Platform Trial to Assess the Efficacy of Multiple Drugs in Amyotrophic Lateral Sclerosis (ALS)

Tricals

Status and phase: Enrolling; Phase 3

Conditions: Amyotrophic Lateral Sclerosis

Treatments: Drug: Lithium Carbonate 400 MG

Study type: Interventional

Funder types: Other

Identifiers

NCT06008249

MAGNET

Details and patient eligibility

About

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

Full 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.

Enrollment: 171 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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171 participants in 2 patient groups, including a placebo group

Lithium carbonate

Experimental group

Description:

Lithium carbonate 400 mg capsules will be taken once daily, starting with one capsule (400 mg daily) initially titrated up to two or three capsules daily, depending on blood lithium levels. The target range for the lithium plasma level will be between ≥0.4 mmol/l and ≤ 0.8 mmol/l. Maximum duration is 24 months.

Treatment:

Drug: Lithium Carbonate 400 MG

Placebo

Placebo Comparator group

Description:

Patients start with 1 capsule to be taken once daily, with subsequent sham dose adjustments made to patients on placebo to maintain blinding in clinical sites.

Treatment:

Drug: Lithium Carbonate 400 MG