Clinical trial NCT06008249: Platform Trial to Assess the Efficacy of Multiple Drugs in Amyotrophic Lateral Sclerosis (ALS)
Official title: A Multi-arm, Adaptive, Group-sequential Trial NETwork to Evaluate Drug Efficacy in Patients With Amyotrophic Lateral Sclerosis (ALS)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Amyotrophic Lateral Sclerosis
Lead sponsor: Stichting TRICALS Foundation
Sponsor class: OTHER
Collaborators: name: Fight MND
name: Research Foundation Flanders
name: MNDA
name: Thierry Latran Foundation
name: Ulla-Carin Lindquist Foundation
name: Luzon Foundation
name: Alan Davidson Foundation
name: My name'5 Doddie Foundation
name: Stichting ALS Nederland
First posted: 2023-08-23
Enrollment: 171
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants will be randomised in a 2:1 ratio to receive either lithium carbonate or placebo
Primary purpose: TREATMENT

Brief summary: The objective of this phase III, placebo-controlled platform study is to investigate the efficacy of drugs for patients with ALS (Amyotrophic lateral sclerosis).

Detailed description: This study uses an innovative multi-arm, adaptive trial design to investigate the efficacy of multiple treatments simultaneously. Currently one study-arm is active, investigating the efficacy and safety of lithium carbonate versus placebo in patients with ALS. Only patients with a specific UNC13A genotype (approximately 1 in 6 ALS patients) are eligible to participate.

Eligibility criteria: Inclusion Criteria:

1. ≥ 18 years at the time of screening.
2. Diagnosis of ALS according to the revised El Escorial criteria (possible, probable-laboratory supported, probable or definite).
3. Capable of providing informed consent and complying with trial procedures, including randomization to sub-studies.
4. TRICALS risk profile \> -6.0 and \< -2.0 \*\*
5. The use of riluzole will be permitted during the study. Subjects taking riluzole must be on a stable dose for at least 30 days prior to the baseline visit, or stopped taking riluzole at least 30 days prior to the baseline visit.
6. Women of childbearing potential\* must have a negative pregnancy test at baseline and be non-lactating.
7. Men must agree to practice contraception for the duration of the trial and for at least 3 months after last dose of study drug.
8. Men must not plan to father a child or to provide sperm for donation for the duration of the trial and 3 months after the last dose of study drug.
9. Women must not be able to become pregnant (e.g. post-menopausal\*\*\*, surgically sterile or using effective birth control methods) for the duration of the study. Effective contraceptives are defined as having a failure rate of less than 1% per year when used consistently and correctly and, when applicable, in accordance with the product label, including: abstinence, hormonal contraception, intrauterine device in place for ≥ 3 months Appendix 1). Women of childbearing potential must have a negative pregnancy test at baseline, and be non-lactating. Women who are pregnant or are actively seeking to become pregnant, and women of reproductive potential who are not using effective contraceptives are excluded.

Exclusion Criteria:

1. Laboratory Criteria at baseline:

   * ALT (alanine transaminase) ≥ 5 times upper limit of normal (ULN)
   * AST (aspartate aminotransferase) ≥ 3 times ULN
   * Bilirubin ≥ 1.5 times ULN
   * Estimated glomerular filtration rate (eGFR) \< 50 mL / min / 1.73 m2 based on Cystatin C, if not available eGFR can also be calculated based on creatinine clearance.
   * Platelet concentration of \< 100 x109 per L
   * Absolute neutrophil count of \< 1x109 per L
   * Haemoglobin \< 100 g/L (\<6.2 mmol/L)
   * Amylase \& lipase ≥ 2 times ULN (suspected pancreatitis)
   * Lactate ≥ 2 times ULN (suspected lactate acidosis)
2. Moderate to severe hepatic impairment according to Child-Pugh classification (Class B or higher; score ≥ 7). Child-Pugh classification is based on bilirubin, albumin, International Normalized Ratio (INR) and presence of encephalopathy or ascites.
3. Participation in any other investigational drug trial or using investigational drug (within 30 days prior to screening).
4. Hypothyroidism unresponsive to thyroid hormone supplementation.
5. Subjects using non-invasive ventilation (NIV, ≥22 h per day) or having a tracheostomy.
6. Subjects taking edaravone within 30 days prior to screening. Edaravone is approved by the FDA, but remains an investigational product in Europe and Australia.
7. Clinically significant history of unstable or severe cardiac (e.g. congestive heart failure, coronary insufficiency and arrhythmias), oncological, hepatic or renal disease, neuromuscular diseases, significant pulmonary disorder or other medically significant illness.
8. Drug or alcohol abuse.
9. Unstable psychiatric illness defined as psychosis or untreated major depression within 90 days of the screening visit. This exclusion criterion is based on a prior psychiatric diagnosis that is unstable as determined by the subject's treating Psychiatrist.
10. Presence of frontotemporal dementia which prevents informed consent.

Lithium carbonate study-specific exclusion criteria:

1. Patients heterozygous or homozygous for the A-allele of rs12608932 (UNC13A)
2. Known allergy or hypersensitivity to lithium, or its excipients, or to the components of the placebo.
3. Brain injury with posttraumatic epilepsy or neurologic deficit, excluding a concussion in the medical history. Brain infarction is an exclusion criterion, a transient ischemic attack is not.
4. Addison disease.
5. Patients with the following co-medication: antipsychotics, digoxin and calcium antagonists, carbamazepine, methyldopa, verapamil and diltiazem.
6. Brugada Syndrome or family history of Brugada Syndrome.
7. Plasma sodium \<120 mmol/L

Primary outcomes:
measure: Overall survival, defined as time to death from any cause or respiratory insufficiency (DRI; defined as tracheostomy or the use of non-invasive ventilation for ≥22 h per day for ≥10 consecutive days)
timeFrame: endpoint or 24 months
Secondary outcomes:
measure: Composite endpoint evaluating daily functioning and survival based on the joint model framework of survival and longitudinal ALSFRS-R total scores
timeFrame: endpoint or 24 months
measure: Daily functioning, defined as mean change from baseline in ALSFRS-R total score.
timeFrame: endpoint or 24 months
measure: Respiratory function, defined as mean change from baseline in SVC (%predicted of normal according to the GLI-2012 reference standard)
timeFrame: endpoint or 24 months
measure: Quality of life, defined as change from baseline on the EQ-5D Visual Analogue Scale (single-item scale)
timeFrame: endpoint or 24 months
measure: Quality of life, defined as change from baseline on the EQ-5D
timeFrame: endpoint or 24 months
measure: Neuropsychological status, defined as change from baseline on the ECAS
timeFrame: endpoint or 24 months
measure: Neuropsychological status, defined as change from baseline on the ALS-FTD-Q.
timeFrame: endpoint or 24 months
measure: Clinical disease stage, defined as mean time spent in each stage of the King's and ALS Milano-Torino staging systems.
timeFrame: endpoint or 24 months
measure: Change from baseline in laboratory parameters: Urinary P75ECD (ectodomain of neurotrophin receptor p75), Neurofilament light and heavy chain, Plasma creatinine
timeFrame: endpoint or 24 months
measure: Tolerability defined as time-to-discontinuation of assigned treatment since randomization
timeFrame: endpoint or 24 months
measure: Safety based on the safety assessments including neurological examinations, clinical laboratory evaluations, vital signs and frequency of adverse events (AEs) or serious adverse events (SAEs).
timeFrame: endpoint or 24 months
Other outcomes:
Locations:
city: Adelaide
country: Australia
facility: Flinders Medical Centre
city: Brisbane
country: Australia
facility: Royal Brisbane and Women's Hospital
city: Parkdale
country: Australia
facility: Calvary Health Care Bethlehem
city: Perth
country: Australia
facility: Perron Institute
city: Sydney
country: Australia
facility: The University of Sydney (Royal prince Alfred hospital)
city: Sydney
country: Australia
facility: Concord hospital Sydney
city: Leuven
country: Belgium
facility: University Hospital Leuven
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht
city: Barcelona
country: Spain
facility: Bellvitge University Hospital
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
city: London
country: United Kingdom
facility: King's College Hospital
city: London
country: United Kingdom
facility: University College London Hospital NHS
city: Stoke-on-Trent
country: United Kingdom
facility: University Hospitals of North Midlands NHS Trust
Study officials:
affiliation: TRICALS Foundation
name: Leonard Van den Berg, MD
role: STUDY_CHAIR
References: