disorders 2. Current significant medical or psychiatric condition 3. Evidence of clinically significant hepatic or renal impairment in the opinion of the investigator, including alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >1.5 the upper limit of normal (ULN) or bilirubin > 1.5ULN. Patients with Gilbert syndrome without evidence of hepatic impairment may be enrolled. 4. Poor peripheral venous access 5. A lifetime history of suicidal behavior or suicidal ideation as determined by a positive response (‘’Yes’’) to either question 4 or question 5 of the C-SSRS at screening 6. For part 2 only: Subjects not eligible for lumbar puncture (anti-coagulation, anti-aggregation or blood coagulation pathologies, recent spine surgery, acquired or congenital spine malformation, clinical signs of intracranial hypertension, cutaneous infection at the punction site) Exclusion criteria for Part 3: 1. Amyotrophic lateral sclerosis (ALS) patients with a known mutation in the SOD1 or C9orf72 gene 2. Tracheotomy and/or ventilator-dependent (or daily use of non-invasive ventilation ≥ 22 hours for 7 consecutive days) 3. After percutaneous gastrostomy (PEG) operation 4. Subjects not eligible for lumbar puncture (anti-coagulation, anti-aggregation or blood coagulation pathologies, recent spine surgery, acquired or congenital spine malformation, clinical signs of intracranial hypertension, cutaneous infection at the punction site) |
| Recruitment start date | 23/09/2022 |
| Recruitment end date | 20/09/2023 |
Locations
Countries of recruitment
- Netherlands
Study participating centre
Centre for Human Drug Research
Zernikedreef 8
Leiden
2333 CL
Netherlands
Leiden
2333 CL
Netherlands
Sponsor information
Verge Genomics
Industry
Industry
Two Tower Place
Suite 950
South San Francisco
94080
United States of America
| Phone | + 1 650 906 9841 |
|---|---|
| sujata@vergegenomics.com |
Funders
Funder type
Not defined
Verge Genomics
No information available
Results and Publications
| Intention to publish date | 20/10/2024 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal |
| IPD sharing plan | The data-sharing plans for the current study are unknown and will be made available at a later date. |
Editorial Notes
26/09/2022: Trial's existence confirmed by the Independent Ethics Committee (Medisch Ethische ToetsingsCommissie) of the Foundation ‘Evaluation of Ethics in Biomedical Research’ (Stichting Beoordeling Ethiek Biomedisch Onderzoek), Assen, the Netherlands.
