A Phase II Randomized, Placebo-Controlled, Double Blinded, Multi-Centre Clinical Trial of Pimozide in Patients With Amyotrophic Lateral Sclerosis

Minimum Age:

18 Years

Maximum Age:

N/A

Can participants use Riluzole?

Yes

Inclusion Criteria:

1. Patients classified as having clinically definite, clinically probable, clinically probable (laboratory-supported) or clinically possible ALS according to the El-Escorial diagnostic criteria for ALS (see Appendix 2).

2. Able to comprehend and willing to sign Informed Consent Form (ICF).

3. Age 18 years of age or greater.

4. ALS Symptom onset of muscle weakness or speech impairment no more than 48 months prior to screen visit. Fasiculations should not be considered.

5. Slow Vital Capacity (SVC) greater than or equal to 50% predicted for sex, age and height at screen.

6. Has the ability to swallow tablets/capsules whole at study entry.

7. Subject with clinical laboratory findings within the normal range or, if outside the normal range, determined by the Investigator at the Screening visit to be not clinically significant.

8. If the subject is taking Riluzole the dose must be stable for 30 days prior to the randomization visit. Riluzole cannot be initiated during the study.

9. If the subject is receiving Edaravone therapy, the dose must be stable for at least 1 cycle of infusion treatments before the randomization visit.

Exclusion Criteria:

1. History of laryngeal spasm, dystonia, or akathisia.

2. Diagnosis of ongoing symptomatic Restless Leg Syndrome or undergoing current treatment for Restless Leg Syndrome. If subject has symptoms that resemble or have the potential to be Restless Leg Syndrome, then further investigation should be undertaken to confirm or rule out diagnosis of Restless Leg Syndrome.

3. Any history of moderate or severe traumatic brain injury as defined by a Glasgow Coma Scale Score of less than 13/15 at any time point following a head injury without sedation or other reason for a decreased level of consciousness.

4. History of neuroleptic malignant syndrome.

5. History of hypersensitivity or serious adverse reaction(s) to a neuroleptic medication.

6. History of hyponatremia < 130 mmol/L

7. Subject with aspartate aminotransferase (AST) or alanine aminotransferase (ALT) value >3.0 times the upper limit of normal at the Screening visit.

8. Current heparin or warfarin use.

9. History of hepatic and/or renal impairment that may affect pimozide metabolism

10. History of current pregnancy, or breastfeeding women, or women planning to become pregnant. Female subjects of childbearing potential (sexually mature female who has not undergone a hysterectomy or who has not been post-menopausal for 12 consecutive months), must practise effective contraception during the study and be willing and able to continue contraception until the Follow-up phone visit after discontinuing study medication. Abstinence can be considered an acceptable method of contraception at the discretion of the investigator.

11. Current antipsychotic use

12. Presence of central nervous system depression, comatose states, liver disorders, renal insufficiency, and blood dyscrasias

13. Presence of Parkinson's syndrome

14. Presence of major depressive disorders as determined by site Investigator.

15. History of clinically significant ECG abnormalities at screen visit, including QTc>500ms.

16. History of congenital long QT syndrome or with a family history of this syndrome and in patients with a history of cardiac arrhythmias or Torsade de Pointes.

17. Presence of acquired long QT interval, and/or concomitant use of drugs known to prolong the QT interval (TCAs, opioids such as methodone, quinolone antibiotics (ciprofloxacin), antimalarials (quinine), Detrol, azole antifungals, Class 1A, III and 1C antiarrhythmics, and macrolide antibiotics.

18. Presence of clinically significant bradycardia (heart rate < 50 beats per minute)

19. Presence of hypokalemia or hypomagnesemia.

20. The concomitant use of CYP 3A4-inhibiting drugs such as azole antimycotics, antiviral protease inhibitors, macrolide antibiotics and nefazodone.

21. The concomitant use of CYP 2D6-inhibiting drugs such as quinidine is also contraindicated.

22. Concomitant use of serotonin reuptake inhibitors, such as, sertraline, paroxetine, citalopram and escitalopram.*

23. Has taken any compound under current or known future study as a potential therapy (including Withania) for ALS less than 30 days prior to dosing OR history of exposure to stem cell therapy for treatment of ALS at any time.

24. Current Neurological impairment due to a condition other than ALS:

1. Subject in whom causes of neuromuscular weakness other than ALS have not been excluded.

2. Subject with a diagnosis of other neurodegenerative diseases (e.g., Parkinson's disease, Frontotemporal dementia, Alzheimer's disease, etc.)

25. Use of non-invasive ventilation (BiPAP or CPAP) prior to Baseline visit at any time.

26. Cognitive impairment as determined by the Site Investigator, subject must not have an impaired ability to provide informed consent and must be able to understand study processes and comply with study procedures.

27. Extrapyramidal Symptom Rating Scale (ESRS) Parkinsonism score of 2 on 2 items or a score > 3 on 1 item; OR Dystonia score of >3 on at least 1 item or a score of 2 on 2 items; OR Tardive Dyskinesia score of >3 on at least 1 item or a score of 2 on 2 items. Do not consider scores greater than 3 for Tremor in any region if due to Benign Essential, Exaggerated, or Physiological Tremor.

28. The concomitant use of SSRIs and tricyclic antidepressants (e.g. amitriptyline, amoxaprine, desipramine, doxepin, imipramine, nortriptyline, protripyline, trimipramine) - and Tolterodine (Detrol) CYP2D6 inhibitor.

- Prohibited medications such as tricyclic antidepressants, antimalarials, and serotonin reuptake inhibitors,(ie sertraline, paroxetine, citalopram, fluoxetine, vilazodone and escitalopram) may be weaned to full discontinuation at the screening visit after consent has been signed (no study procedures including adjustments to medication may occur until informed consent has been provided).