The primary efficacy objective for this study is to evaluate the efficacy of RO7234292 compared with placebo.The secondary efficacy objective for this study is to evaluate the efficacy of RO7234292 compared with placebo.The safety objective for this…
ID
Source
Brief title
Condition
- Movement disorders (incl parkinsonism)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Efficacy: change from baseline in the composite Unified Huntington's Disease
Rating Scale (cUHDRS) score at Week 101.
Biomarker: change from baseline in CSF mHTT protein level at Week 101.
Secondary outcome
Efficacy:
Change from baseline in scores for the following individual scales at Week 101:
- TFC
- Total Motor Score (TMS)
- Symbol Digit Modalities Test (SDMT)
- Stroop Word Reading Test (SWR)
Change from baseline in the Clinical Global Impression, Severity Scale (CGI-S)
score at Week 101:
- Proportion of patients with a decrease from baseline of > 1 point on the TFC
at Week 101
- Proportion of patients with a decline from baseline of > 1.2 points on the
cUHDRS at Week 101
- Proportion of patients with an unchanged or improved score on the Clinical
Global Impression, Change Scale (CGI-C) score from baseline at Week 101
Biomarker:
- Change from baseline in whole and regional brain volumes (caudate, whole
brain, and ventricular), as determined by structural magnetic resonance imaging
(MRI), at Week 101
- Change from baseline in CSF neurofilament light chain (NfL) protein level at
Week 101
For exploratory, safety, PK and immunogenicity endpoints, please see protocol
section 2.
Background summary
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease
caused by expansion of CAG repeats in exon 1 of the Huntingtin HTT gene on
chromosome 4, which encodes for a mutant huntingtin (mHTT) protein. Based upon
nonclinical and clinical evidence, mHTT is considered the primary driver of HD
pathophysiology. Individuals who carry at least 40 CAG repeats inevitably
experience progressive motor, cognitive, and functional decline usually in
adult life, with a mean age of motor onset of 45 years. The average illness
course post-motor onset is approximately 10-20 years, with pneumonia, heart
failure, or other complications frequently cited as the cause of death.
Individuals with end-stage disease have complete physical disability and
profound body wasting.
Currently approved treatments aim to reduce the burden of symptoms, maximize
function, and improve the patient's quality of life. To date, there are no
approved treatments able slow or stop the clinical progression of HD. The ASO
RO7234292 is designed to target the cause of HD and offers the potential to
meet this unmet medical need.
This study will evaluate the efficacy, safety, pharmacokinetic (PK), and
biomarker effects of RO7234292 compared with placebo in patients with manifest
HD.
Study objective
The primary efficacy objective for this study is to evaluate the efficacy of
RO7234292 compared with placebo.
The secondary efficacy objective for this study is to evaluate the efficacy of
RO7234292 compared with placebo.
The safety objective for this study is to evaluate the safety and tolerability
of RO7234292 compared with placebo.
The PK objective for this study is to characterize the RO7234292 PK profile in
plasma and trough CSF.
The immunogenicity objective for this study is to evaluate the immune response
to RO7234292.
The biomarker objective for this study is to evaluate the effects of RO7234292
compared with placebo.
Study design
Study BN40423 is a Phase III, randomized, placebo-controlled, double-blind,
multicenter clinical study to evaluate the efficacy, safety, PK, and biomarker
effects of intrathecally administered RO7234292 in patients with manifest HD.
Approximately 660 patients will be enrolled in the study.
Upon completion of the screening period, eligible patients will be randomly
allocated in a 1:1:1 ratio to receive RO7234292 every 8 weeks (RO7234292 Q8W
arm), RO7234292 every 16 weeks (RO7234292 Q16W arm), or placebo Q8W (placebo
arm) by IT injection, as described in Table 1 of the protocol.
To maintain the study blind and integrity, patients in the RO7234292 Q16W arm
will also receive placebo (i.e., alternating doses of active drug and placebo).
Patients will undergo safety and tolerability evaluations that include
neurologic examinations, vital signs, ECGs, clinical laboratory tests, MoCA,
C-SSRS, neuroimaging assessments (neurologic safety sequences), and adverse
events including related concomitant medications, as detailed in Appendix 1 of
the protocol.
Patients who complete the treatment period will return to the clinic for an
end-of-treatment visit at Week 101. Patients will then be given the option on
an individual basis of receiving RO7234292 in an OLE study (BN40955) upon
completion of Study BN40423, provided they meet eligibility criteria and the
data from the ongoing RO7234292 program support continued development.
Intervention
Patients are randomized in one of the following three arms in a 1: 1: 1 ratio:
- RO7234292 (RO7234292 Q8W arm);
- RO7234292 (RO7234292 Q16W arm); or
- Q8W placebo (placebo arm)
Patients on the RO7234292 Q16W arm will also receive placebo (i.e., alternate
doses of the active drug and placebo).
Note: no further study treatment will be administered in this study as of 22
March 2021.
Study burden and risks
RO7234292 has had limited testing in humans, with up to 9 months in 46 patients
as of 30 January 2019. Patients have received a regimen of either every 4
weeks (Q4W) (23 patients) or every 8 weeks (Q8W) (23 patients). Adverse
events or laboratory changes based on human and laboratory studies of
RO7234292, knowledge of similar drugs, or theoretical risks are listed below.
There may be side effects that are not known at this time.
* Pain after lumbar puncture (17 patients) and post-lumbar puncture events (for
example, headache and nausea) (7 patients) (observed equally across the Q4W or
Q8W treatment regimens)
* Falling at least once during study (observed in 12 Q4W and 8 Q8W patients)
* Increase in white blood cells in the fluid surrounding the spinal cord and
brain*which may indicate inflammation from the lumbar puncture or the study
drug (observed in 14 Q4W and 6 Q8W patients)
* Increase in proteins in the fluid surrounding the spinal cord and brain,
which may indicate inflammation from the lumbar puncture or the study drug
(observed in 15 Q4W and 5 Q8W patients)
* Inflammation of the lower back spinal nerve roots
(radiculopathy/radiculitis), which may lead to changes in reflex responses,
motor, or sensory symptoms (observed in 2 patients in the Q4W group who had
ankle reflex loss without motor or sensory symptoms)
* Changes observed in muscle strength, ankle reflex changes, balance
difficulties, and some temporary changes in sensory function (1 patient in Q4W
group)
In the patient information leaflet, additional theoretical risks are described.
In addition, potential risks have been described for the unborn child, and for
the study procedures.
In addition to the mentioned risks listed here, the study drug and the study
procedures may come with other, unknown risks.
Beneluxlaan 2a
Woerden 3446 GR
NL
Beneluxlaan 2a
Woerden 3446 GR
NL
Listed location countries
Age
Inclusion criteria
* Signed Informed Consent Form
* Age 25 to 65 years, inclusive
* Manifest HD diagnosis, defined as a diagnostic confidence level (DCL) score
of 4
* Independence Scale (IS) score * 70
* Genetically confirmed disease by direct DNA testing with a CAP score >400,
calculated as follows: CAP <= Age x (CAG repeat length - 33.66)
* Ability to read the words "red," "blue," and "green" in native language
* Ability to walk unassisted without a cane or walker and move about without a
wheelchair on a daily basis as determined at screening and baseline visit
o Long-distance (e.g., > 50 meters) use of wheelchairs for convenience or
transfer is permitted.
* Body mass index 16-32 kg/m2; total body weight > 40 kg
* Ability to undergo and tolerate MRI scans, to tolerate blood draws and lumbar
punctures
* Creatinine Clearance (CrCl) * 60 mL/min (Cockcroft-Gault formula)
* Ability and willingness, in the investigator's judgment, to comply with all
aspects of the protocol including completion of interviews and questionnaires
for the duration of the study
* Ability and willingness, in the investigator's judgment, to carry a
smartphone, wear a digital monitoring device, and complete smartphone-based
tasks
* Stable medical, psychiatric, and neurological status for at least 12 weeks
prior to screening and at the time of enrollment
* Signed study companion consent for participation who fulfills all of the
criteria as specified in protocol section 4.1.1.
* For women of childbearing potential: agreement to remain abstinent (refrain
from heterosexual intercourse) or use contraceptive measures, as defined in
protocol section 4.1.1.
* For men: agreement to remain abstinent (refrain from heterosexual
intercourse) or use a condom, and agreement to refrain from donating sperm, as
defined in protocol section 4.1.1.
Exclusion criteria
* History of attempted suicide or suicidal ideation with plan that required
hospital visit and/or change in level of care within 12 months prior to
screening
* Current suicidal ideation is demonstrated by the C-SSRS per judgment of the
investigator. If suicidal ideation is present, a risk assessment should be done
by an appropriately qualified mental health professional to assess whether it
is safe for the patient to participate in the study.
* Current active psychosis, confusional state, or violent behavior
* Any serious medical condition or clinically significant laboratory, or vital
sign abnormality or claustrophobia at screening that, in the investigator's
judgment, precludes the patient's safe participation in and completion of the
study
* History known to the investigator or presence of an abnormal ECG that is
clinically significant in the investigator's opinion, including complete left
bundle branch block, second-or third-degree atrioventricular heart block, or
evidence of prior myocardial infarction
* Lifetime clinical diagnosis of chronic migraines
* Pregnant or breastfeeding, or intending to become pregnant during the study
or within 5 months after the final dose of study drug
* Women of childbearing potential must have a negative serum pregnancy test
result at baseline and a confirmatory urine pregnancy test prior to initiation
of study drug.
* Presence of an implanted shunt for the drainage of CSF or an implanted CNS
catheter
* Positive for hepatitis C virus (HCV) antibody or hepatitis B surface antigen
(HBsAg) at screening
* Known HIV infection
* Current or previous use of an antisense oligonucleotide (including small
interfering RNA)
* Current or previous use of anti-psychotics prescribed for a primary
independent psychotic disorder (i.e., schizophrenia, schizoaffective disorder,
bipolar disorder type I, severe with psychotic features), cholinesterase
inhibitors, memantine, amantadine, or riluzole within 12 weeks from initiation
of study treatment
* Current use of antipsychotics for motor symptoms or mood stabilization (i.e.,
irritability or aggressive behavior) and/or tetrabenazine, valbenazine, or
deutetrabenazine at a dose that has not been stable for at least 12 weeks prior
to screening or is anticipated to change between screening and treatment
initiation
* Current use of supplements (e.g., coenzyme Q10, vitamins, creatine) at a dose
that has not been stable for at least 6 weeks prior to screening or is
anticipated to change during the study
* Current use of an antidepressant or benzodiazepine at a dose that has not
been stable for at least 12 weeks prior to screening or is anticipated to
change between screening and treatment initiation
* Treatment with investigational therapy within 4 weeks or 5 drug-elimination
half-lives prior to screening, whichever is longer
* Antiplatelet or anticoagulant therapy within 14 days prior to screening or
anticipated use during the study, including, but not limited to, aspirin
(unless * 81 mg/day), clopidogrel, dipyridamole, warfarin, dabigatran,
rivaroxaban, and apixaban
* History of bleeding diathesis or coagulopathy
* Platelet count less than the lower limit of normal
* Platelet counts between 125,000 and 150,000 mm3 are permissible as long as
the investigator confirms there is no evidence of current bleeding diathesis or
coagulopathy.
* History of gene therapy, cell transplantation, or any experimental brain
surgery
* Concurrent or planned participation in any interventional clinical study,
including explicit pharmacological and non-pharmacological interventions (e.g.,
lumbar puncture) Observational studies (e.g., ENROLL-HD prospective study) are
acceptable.
* Drug and/or alcohol abuse or psychological or physiological dependency within
12 months prior to screening, as per the investigator's judgment
* Poor peripheral venous access
* Scoliosis or spinal deformity or surgery making IT injection not feasible in
an outpatient setting and potentially interfering with distribution of
RO7234292 up the neuraxis
* An infection requiring oral or IV antibiotics within 14 days prior to
screening and prior to randomization
* Antiretroviral medications, including antiretroviral medication taken as
prophylaxis within 12 months of study enrollment
* Malignancy within 5 years prior to screening, except basal or squamous cell
carcinoma of the skin or carcinoma in situ of the cervix that has been
successfully treated
* Preexisting intra-axial or extra-axial (e.g., tumor, arterio-venous
malformation) as assessed by a centrally read MRI scan during the screening
period
Design
Recruitment
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 | EUCTR2018-002987-14-NL |
| ClinicalTrials.gov | NCT03761849 |
| CCMO | NL68007.000.19 |