A Clinical Study to Evaluate CAD-1883 in Essential Tremor

• ClinicalTrials.gov Identifier: NCT03688685
• Recruitment Status: Completed
• First Posted: September 28, 2018
• Last Update Posted: October 23, 2019
• Sponsor: Cadent Therapeutics
• Information provided by (Responsible Party): Cadent Therapeutics

Study Description

Brief Summary:

This is an open-label study designed to evaluate the safety, tolerability and efficacy of CAD-1883, a positive allosteric modulator of the SK channel, administered twice daily orally to adult patients with ET. Patients with the diagnosis of ET based on the Movement Disorder Society (MDS) criteria with a documented severity of tremor based on the clinician-administered TETRAS Performance Subscale are eligible to be enrolled in the study.

Condition or disease	Intervention/treatment	Phase
Essential Tremor	Drug: CAD-1883	Phase 2

Detailed Description:

This is an open-label study designed to evaluate the safety, tolerability and efficacy of CAD-1883, a positive allosteric modulator (PAM) of the SK channel, administered twice daily orally to adult subjects with ET. Positive modulation of the small-conductance calcium-activated potassium channels (SK) present in different regions of the brain aims to increase the channel sensitivity to calcium resulting in reduction in neuronal firing rate. In patients with ET, improving the regularity of firing of action potentials in the olivo-cerebellar network can lead to improvement in motor function.

During the Screening period, each subject will undergo full assessment including medical and treatment history for ET, physical examination and other screening assessments. Patients with the diagnosis of ET based on the Movement Disorder Society (MDS) criteria with a documented severity of tremor based on the clinician-administered TETRAS Performance Subscale are eligible to be enrolled in the study. The study consists of treatment groups receiving twice daily oral dosing of CAD-1883 for a treatment period of 14 days.

This study is designed to enable the assessment of safety and tolerability of CAD-1883 in patients with ET as well as the determination of early treatment effect on reducing the magnitude and severity of tremor while limiting the potential risk associated with a novel investigational drug.

Safety and tolerability will be monitored throughout the study duration including in-clinic assessments of adverse events (AEs), serious adverse events (SAEs), vital signs, 12-lead ECG, urinalysis, hematology, clinical chemistry, and CAD-1883 plasma concentration level on Days 1, 7, 14 and 21.

Efficacy will be evaluated using the clinician-administered TETRAS Performance Subscale as well as the use of a wearable sensor in the clinic and at home.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 25 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2a Open-Label Study to Evaluate the Safety, Tolerability and Efficacy of CAD-1883 Oral Treatment in Adults With Essential Tremor
• Actual Study Start Date: January 23, 2019
• Actual Primary Completion Date: September 10, 2019
• Actual Study Completion Date: September 24, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Open-label study of CAD-1883; Open-label study designed to evaluate the safety, tolerability, and efficacy of CAD-1883 administered twice daily orally to adult subjects with ET	Drug: CAD-1883; Treatment groups receiving twice-daily oral dosing of CAD-1883 for a treatment period of 14 days.

Outcome Measures

Primary Outcome Measures :

1. Evaluate the occurrence and severity of treatment emergent AEs. [ Time Frame: 21 days after first treatment ]
   Evaluate the occurrence and severity of treatment emergent AEs.
2. Evaluate the occurrence and severity of treatment emergent AEs. [ Time Frame: 7 days after the last treatment ]
   Evaluate the occurrence and severity of treatment emergent AEs.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Adult subjects aged between 18 and 75 years old, inclusive, with history of tremor that fulfills the diagnostic criteria of ET according to Movement Disorder Society (MDS) Consensus Statement on the classification of tremors from the task force on tremor of the International Parkinson and Movement Disorder Society (Bhatia, 2018).
2. Duration of ET illness since the first symptoms were noticeable of at least 3 years or more prior to screening, based on the subject's self-report, with onset prior to age 65 years old, per the Principal Investigator's assessment during screening.
3. Except for ET, subjects must be otherwise healthy as determined by the Investigator, based upon a medical evaluation including medical history, physical examination, laboratory tests, and 12-lead ECG.
4. Subjects are able to understand study activities required, can give written informed consent, and are willing to comply with the requirements and restrictions of the study.
5. Women of childbearing potential must undertake a pregnancy test with documented negative serum pregnancy test at Screening and negative urine pregnancy test result at Pre-dose, Days 7 and 14 before administration of the study drug, and then at the Follow-up visit (Day 21).
6. Postmenopausal women must have had ≥365 days of spontaneous amenorrhea, with documented follicle-stimulating hormone (FSH) ≥38 IU/mL, prior to screening. If needed, per Investigator's judgment, FSH level can be performed at Screening.
7. Surgically sterile women must have documentation of a hysterectomy, bilateral ovariectomy, or bilateral tubal ligation.
8. Female subjects with reproductive potential and male subjects with reproductive potential or who have female partners of reproductive potential, must agree to use two effective methods of contraception from signing informed consent until 90 days after the last dose of study drug. Acceptable forms of contraception include double barrier (ie, condom with spermicide); surgically sterilized partner (180-day minimum); or abstinence.

Exclusion Criteria:

1. Prior or ongoing medical condition or any abnormal finding on the Screening visit physical exam, ECG, laboratory testing that, in the Investigator's opinion, could adversely affect the safety of the subject or the conduct of the study assessments.
2. Any neurological abnormality other than ET upon neurological exam, including dystonia, ataxia, or any other neurodegenerative disease, including multiple sclerosis or Parkinson's disease.
3. Significant cognitive impairment or dementia that, in the opinion of the Investigator, would interfere with participation in the study.
4. An unstable thyroid condition that, per the Investigator's judgment, has not stabilized over the past 90 days prior to screening. This includes current clinical history of hypo- or hyperthyroidism, thyrotoxicosis or significant abnormality of thyroid function testing at Screening.
5. History of, or evidence of psychogenic tremor at Screening.
6. History of anaphylaxis, hypersensitivity reactions (including to any of CAD-1883 excipients), or clinically significant drug allergies.
7. Alkaline phosphatase, aspartate aminotransferase (AST), and/or alanine aminotransferase (ALT) level >2.0 x upper limit of normal (ULN) at Screening and/or at Pre-dose.
8. Serum creatinine >120 μmol/L and/or creatinine clearance <60 mL/min (according to Cockcroft-Gault formula) at Screening and/or at Pre-dose.
9. Total bilirubin >2.0 x ULN at Screening and/or at Pre-dose. Note: isolated bilirubin >2.0 x ULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%.
10. History of Long QT syndrome and/or QTcF (Fridericia's correction) interval >450 msec (males) or >470 msec (females) per 12-lead ECG done at Screening.
11. History of Alcohol Use Disorder per Diagnostic Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) criteria.
12. History of human immunodeficiency virus (HIV) infection or positive screening result for: HIV 1 or 2 antibodies, hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb), or hepatitis C virus antibody (HCVAb).
13. Has a diagnosis of epilepsy or any history of seizure as an adult, head trauma, stroke, transient ischemic attack within 1 year prior to Screening, unexplained loss of consciousness within 1 year prior to Screening, or any lifetime history of asymptomatic or symptomatic orthostatic hypotension (eg, postural syncope).
14. History of unstable angina, myocardial infarction, chronic heart failure (New York Heart Association Class 3 or 4), or clinically significant conduction abnormalities (eg, unstable atrial fibrillation) within 1 year prior to screening.
15. Any major psychiatric disorder that is uncontrolled (for the past 90 days) that, per the Investigator's judgment, can interfere with any of the study procedures.
16. Subject has cancer, except for the following: basal cell carcinoma or successfully treated squamous cell carcinoma of the skin; cervical carcinoma in situ; prostatic carcinoma in situ; or other malignancies curatively treated and with no evidence of disease recurrence for at least 3 years.
17. Subjects with scheduled surgeries during the study period.

Contacts and Locations

Locations

United States, Alabama

Cadent Investigational Site

Anniston, Alabama, United States, 36207

United States, Arkansas

Cadent Investigational Site

Rogers, Arkansas, United States, 72758

United States, California

Cadent Investigational Site

San Diego, California, United States, 92103

United States, Florida

Cadent Investigational Site

Hallandale Beach, Florida, United States, 33009

United States, Michigan

Cadent Investigational Site

Farmington Hills, Michigan, United States, 48334

United States, Missouri

Cadent Investigational Site

Saint Louis, Missouri, United States, 63141

United States, Ohio

Cadent Investigational Site

Dayton, Ohio, United States, 45400

Sponsors and Collaborators

Cadent Therapeutics

More Information

• Responsible Party: Cadent Therapeutics
• ClinicalTrials.gov Identifier: NCT03688685 History of Changes
• Other Study ID Numbers: CAD1883-201
• First Posted: September 28, 2018
• Last Update Posted: October 23, 2019
• Last Verified: October 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Cadent Therapeutics:

ET; Essential Tremor

Additional relevant MeSH terms:

Tremor; Essential Tremor; Dyskinesias; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Movement Disorders; Central Nervous System Diseases