This study has been transitioned to CTIS with ID 2023-504226-18-00 check the CTIS register for the current data. This study will evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of satralizumab compared with placebo in each of…
ID
Source
Brief title
Condition
- Autoimmune disorders
- Cranial nerve disorders (excl neoplasms)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To evaluate the efficacy of satralizumab compared with placebo on degree of
disability and clinical severity:
• Proportion of participants with mRS score improvement = or > 1 from baseline
and no use of rescue therapy at Week 24
Secondary outcome
A. To evaluate the efficacy of satralizumab compared with placebo:
• Time to mRS score improvement = or > 1 from baseline without use of rescue
therapy
• Time to rescue therapy
• Time to seizure freedom (seizure freedom defined as a cessation of seizures
for at least 6 consecutive weeks) or cessation of status epilepticus without
use of rescue therapy
• Change in CASE score from baseline at Week 24
• MOCA total score at Week 24
• RAVLT score at Week 24 (LGI1 AIE cohort)
• mRS score at Week 24 (as measured on a 7-point scale; NMDAR AIE cohort)
B. To evaluate the safety of satralizumab compared with placebo:
• Incidence, seriousness, and severity of adverse events, with severity
determined according to National Cancer Institute Common Terminology Criteria
for Adverse Events, Version 5.0
• Change from baseline in targeted vital signs, clinical laboratory test
results, ECG results, weight, height ( < 18 years only), and C-SSRS
Background summary
See chapter 22 for more background
Acute encephalitis is a rare and debilitating neurological disorder that
develops in patients of all ages, presenting as a rapidly progressive
encephalopathy as a consequence of brain inflammation (Venkatesan et al. 2013).
Autoimmune encephalitis (AIE) includes disorders that are associated with an
identifiable etiological driver, usually a tumor, and disorders that are
regarded as idiopathic.
Although a majority of patients with cell surface antibodypositive disease
achieve a stable condition with currently used treatment options, no
prospective randomized trials have been reported to date in this population,
and all therapeutics are used based on anecdotal evidence. Several limitations
apply to the current AIE treatment paradigm that highlight remaining critical
unmet needs for treatments with rapid and demonstrated effects on long-term
efficacy and safety. For example, not all patients respond to these
medications, and deficiencies remain, including cognitive deficits,
insufficient seizure resolution, dependence on high-dose corticosteroids, and a
need for durable, faster-acting agents. There is an urgent need for
prospectively generated evidence in AIE to guide treatment choice to address
both acute as well as long-term effects of this rare neurological disorder.
Satralizumab is a recycling, humanized, antiIL-6 receptor (IL-6R) monoclonal
antibody.
Given the pathological relevance of autoantibodies and pro-inflammatory T cells
in AIE, IL-6 inhibition through satralizumab is expected to dampen immune
mechanisms that underlie the clinical phenotype of AIE.
Study objective
This study has been transitioned to CTIS with ID 2023-504226-18-00 check the CTIS register for the current data.
This study will evaluate the efficacy, safety, pharmacokinetics, and
pharmacodynamics of satralizumab compared with placebo in each of the following
cohorts:
• NMDAR autoimmune encephalitis (AIE) cohort: adults and adolescents (12-16)
with definite or probable NMDAR encephalitis
• LGI1 AIE cohort: adults with LGI1 encephalitis
Study design
This Phase III, randomized, double-blind, placebo-controlled, multicenter study
is designed to evaluate the efficacy, safety, pharmacokinetics, and
pharmacodynamics of satralizumab compared with placebo for the treatment of
NMDAR encephalitis and LGI1 encephalitis. For efficacy analyses, the NMDAR AIE
and LGI1 AIE cohorts will be treated as separate populations in a basket study
design. The study will include a screening period of up to 28 days in length,
during which patients* eligibility will be evaluated for study participation.
Screening will be followed by:
• Part 1: a primary treatment period of 52 weeks
• Part 2: an optional extension period lasting approximately 2 years from when
the last participant enters the extension period or until commercial
satralizumab is available for the treatment of AIE
A pharmacokinetic (PK) interim analysis will be performed once approximately 30
participants across both cohorts (to include approximately 15 participants
receiving satralizumab) have received a minimum of 8 weeks of study treatment,
to confirm that target concentrations are achieved.
The total duration of study participation for each individual is expected to be
approximately 3 to 5 years.
Intervention
During Part 1, participants will be randomly assigned in a 1:1 ratio to receive
placebo or 60 mg, 120 mg, or 180 mg depending of weight satralizumab in each of
the NMDAR AIE and LGI1 AIE cohorts.
In Part 2, participants will be asked to choose from one of the following
options:
• Option 1: continue on randomized, double blind study drug
• Option 2: start open label satralizumab based on body weight, as described
above. In order to maintain the blinding of treatment assignment during Part
1, the following will occur:
-Participants who received placebo during Part 1 and choose to start open-label
treatment in Part 2 will receive satralizumab SC at Weeks 0, 2, 4, and every 4
weeks (Q4W) thereafter.
-Participants who received satralizumab during Part 1 and choose to start open
label treatment will continue to receive satralizumab SC Q4W in Part 2, with a
dose of placebo administered at extension Week 2 in order to maintain the
blinding of treatment assignment during Part 1.
• Option 3: stop study treatment and continue follow-up assessments
Study burden and risks
All currently available treatment options for AIE (including high dose
corticosteroids and cyclophosphamide) carry substantial potential safety risks.
There is no evidence from randomized controlled trials to support treatment
decisions. In addition, not all patients respond to currently used
medications, and deficiencies remain, including cognitive deficits,
insufficient seizure resolution, dependence on high dose corticosteroids and a
need for durable, faster acting agents. The proposed trial of satralizumab
will address these unmet needs and establish the effectiveness of satralizumab
in patients with NMDAR or LGI1 encephalitis. Taking into account the potential
for efficacy in patients for which no approved drug exists, the safety profile
for satralizumab, and the risk-mitigation measures for the study, the
benefit/risk ratio is expected to be acceptable for satralizumab in the
treatment of both NMDAR and LGI1 encephalitis.
Refer to Appendix 6 of the protocol for information on anticipated risks for
satralizumab and risk mitigation measures, including guidelines for managing
adverse events associated with satralizumab.
Beneluxlaan 2A
Woerden 3446AA
NL
Beneluxlaan 2A
Woerden 3446AA
NL
Listed location countries
Age
Inclusion criteria
Zie paraaf 5.1. en 5.2 in het protocol V2
Inclusion Criteria for All Participants
* Capable of giving signed informed consent as described in Appendix 1
* Reasonable exclusion of tumor or malignancy before baseline visit
(randomization)
* Onset of AIE symptoms, < 9 months before randomization
* Meet the definition of "New Onset" or "Incomplete Responder" AIE
- Has a stable (for at least 24 hours) mRS score = or > 2, measured at baseline
- Has received their first acute first-line therapy within 6 weeks prior to
randomization (baseline visit)
- Has not received prior treatment with rituximab or any other ISTs
(e.g., cyclophosphamide, mycophenolate mofetil, methotrexate,
cyclosporine, tacrolimus, azathioprine) or tocilizumab for AIE
- Incomplete Responder: defined as a participant with NMDAR or LGI1 AIE who
satisfies the following criteria:
o Has a stable (for at least 24 hours) mRS score = or > 2, measured at baseline
o Has received their first acute first-line therapy more than 6 weeks prior to
randomization (baseline visit).
o Has received immunotherapy beyond their first acute first-line therapy
course.
* For women of childbearing potential: agreement to remain abstinent or use
adequate contraception during the treatment
period and for at least 3 months after the final dose of satralizumab or placebo
Additional Inclusion Criteria for the NMDAR AIE Cohort
In addition to the criteria outlined in Section 5.1.1, participants are
eligible to be included
in the NMDAR AIE cohort only if all of the following criteria apply:
* Age, > 12 years at the time of signing Informed Consent Form
* Signed Assent Form
* Diagnosis of probable or definite NMDAR encephalitis
Additional Inclusion Criteria for the LGI1 AIE Cohort
In addition to the criteria outlined in Section 5.1.1, participants are
eligible to be included
in the LGI1 AIE cohort only if all of the following criteria apply:
* Age, > 18 years at the time of signing Informed Consent Form
* Diagnosis of LGI1 encephalitis
Exclusion criteria
* Any untreated teratoma or thymoma at baseline visit (randomization). Teratoma
or thymoma detected prior to or during the screening period is allowed if
deemed cured after treatment (usually surgical removal) by 1 week prior to
baseline
* History of carcinoma or malignancy, unless deemed cured by adequate treatment
with no evidence of recurrence for = and > 5 years before screening (except
basal cell and
squamous cell carcinomas of the skin, or in situ carcinoma of the cervix uteri
that
have been completely excised and cured)
* For patients with NMDAR AIE, history of negative anti-NMDAR antibody in CSF
using a cell based assay within 9 months of symptom onset
* Historically known positivity to an intracellular antigen with high cancer
association
(e.g., anti-Hu, anti-Ma2, anti-CRMP5, anti-Yo, anti-amphiphysin, AMPA, mGluR5,
and GABAB) or GAD-65
* Historically known positivity to any cell surface neuronal antibodies other
than
NMDAR and LGI1 (e.g., caspr2, IgLON5, DPPX, GABAA, and neurexin-3α)
* Confirmed paraneoplastic encephalitis
* Confirmed central or peripheral nervous system demyelinating disease (e.g.,
multiple sclerosis, chronic inflammatory demyelinating polyneuropathy)
* Alternative causes of associated symptoms, including CNS infections, septic
encephalopathy, metabolic encephalopathy, epileptic disorders, mitochondrial
disease, Klein-Levin syndrome, Creutzfeldt-Jakob disease, rheumatologic
disorders,
Reyes syndrome, or inborn errors of metabolism
* History of herpes simplex virus encephalitis in the previous 24 weeks
* Any previous/concurrent treatment with IL-6 inhibitory therapy (e.g.,
tocilizumab),
alemtuzumab, total body irradiation, or bone marrow transplantation
* Any previous treatment with anti-CD19 antibody, complement inhibitors,
neonatal Fc
receptor antagonists, anti*B-lymphocyte stimulator monoclonal antibody
(e.g., belimumab)
* Any previous treatment with T-cell depleting therapies, cladribine, or
mitoxantrone
* Treatment with oral cyclophosphamide within 1 year prior to baseline
* Treatment with any investigational drug (including bortezomib) within 24
weeks prior
to screening (or within 5 half-lives of the investigational drug; whichever is
longer)
* Concurrent use of more than one IST (e.g.. azathioprine, mycophenolate
mofetil, or
IV cyclophosphamide) as background therapy
The combination of an OCS with another permitted IST drug is allowed.
* Contraindication to all of the following rescue treatments: rituximab, IVIG,
high-dose
corticosteroids, or IV cyclophosphamide
* Any surgical procedure, except laparoscopic surgery or minor surgeries
(defined as
procedures that require only local anesthesia or conscious sedation, i.e., do
not
require general, neuraxial or regional anesthesia, and are done on an
ambulatory/outpatient basis; e.g. toenail surgery, mole surgical excision,
wisdom
tooth extraction), within 4 weeks prior to baseline, excluding surgery for
thymoma or
teratoma removal
* Planned surgical procedure (except minor surgeries) during the study
* Evidence of progressive multifocal leukoencephalopathy
* Evidence of serious uncontrolled concomitant diseases that may preclude
patient
participation, such as other nervous system disease, cardiovascular disease,
hematologic/hematopoiesis disease, respiratory disease, muscular disease,
endocrine disease, renal/urologic disease, and digestive system disease
* Congenital or acquired immunodeficiency, including HIV infection
* Active or presence of recurrent bacterial, viral, fungal, mycobacterial
infection, or
other infection (excluding fungal infection of nail beds or dental caries) at
baseline
* Infection requiring hospitalization or treatment with IV anti-infective
agents within
4 weeks prior to baseline visit
* Positive hepatitis B (HBV) test at screening (defined as either of the
following):
- Positive hepatitis B surface antigen (HBsAg)
- Positive total hepatitis B core antibody (total HBcAb) confirmed by a positive
viral DNA polymerase chain reaction test
* Positive hepatitis C (HCV) test at screening (defined as positive HCV
antibody and
detectable HCV RNA)
Participants with positive HCV antibody and undetectable HCV RNA 12 weeks
after HCV treatment completion are eligible to participate in the study.
* Evidence of latent or active tuberculosis (TB) (excluding patients receiving
chemoprophylaxis for latent TB infection)
If a patient is positive for latent TB, then the patient must be treated with
appropriate anti-mycobacterial therapy for at least 4 weeks prior to initiating
study treatment administration. Refer to Appendix 10 for details on TB
screening and treatment.
* History of drug or alcohol abuse within 1 year prior to baseline
* History of diverticulitis or concurrent severe gastrointestinal (GI)
disorders (such as
symptomatic diverticulosis) that, in the investigator*s opinion, may lead to
increased
risk of complications such as GI perforation
* Receipt of live or live-attenuated vaccine within 6 weeks prior to baseline
visit
* History of blood donation (1 unit or more), plasma donation or platelet
donation
within 90 days prior to screening
* History of severe allergic reaction to a biologic agent (e.g., shock,
anaphylactic
reactions)
* Active suicidal ideation within 6 months prior to screening, or history of
suicide
attempt within 3 years prior to screening
* Any serious medical condition or abnormality in clinical laboratory tests
that, in the
investigator's judgment, precludes safe participation in and completion of the
study
* Pregnant or breastfeeding, or intending to become pregnant during the study or
within 3 months after the final dose of study drug
Women of childbearing potential must have a negative serum pregnancy test
result at screening and negative urine dipstick pregnancy test prior to
initiation
of study treatment
* Certain laboratory abnormalities at screening (see protocol section 5.2:
If a retest is conducted, the last value obtained determines the patient*s
eligibility for
randomization.
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 |
|---|---|
| EU-CTR | CTIS2023-504226-18-00 |
| EudraCT | EUCTR2021-002395-39-NL |
| CCMO | NL80647.078.22 |