Clinical trial: A Clinical Trial of Pimozide in Patients With Amyotrophic Lateral Sclerosis (ALS) (NCT03272503)

Eligibility criteria:
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).
No condition on gender to be admitted to the trial.
No healthy subjects accepted to join the trial.
Subject must be at least 18 Years old.


Patient description (medical language): A 47-year-old man comes to the clinic for the follow up of his neuromuscular disease. He experienced gradual, progressive weakness of the left upper extremity over the last year.  Over the last few months, he has also noticed weakness in the right upper extremity.  BP is 120/75, PR is 80 and temperature is 37 C. Reflexes are brisk in the upper extremities, and the plantar responses are extensor.  Mild gait ataxia is present. The patient is under treatment of Riluzole 50 mg BID with the diagnosis of ALS.

Patient description (patient's own words): I've been suffering from a neuromuscular disease for a while now, and I went to my doctor's office. I'm now a 47-year-old man and over the past year I experienced a progressive and gradual weakness of my left upper extremity, and over the past month, I also noticed a weakness over my right upper extremity. My heart rate was 120/75, and my  PR was 80 with 37°C for temperature. My reflexes are not good in my upper extremities, and I have trouble with my balance. I'm also under Exservan 50 mg for my sclerosis.

Does the patient match the trial criteria? Entailment