Part 1:Primary Objective- To assess the safety and tolerability of SBT-020 in early stage HD patients. Secondary Objective- To investigate the effect of SBT-020 on mitochondrial function, measured by dynamic 31P-MRS in calf muscles of early stage HD…
ID
Source
Brief title
Condition
- Movement disorders (incl parkinsonism)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Tolerability / safety endpoints
- AEs leading to premature discontinuation of study drug.
- Treatment-emergent (S)AEs up to 5 pharmacokinetic half-lives after study drug
discontinuation.
- Change from baseline to End-of-Study in vital signs: blood pressure and heart
rate.
- Treatment-emergent ECG abnormalities up to 5 pharmacokinetic half-lives after
study drug discontinuation.
- Treatment-emergent marked laboratory abnormalities up to 5 pharmacokinetic
half-lives after study drug discontinuation.
Pharmacokinetic endpoints
Part 1:
- Plasma SBT-020 concentration.
Part 2:
- Plasma SBT-020 concentration.
Pharmacodynamic endpoints
- Mitochondrial function by 31P-MRS
o Phosphocreatine recovery time (in seconds), measured by 31P-MRS in calf
muscles
o Difference between Pi/PCr ratio before, during and after visual stimulation,
measured by 31P-MRS in the brain
- Intensity of red-green fluorescence, measured by flow-cytometry in PBMCs
- Various exploratory plasma and urinary biomarkers for mitochondrial function
- Neuropsychological assessments (only included in part 2)
o total number of correct responses in 90 seconds on the Symbol Digit Modality
Test (SDMT)
o total number of correct responses in 45 seconds per trial on the Stroop
colour word interference test
o completion time in seconds and number of errors for each trial on the Trail
Making Test (TMT)
o total number correct on the Visual Verbal Learning Test (VVLT)
o the total number of (commission and omission) errors and the mean reaction
time of all correct response trials on the Sustained Attention
to Response Task (SART) test
o average performance (%) on the Adaptive Tracking task
- Motor function (only done during part 2)
o total motor score (TMS) (range 0-124) on the UHDRS
o total functional capacity score (TFC) score (range 0-13) on the UHDRS
o mean tapping rate and standard deviation on the Finger tapping test
o saccadic reaction time (seconds), saccadic peak velocity (degrees/second),
saccadic inaccuracy (%) on the Saccadic eye movements test
o percentage of time the eyes are in smooth pursuit of the target (%) on the
Smooth pursuit test
o antero-posterior sway (in mm) on the Bodysway test
Secondary outcome
Not Applicable
Background summary
Huntington*s disease (HD) is an autosomal dominant inherited neurodegenerative
disorder characterized by a triad of symptoms including motor disturbances,
cognitive dysfunction and psychiatric symptoms (1-3). There is strong evidence
that mitochondrial dysfunction is part of the pathogenesis of HD.
Pharmacologically inhibiting succinate dehydrogenase in rodent and primates,
thereby inhibiting complex II of the mitochondrial electron transport chain,
resulted in pathology and symptomatology resembling HD (4, 5). Furthermore, in
vitro research has shown that mutant huntingtin inhibits the import of nuclear
coded mitochondrial proteins and down regulates the activity of
peroxisome-activated receptor gamma (PPAR*), required for mitochondrial
biogenesis (6). Using dynamic in vivo 31 phosphorus Magnetic Resonance
Spectroscopy (31P-MRS) in the calf muscles it has been shown that HD patients
exhibit a prolonged phosphocreatine recovery time (*PCr) compared to healthy
controls, which can be translated into a reduduced mitochondrial function in HD
patients (7, 8). Mitochondrial function in HD patients might therefore be
beneficial for the disease progression by maintaining the energy level inside
the striatum cells and thus preventing cell death. SBT-020 is an experimental
mitochondrial function enhancing agent, which has showed promising results in
pre-clinical animal models. While the exact mechanism of action is not
completely understood, it is hypothesized that the compound can improve the
mitochondrial function in HD patients, thereby slowing neuronal degeneration
and disease progression.
Study objective
Part 1:
Primary Objective
- To assess the safety and tolerability of SBT-020 in early stage HD patients.
Secondary Objective
- To investigate the effect of SBT-020 on mitochondrial function, measured by
dynamic 31P-MRS in calf muscles of early stage HD patients.
- To assess the pharmacokinetics of SBT-020 in plasma in early stage HD
patients.
- To assess the pharmacokinetics of SBT-020 (and SBT-020-related components) in
urine in early stage HD patients.
- To investigate the effect of SBT-020 on mitochondrial function, by measuring
the mitochondrial membrane potential (MMP) in isolated peripheral blood
mononuclear cells (PBMCs).
Part 2:
Primary Objective
- To assess the safety and tolerability of longer term treatment with SBT-020
in early stage HD patients.
Secondary Objective
- To investigate the effect of SBT-020 on mitochondrial function, measured by
dynamic 31P-MRS in calf muscles of early stage HD patients.
- To investigate the effect of SBT-020 on bioenergetic profile, measured by
31P-MRS in the brain of early stage HD patients.
- To assess the plasma concentration of SBT-020 in plasma in early stage HD
patients.
- To investigate the effect of SBT-020 on mitochondrial function, by measuring
the MMP in PBMCs.
- To investigate the effect of SBT-020 on an exploratory set of urinary and
plasma biomarkers related to mitochondrial function in early stage HD patients.
- To investigate effects of SBT-020 on cognition and other CNS functions, using
the NeuroCart test battery.
- To investigate effects of SBT-020 on motor functioning, using the NeuroCart
test battery and unified Huntington*s disease rating scale.
Study design
- Part 1: A randomized, double-blind, placebo-controlled, repeat dose study of
SBT-020 administered subcutaneously for 7 Days
- Part 2: A randomized, double-blind, placebo-controlled, repeat dose study of
SBT-020 administered subcutaneously for 28 Days
Intervention
SBT-020 or placebo subcutaneously
Study burden and risks
As shown the first in man study, single and multiple doses of SBT-020 were
generally safe and well tolerated at all dose levels when administered by SC
injection to healthy male and female subjects. There were no serious or severe
IMP-related AEs recorded during the study; 3 subjects were withdrawn as a
result of unrelated AEs. Overall, the incidence of AEs was low in Part 1 and
slightly higher in Part 2; with injection site reactions reported most
frequently. The current study will establish safety and PK data in the target
population, therefore being the first step into bringing forth the first
medical intervention in Huntington*s Disease. With the chosen methods (i.e.
31P-MRS) the proof of pharmacology of SBT-020 could be established, thus
showing the ability to improve mitochondrial function and expanding the range
of target populations.
275 Grove Street 3-107
Newton MA 02466
US
275 Grove Street 3-107
Newton MA 02466
US
Listed location countries
Age
Inclusion criteria
1. Male or female patient with a DNA confirmed diagnosis (CAG expansion of 36 or more repeats in the HTT gene) of HD
2. At least 18 years of age
3. Unified Huntington*s Disease Rating Scale (UHDRS) Total Motor Score (TMS) of 5 or more
4. Unified Huntington*s Disease Rating Scale (UHDRS) Total Functional Capacity Score (TFC) of 7 or more
5. tPCr of at least 32.4 seconds, measured by dynamic 31P-MRS of the calf muscles.
6. Absence of evidence of any significant active or chronic disease (apart from HD), following a detailed medical and surgical history, a complete physical examination including vital signs, 12-lead ECG, haematology, blood chemistry, and urinalysis, that might interfere with the study activities or patient*s safety by participating in the study, as judged by the investigator. Psychiatric comorbidities to HD (such as a major depressive disorder), are allowed under the scrutiny of the investigator.
7. Agrees to refrain from making any new, major life-style changes (e.g. starting a new diet or changing their exercise pattern)
8. Must agree to use adequate methods of contraception. Female subjects of childbearing potential must use two adequate forms of contraception, one of which must be a barrier method for the duration of the study and for 30 days after the last dose. Male subjects with a partner of childbearing potential must use two adequate forms of contraception, one of which must be a barrier method, for the duration of the study and for 30 days after the last dose.
9. Able to participate and willing to give written informed consent and to comply with the study restrictions.
Exclusion criteria
1. Positive test for drugs of abuse, such as metamphetamines and cocaine, at screening or pre-dose, except those prescribed by a physician for treatment of intercurrent medical issues due to HD.
2. History (within 3 months of screening) of alcohol consumption exceeding 2 standard drinks per day on average. Alcohol consumption will be prohibited during study confinement and at least 24 hours before screening and before each scheduled visit.
3. History of active malignancy within the last 5 years, with the exception of localized or in situ carcinoma (e.g., skin basal or squamous cell carcinoma).
4. Positive Hepatitis B surface antigen (HBsAg), Hepatitis C antibody (HCV Ab), or human immunodeficiency virus antibody (HIV Ab) at screening.
5. Aspartate transaminase (AST), alanine transaminase (ALT), gamma glutamyl transferase (GGT) or total bilirubin levels >1.5 times the upper limit of normal at screening.
6. eGFR < 60 mL/min (calculated by the Modification of Diet in Renal Disease equation) at Screening.
7. Clinically significant abnormalities, as judged by the Investigator, in laboratory test results (including hepatic and renal panels, complete blood count, chemistry panel and urinalysis). In the case of uncertain or questionable results, tests performed during screening may be repeated before randomization to confirm eligibility or judged to be clinically irrelevant for HD patients.
8. Participation in an investigational drug or device study within 3 months prior to screening.
9. Loss or donation of blood over 500 mL within three months (males) or four months (females) prior to screening.
10. Concomitant disease or condition that could interfere with, or for which the treatment of might interfere with, the conduct of the study, or that would, in the opinion of the Investigator, pose an unacceptable risk to the subject in this study.
11. Presence of any contraindication to have MRI scans performed (e.g. claustrophobia, pacemaker, vascular clips etc.). MRI contraindications for both the 7 Tesla (part 1 and 2) and 3 T (part 2 only) MRIs will be assessed, using MRI contra-indications questionnaires and, if necessary, a plain radiograph.
12. Unwillingness to refrain from smoking more than half pack cigarettes per day (i.e. 10 units).
13. Specific cardiac abnormalities on the resting ECG at screening: QTcF> 450 or < 300 msec, evidence of atrial fibrillation, atrial flutter, complete branch block, Wolf-Parkinson-White Syndrome, or cardiac pacemaker.
14. Any confirmed significant allergic reactions (urticaria or anaphylaxis) against any drug, or multiple drug allergies (non-active hay fever is acceptable).
15. Unwillingness or inability to comply with the study protocol for any other reason.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-003730-25-NL |
| CCMO | NL59198.056.16 |