| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| A progressive neurodegenerative disorder that affects the involuntary nervous system and movement. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10064060 |
| E.1.2 | Term | Multiple system atrophy |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• To evaluate the efficacy of BHV-3241, compared to placebo, as measured by a change from baseline in a modified Unified MSA Rating Scale (UMSARS), consisting of a subset of items from Part I and Part II, at Week 48.
• To assess the safety and tolerability of BHV-3241, relative to placebo, in subjects with MSA. |
|
| E.2.2 | Secondary objectives of the trial |
Key Secondary
• To evaluate the efficacy of BHV-3241, compared to placebo, as
measured by the Clinical Global Impression of Improvement (CGI-I)
score at Week 48
•To evaluate the impact of BHV-3241 on quality of life, compared to
placebo, as measured by a change from baseline in the motor subscale
of the MSA-Quality of Life (MSA-QoL) scale at Week 48
• To evaluate the impact of BHV-3241 on quality of life, compared to
placebo, as measured by a change from baseline in the non-motor
subscale of the MSA- QoL scale at Week 48.
•To evaluate the efficacy of BHV-3241, compared to placebo, as
measured by a change from baseline in the UMSARS Part I and Part II
total score at Week 48.
Other Secondary
• To assess the impact of BHV-3241, relative to placebo, as measured by
a change from baseline at Week 48 in the following instruments:
- Patient Global Impression of Severity (PGI-S),
- Clinical Global Impression of Severity (CGI-S),
- UMSARS Part III
- UMSARS Part IV |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Title:Optional Cerebrospinal fluid (CFS) sub-study
Objective: To evaluate BHV-3241 PK concentrations and PD biomarkers in
the CSF at Baseline and second at Week 48 or early withdrawal.
Potential Exploratory CSF analytes may include concentrations of BHV-3241 and neurofilament light chain (NfL).
|
|
| E.3 | Principal inclusion criteria |
Informed Consent
a. Subjects must provide a written signed and dated informed consent
form/forms (IRB/EC specific)in accordance with regulatory and
institutional guidelines prior to the initiation of any protocol required
procedures. Only patients with the capacity to understand the nature ,
significance, and scope of the clinical trial interventions and to express
their wishes accordingly may provide consent to participate in the study.
b. Caregivers must be willing to sign and date an IRB/EC-approved
written informed consent form that outlines the caregiver expectations
and responsibilities in this study in accordance with regulatory and
institutional guidelines, as appropriate.
Age and Sex
a. Male and female subjects between the ages of > or = 40 to = or <80
years at time of Screening.
Target Population
a. Diagnosis of probable or possible MSA according to consensus clinical
criteria including subjects with MSA of either subtype (MSA-P or MSA-
C).
b. Able to ambulate without the assistance of another person, defined as
the ability to take at least 10 steps. Use of assistive devices is allowed.
c. Anticipated survival of at least 3 years at the time of Screening, as
judged by the Investigator.
d. A brain MRI scan (conducted within the 14 days prior to Baseline/Day
1, approximately) that does not rule out a diagnosis of MSA.
e. Able to tolerate MRI.
f. Body mass index (BMI) = or < 40 kg/m2at Screening.
g. Able to swallow tablets whole and anticipated to be able to do so
throughout the duration of the study.
h. Willing and able to adhere to the study drug regimen.
i. Willing and able to perform all protocol-specified assessments and
comply with the study visit schedule.
j. Able to read, understand, and speak local language fluently to ensure
comprehension of informed consent and protocol-specified assessments.
k. Must have reliable caregiver to accompany subject to study visits.
With the same Caregiver giving caregiver completing assessments at
Baseline, Week 24 and Week 48/ Early discontinuation, when possible.
Caregiver must be able to read, understand, and speak local language
fluently to ensure comprehension of informed consent and protocol-
specified assessments. Caregiver must also have frequent contact with
subject (at least 3 hours per week at one time or different times) and be
willing to monitor the subject's health and concomitant medications
throughout the study.
l. If subject is receiving treatment for MSA, the doses must have been
stable for at least 30 days prior to Baseline/Randomization and
medication present at Baseline. expected to remain relatively stable during the study period. This may include medications commonly used
for Parkinson's disease or those for autonomic dysfunction.
m. Stable on other chronic medications and supplements for at least 30
days prior to Baseline/Randomization and expected to remain relatively
stable during the study period..
n. Women of child bearing potential (WOCBP) and fertile men (including
those vasectomized for less than 6 months) with female partners who
are WOCBP (not surgically sterile and not post-menopausal) must agree
to use highly effective birth control, including two methods of
contraception, for the duration of the study (beginning 30 days prior to
Baseline/Randomization and extending to 30 days for women and 90
days for men after the last dose of study drug). The two methods of
contraception should include:
- one barrier method (e.g. diaphragm with spermicide, condom with
spermicidal gel, cervical cap);
- and one other method that could include hormonal contraceptives (e.g.
oral contraceptives, injectable contraceptives, contraceptive implant,
patch) used for at least 4 weeks prior to sexual intercourse.
o. WOCBP must have a negative serum pregnancy test at Screening and
a negative urine pregnancy test within approximately 24 hours prior to
dosing at Baseline/Randomization.
|
|
| E.4 | Principal exclusion criteria |
Target Disease Exceptions
a. Subjects having advanced disease as defined in the protocol.
b. Subjects having significant cognitive impairment, defined by a score of
less than or equal to 20 on the MoCA
Medical History Exclusions
a. Any condition that would interfere with the subject's ability to comply
with
study instructions, place the subject at unacceptable risk, and/or
confound the
interpretation of safety or efficacy data from the study, as judged by the
Investigator.
b. Diagnosis of neurological disorders, other than MSA as defined in the
protocol
c. History of or Screening brain MRI scan indicative of significant
abnormality.
d. Contraindication to MRI examination for any reason.
e. For optional CSF sub-study: contraindication to undergoing an LP.
f. Presence of clinically significant thyroid disease with abnormal free T4
levels and TSH >10mIU/L (despite treatment) at Screening , confirmed
by repeat.
g. Within 1 year prior to Screening or between Screening and Baseline
(Day -1), any of the following: myocardial infarction; hospitalization for
congestive heart failure; hospitalization for, or symptoms of, unstable
angina; or syncope not related to MSA.
h. Diagnosis of clinically significant psychiatric disorder as defined in the
protocol.
i. History of substance use disorder (drug or alcohol) in the last 12
months, with
the exception of nicotine, as defined by DSM-V criteria.
j. History or presence of gastrointestinal or other disease known to
interfere with absorption, distribution, metabolism, or excretion of
drugs, or a history of surgery known to interfere with absorption or
excretion of drugs (i.e. gastric bypass).
k. History of any other clinically significant disease that, based on the
judgment of the Investigator, is clinically unstable, is likely to
deteriorate during the course of the study, could put the patient at risk
because of participation in the study, could affect the subject's ability to
complete the study, or could influence the study results.
l. History of human immunodeficiency virus infection.
m. Hematologic or solid malignancy diagnosis within 5 years prior to
Screening.
n. Any major surgery within 4 weeks of Screening.
o. Blood transfusion within 4 weeks of Screening.
p. History of brain surgery for Parkinsonism.
q. History of stem-cell treatment.
r. Women who are pregnant or breastfeeding.
s. Subjects or prisoners who are involuntarily detained or incarcerated
for treatment of either a psychiatric or physical illness must not be
enrolled into the study.
t. Any medical condition, based on the judgement of the Investigator,
that would confound the ability to adequately assess safety and efficacy
outcome measures
Physical and Laboratory Test Findings
a. Evidence of organ dysfunction or any clinically significant deviation
from normal in physical examination, vital signs, ECG, or clinical
laboratory determinations beyond what is consistent with the target
population.
b. Clinically significant abnormality on 12-lead ECG prior to study drug
administration beyond what is consistent with the target population,
confirmed by repeat.
c. QTcF (Fridericia) interval ≥ 470 msec during the Screening/Baseline
period or uncontrolled arrhythmia or frequent premature ventricular
contraction (PVCs) (> 5/minute) or Mobitz Type II second or third
degree atrioventricular (AV) block or left bundle branch block, or right
bundle branch block with a QRS
duration ≥ 150 msec or intraventricular conduction defect with a QRS
duration ≥ 150 msec or evidence of acute or sub-acute myocardial
infarction or ischemia or other ECG findings that, in the Investigator's
opinion, would preclude participation in the study.
d. Abnormal free T4 levels and TSH >10mIU/L (despite treatment) at
Screening, confirmed by repeat.
e. Total bilirubin, alanine aminotransferase (ALT) or aspartate
aminotransferase (AST) greater than 2 times the upper limit of normal
(ULN), confirmed by repeat. If the patient has Gilbert's Syndrome, the
patient can be discussed with the Medical Monitor.
f. Pathologic renal findings at Screening as defined in the protocol.
g. Hematologic abnormalities at Screening as defined in the protocol.
h. Hemoglobin A1C = or >7.5%, confirmed by repeat.
i. Urine drug screen positive for a drug of abuse, for which the patient
does not have a valid prescription and is suspected of abusing, in the
judgement of the investigator.
j. Human Immunodeficiency Virus (HIV) positive at Screening (indicated
by positive confirmatory Western Blot).
k. HBsAg or HCV positive at Screening.
l. For WOCBP, positive serum β-hCG which is indicative of pregnancy and
not false positive at screening or positive urine test at Baseline
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Change from baseline in a modified UMSARS score, based on a subset
of items from Part I and II, at Week 48.
• The frequency of unique subjects with: serious adverse events;
adverse events leading to discontinuation; adverse events judged to be
related to study medication; clinically significant ECG abnormalities and
clinically significant laboratory abnormalities. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Efficacy:
Unified MSA Rating Scale (UMSARS) Parts I-II - Screening, Baseline, Wks 4, 12, 24, 36, 48 or early discontinuation or from week 48-60 due to covid delays
Safety:
Physical Examination; Vital Signs; Sheehan Suicidality Tracking Scale -
Screening, Baseline, Wks 2, 4, 12, 24, 36, 48 or Early Discontinuation or from week 48-60 due to covid delays.
Physical Measurements - Screening, Baseline, Wk48 or Early Discontinuation or from week 48-60 due to covid delays.
ECG (12-lead); Laboratory Tests; Pregnancy Test - Screening, Baseline,
Wk 4, 12, 24, 36, 48 or Early Discontinuation or from week 48-60 due to covid delays.
SAE/AEs - throughout the study
|
|
| E.5.2 | Secondary end point(s) |
Key Secondary
• The CGI-I score at Week 48.
• Change from Baseline in MSA-QoL motor subscale at Week 48.
• Change from Baseline in the non-motor subscale at Week 48.
• Change from Baseline UMSARS Part I and II total at Week 48.
Other Secondary
• Change from baseline at Week 48 on the following instruments:
- PGI-S,
- CGI-S,
- UMSARS Part III,
- UMSARS Part IV. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Clinical Global Impression of Improvement (CGI-I)- Wks 4, 12, 24, 36, 48 or Early Discontinuation or from week 48-60 due to covid delays.
• MSA QoL at Baseline and Weeks 24 and 48 or Early Discontinuation or from week 48-60 due to covid delays
• UMSARS (Part I - IV) - Screening, Baseline, Wks 4, 12, 24, 36, 48 or early discontinuation or from week 48-60 due to covid delays
• Patient Global Impression of Severity (PGI-S) - Baseline, Wks 4, 12, 24, 36, 48 or Early Discontinuation or from week 48-60 due to covid delays
• Clinical Global Impression of Severity (CGI-S) - Baseline, Wks 4, 12, 24, 36, 48 or Early Discontinuation or from week 48-60 due to covid delays |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Austria |
| China |
| France |
| Germany |
| Italy |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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