An Open Pilot Trial of BHV-4157

Brief Title

Open Pilot Trial of BHV-4157

Official Title

An Open Pilot Trial of BHV-4157 in Adult Subjects With Cerebellar Ataxia

Brief Summary

      24 adults, between the ages of 18 and 75 years, with cerebellar ataxia will be enrolled in a
      12 week trial of BHV-4157 for treatment of ataxia. BHV-4157 is a pro-drug of riluzole (which
      is currently FDA-approved for ALS, Lou Gehrig's disease). There will be 5 visits to UCLA
      required--Screening when general and neurological examination, blood and urine testing, ECG,
      and questionnaires will be administered; Baseline when general and neurological examination
      and questionnaires will be administered and study drug dispensed; Week 4 and Week 12 when
      general and neurological examination, blood and urine testing, ECG, and questionnaires will
      be administered; 2 weeks after finishing study drug when general examination and blood
      testing will be completed. There is an option for a 36 week extension of the study drug
      trial.
    


Study Phase

Phase 3

Study Type

Interventional


Primary Outcome

Scale for the Assessment and Rating of Ataxia

Secondary Outcome

 8-Meter Walk Test

Condition

Spinocerebellar Ataxias

Intervention

BHV-4157

Study Arms / Comparison Groups

 Open Arm
Description:  All subjects will receive the same dosage throughout the study.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

24

Start Date

December 15, 2017

Completion Date

September 2024

Primary Completion Date

April 2024

Eligibility Criteria

        Inclusion Criteria:

          1. Informed Consent a. Subjects (or legally acceptable representative as required by the
             IRB/IEC) must provide a written signed informed consent form/forms (IRB/EC specific)
             prior to the initiation of any protocol required procedures.

          2. Age and Sex a. Male and female outpatient subjects between the ages of 18 - 75,
             inclusive

          3. Target Populations

             a. Subjects with (1) a known or suspected diagnosis of a specific hereditary ataxia:
             SCA3/dizziness-predominant or SCA1, SCA2, SCA3, SCA6, already taking Riluzole for more
             than 8 weeks; (2) non-genetic pure cerebellar ataxia; (3) MSA-C: i. SCA subjects
             should have confirmed genotypic diagnosis from a CLIA-certified lab or a family member
             that has had such testing.

             ii. Alternatively, subjects must be willing to undergo genetic testing from a
             CLIA-certified lab if testing has not been previously done on the study subject and a
             copy of results is not available for verification.

             b. Ability to ambulate 8 meters without assistance (canes and other devices allowed);
             c. Determined by the investigator to be medically stable at Baseline as assessed by
             medical history, physical examination, laboratory test results available in medical
             record, and electrocardiogram testing available in medical record. Subjects must be
             physically able and expected to complete the trial as designed; d. Minimum of 6 years
             of education; e. Subjects must have adequate hearing, vision, and language skills to
             perform interviews as specified in the protocol; f. Subjects must be able to
             understand and agree to comply with the prescribed dosage regimens and procedures;
             report for regularly scheduled office visits; and reliably communicate with study
             personnel about adverse events and concomitant medications; g. Women of childbearing
             potential (WOCBP) and men must be using an acceptable method of contraception to avoid
             pregnancy throughout the study and for up to 30 day after the last dose of
             investigational product in such a manner that risk of pregnancy is minimized. The
             requisite drug interaction studies to determine the interaction of BHV-4157 with oral
             contraceptives have not been performed to date. It is therefore not possible to
             determine the efficacy of oral contraceptives as an effective method of contraception
             for WOCBP who participation this study. Oral estrogen and progestin hormonal
             contraceptives as a sole method of contraception are therefore prohibited. It is
             required that all WOCBP use two methods of contraception for the duration of the study
             (i.e. beginning at first treatment to 30 days after the last dose of study drug).The
             two methods should include one barrier method (ex. condom with spermicidal gel,
             intrauterine devices, cervical cap etc.) and one other method. The other method could
             include oral contraceptives or another barrier method.

             h. Women of childbearing potential must have a negative serum pregnancy test at
             screening and a negative urine pregnancy test within 72 hours of dosing.

             i. SCA subjects (SCA3/dizziness predominant; SCA1, 2, 3, 6 on Riluzole for more than 8
             weeks) will not be limited to Inclusion Criteria of Screening SARA score ≥8 or Score
             of ≥ 2 on gait subsection of the SARA.

             j. Non-genetic pure cerebellar and MSA-C subjects will be limited to Inclusion
             Criteria of Screening SARA score ≥8 or Score of ≥ 2 on gait subsection of the SARA.

             Exclusion Criteria:

          1. Target Disease Exceptions

             a. Any medical condition other than one of the hereditary ataxias specified in the
             inclusion criteria that could predominantly explain or contribute significantly to the
             subjects' symptoms of ataxia (for example, alcoholism, vitamin deficiencies, multiple
             sclerosis, vascular disease, tumors, paraneoplastic disease, head injury, idiopathic
             late onset ataxia, multisystem atrophy) or that can confound assessment of ataxia
             symptoms (for example, stroke, arthritis); b. MMSE score < 24; c. Subjects with
             prominent spasticity or dystonia that meet either of the following criteria: i. In the
             opinion of the investigator will compromise the ability of the SARA instrument to
             assess underlying ataxia severity; or, ii. Are associated on the INAS instrument at
             screening with moderate or severe scores on dystonia (at least 3 of 5 items) or
             spasticity (at least 2 of 3 items) or rigidity (at least 2 of 3 items) d. SARA total
             score of > 30 points at screening; e. Subjects may not have started physical or
             occupational therapy within one month of screening and are not expected to start such
             therapy during the initial 12 week treatment phase. Subjects with ongoing occupational
             or physical therapy may be allowed to continue as long as the intensity remains
             unchanged from two months prior to screening throughout the randomization period.

          2. Medical History Exclusions

             a. Clinical history of stroke. Note: Subjects with a history of transient ischemic
             attack (TIA) may be enrolled, if it occurred at least 3 months prior to screening and
             the subject is prescribed appropriate treatment [e.g., platelet aggregation
             inhibitors]; b. Immunocompromised subjects. Note: Subjects taking a systemic
             immunosuppressive agent may enter treatment phase if they are on a stable dose, have
             no clinically relevant immunosuppression, and have a white blood count (WBC) within
             normal limits; c. Active liver disease or a history of hepatic intolerance to
             medications that in the investigator's judgment, is medically significant; d. History
             of medically significant gastrointestinal (GI) illnesses including: i. A current
             diagnosis of active, peptic ulceration or gastrointestinal bleeding within the last 6
             months and/or chronic inflammatory bowel disease at screening; ii. A history of any
             gastrointestinal surgery that impacts the absorption of study drug; iii. Chronic or
             frequent episodes of loose stools; bowel movements; e. Vitamin B12 or folate
             deficiency Note: Subjects with a B12 deficiency can participate in the study if they
             are on stable Vitamin B12 replacement for at least 3 months prior to randomization and
             their B12 levels are within normal limits prior to randomization; f. Hematologic or
             solid malignancy diagnosis within 5 years prior to screening. (Note: Subjects with a
             history of localized skin cancer, basal cell or squamous cell carcinoma, may be
             enrolled in the study as long as they are cancer free prior to randomization. Subjects
             with other localized cancers (without metastatic spread) who have previously completed
             their course of treatment more than 2 years prior to baseline, are not currently
             receiving treatment and have been in remission may be enrolled only if, in the opinion
             of the investigator, there is no expectation for recurrence or further cancer
             treatment during the study period. Antihormonal therapy (e.g., tamoxifen) is allowed
             if the subject's cancer is in remission and the subject is on maintenance therapy to
             reduce their risk of recurrence; g. Any unstable cardiovascular (includes uncontrolled
             hypertension), pulmonary, gastrointestinal, or hepatic disease 30 days prior to
             screening; h. End-stage cardiovascular disease (e.g., Congestive Heart Failure New
             York Heart Association/CHF NYHA Class III or IV or unstable angina); i. Treated for,
             or have had a lifetime diagnosis of, schizophrenia or bipolar disorder; j. Active
             major depressive episode within the past 6 months. Note: Subjects on a stable
             maintenance dose of a non- tricyclic, non-monoamine oxidase inhibitor (MAOI)
             antidepressant medication (e.g., serotonin reuptake inhibitor, bupropion) with
             symptoms in remission may be eligible; k. History of neurosyphilis (as indicated by a
             positive rapid plasma reagin [RPR] test and a positive confirmatory test); l. History
             of drug or alcohol abuse within 12 months as defined by DSM-IV-TR-TR criteria; m.
             History or evidence of any medical, neurological or psychological condition that would
             expose the subject to an undue risk of a significant adverse event or interfere with
             assessments of safety and efficacy during the course of the trial as determined by the
             clinical judgment of the investigator; n. History of chronic pulmonary disease or
             chronic pulmonary symptoms

          3. Physical and Laboratory Test Findings

             a. Uncontrolled hypertension at screening (e.g., repeated diastolic measurements ≥ 96
             mmHg); b. Subjects with history of hypothyroidism may participate in the study,
             provided they are euthyroid on stable thyroid replacement therapy for at least 3
             months prior to Baseline, and therapy is expected to remain stable during the course
             of the study; c. Hepatic test abnormalities at screening: i. Aspartate
             Aminotransferase (AST), Alanine Aminotransferase (ALT) or GGT > 2 times the upper
             limit of normal; or ii. Total bilirubin > 2 times the upper limit of normal (ULN); d.
             If diabetic, HbA1C > 7.5% within 3 months of screening; e. Pathologic renal findings
             at screening as defined by the presence of either of the following criteria within 3
             months of screening: i. Estimated glomerular filtration rate (eGFR) according to the
             re-expressed abbreviated (four- variable) Modification of Diet in Renal Disease (MDRD)
             Study equation < 30 ml/min/ 1.73m2; The MDRD estimation is calculated as follows: eGFR
             (mL/min/1.73m2) = 175 x (standardized Scr)-1.154 x (Age)-0.203 x (0.742 if female) x
             (1.212 if Black). [Scr: Standardized serum creatinine] ii. Quantitative urine
             protein/creatinine ratio greater than 0.2. This test may be repeated if clinically
             indicated. In the event of a urinary tract infection (UTI), the test may be repeated
             after the UTI has resolved; f. Hematologic abnormalities within 3 months of screening:
             i. Hemoglobin < 10 g/dL; or ii. WBC < 3.0 x 103/mm3; or iii. Platelet count <
             100,000/mm3; g. QTc (Bazett's) and QTc (Fridericia) interval > 480 msec within 3
             months of screening and confirmed by repeat measurement or uncontrolled arrhythmia or
             frequent premature ventricular contraction (PVCs) (> 5/minute) or Mobitz Type II
             second or third degree atrioventricular (AV) block or evidence of acute or sub-acute
             myocardial infarction or ischemia. [Note: Subjects with MRI compatible pacemakers or
             bundle branch block (BBB) and a paced QTc (Fridericia) < 480 msec and a stable cardiac
             status may be enrolled after obtaining a cardiology consult. It must be determined by
             the consulting cardiologist that the subject's cardiac status is stable and does not
             pose a risk for participation in the trial.]

          4. Prohibited Treatments and/or Therapies

               1. History of not tolerating treatment with riluzole for any reason

               2. Treatment with riluzole in the 30 days prior to screening and/or during the
                  study; [with the exception of the switch group of SCA subjects].

               3. Prior trial of riluzole treatment of at least 8 weeks duration ; [with the
                  exception of the switch group of SCA subjects].

               4. Use of chlorzoxazone is prohibited 30 days prior to screening and during the
                  study;

               5. Use of aminopyridine is prohibited 30 days prior to screening and during the
                  study;

               6. Use of tricyclic antidepressants and mono-amine-oxidase (MAO) inhibitors are
                  prohibited 30 days prior to screening and during the study;

               7. Use of any approved treatments for Alzheimer's Disease (AD). Subjects should be
                  free of such medications (donepezil, galantamine, rivastigmine and memantine) for
                  at least 3 months prior to Baseline with no plans to start such medications
                  during the study; or, subjects should be on stable doses of these medications for
                  at least 3 months prior to the baseline visit;

               8. Use of memantine is prohibited 30 days prior to screening and during the study;

               9. A new anxiolytic or sleep medication not taken at a stable dose within 30 days
                  prior to screening. Note: Low dose anxiolytic pre-medications prior to diagnostic
                  testing (e.g., MRI) as well as sleep medications taken prn (as needed) are
                  allowed;

              10. Chronic NSAID use (e.g., naproxen, acetylsalicylic acid, ibuprofen) should be
                  treated with proton pump inhibitors unless otherwise clinically prohibited;

              11. Medical marijuana use within 30 days of baseline visit (and subjects will be
                  expected to refrain from use during the period of the study).
      

Gender

All

Ages

18 Years - 75 Years

Accepts Healthy Volunteers

No

Contacts

, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT03408080

Organization ID

17-001508


Responsible Party

Sponsor

Study Sponsor

University of California, Los Angeles


Study Sponsor

, , 


Verification Date

June 2022