Assessing multiple drugs for treating ALS

A Multi-arm, Adaptive, Group-sequential Trial NETwork to Evaluate Drug Efficacy in Patients With Amyotrophic Lateral Sclerosis (ALS)

This study is testing if lithium carbonate can help people with ALS who have a specific gene type feel better compared to a placebo.

Quick facts

• Phase: PHASE3
• Study type: Interventional
• Enrollment: 171 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Stichting TRICALS Foundation (other)
• Locations: 13 sites (Adelaide and 12 other locations)
• Trial ID: NCT06008249 on ClinicalTrials.gov

What this trial studies

This phase III, placebo-controlled platform trial aims to evaluate the efficacy of various treatments for patients with Amyotrophic Lateral Sclerosis (ALS) using an innovative multi-arm, adaptive design. Currently, it focuses on the effects of lithium carbonate compared to a placebo in patients with a specific UNC13A genotype, which affects approximately 1 in 6 ALS patients. Participants must meet specific eligibility criteria, including age and ALS diagnosis, and must be capable of providing informed consent. The study allows for the concurrent use of riluzole, provided patients have been on a stable dose prior to the trial.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older diagnosed with ALS who possess the UNC13A genotype.

Not a fit: Patients without the specific UNC13A genotype or those with other forms of ALS may not benefit from this study.

Why it matters

Potential benefit: If successful, this trial could lead to new treatment options for ALS patients, potentially improving their quality of life.

How similar studies have performed: Other studies have shown promise in using adaptive trial designs for ALS, but the specific approach of this trial is relatively novel.

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

Where this trial is running

Adelaide and 12 other locations

• Flinders Medical Centre — Adelaide, Australia (NOT_YET_RECRUITING)
• Royal Brisbane and Women's Hospital — Brisbane, Australia (NOT_YET_RECRUITING)
• Calvary Health Care Bethlehem — Parkdale, Australia (NOT_YET_RECRUITING)
• Perron Institute — Perth, Australia (NOT_YET_RECRUITING)
• The University of Sydney (Royal prince Alfred hospital) — Sydney, Australia (RECRUITING)
• Concord hospital Sydney — Sydney, Australia (NOT_YET_RECRUITING)
• University Hospital Leuven — Leuven, Belgium (RECRUITING)
• University Medical Center Utrecht — Utrecht, Netherlands (RECRUITING)
• Bellvitge University Hospital — Barcelona, Spain (RECRUITING)
• Karolinska University Hospital — Stockholm, Sweden (RECRUITING)
• King's College Hospital — London, United Kingdom (RECRUITING)
• University College London Hospital NHS — London, United Kingdom (NOT_YET_RECRUITING)
• University Hospitals of North Midlands NHS Trust — Stoke-on-Trent, United Kingdom (NOT_YET_RECRUITING)

Study contacts

• Study coordinator: Roel Vink, PhD

Conditions: Amyotrophic Lateral Sclerosis