• To assess the efficacy of rozanolixizumab as measured by seizure freedom• To assess the efficacy of ozanolixizumab as measured by change in cognitive function• To assess the efficacy of ozanolixizumab as measured by use of rescue medication• To…
ID
Source
Brief title
Condition
- Autoimmune disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• To assess the efficacy of rozanolixizumab as measured by seizure freedom:
Seizure freedom (defined by 28 consecutive days of
no seizures) maintained until the end of the Treatment Period (Week 25)
Secondary outcome
• To assess the efficacy of rozanolixizumab as measured by a change in
cognitive function: Change from Baseline in Repeatable Battery for the
Assessment of Neuropsychological Status (RBANS) total scale index score at the
end of the Treatment Period (Week 25)
• To assess the efficacy of rozanolixizumab as measured by use of rescue
medication: Use of rescue medication due to an absence or loss
of clinical benefit during the Treatment Period
• To assess the efficacy of rozanolixizumab as measured by the onset of seizure
freedom: Time to first occurrence of seizure freedom
(TTFSF) defined by the number of days after randomization to the first day of
the first 28
consecutive days without seizures during the Treatment Period
• To assess the safety and tolerability of rozanolixizumab: Incidence of
treatment-emergent
Background summary
Rationale: Autoimmune encephalitis (AIE) is a group of disorders where the
immune system
causes inflammation of the brain, leading to debilitating neurological and
psychiatric symptoms.
There are currently no approved treatments for AIE. Leucine-rich glioma
inactivated 1 AIE
(LGI1 AIE) has a distinct clinical presentation and has been identified as a
variant that may be
suitable for immunotherapy, and therefore for treatment with rozanolixizumab,
which blocks the
activity of neonatal Fc receptor (FcRn), accelerates the catabolism of
antibodies and reduces the
concentration of immunoglobulin (Ig) G.
To date, rozanolixizumab has been administered to human study participants in 4
completed
clinical studies (UP0018, UP0060, MG0002, and TP0001) and 6 ongoing studies
(CIDP01,
CIDP04, MG0003, MG0004, TP0003, and TP0006).
Overall, repeated administrations of rozanolixizumab at a dose of approximating
7mg/kg sc were
generally well tolerated, with an acceptable safety profile in the completed
studies. The TEAE
profile was similar between rozanolixizumab and placebo, except for headaches
where increased
frequency and severity was observed in the rozanolixizumab-treated study
participants. The peak
and total exposure of rozanolixizumab showed nonlinear increases consistent
with targetmediated
drug disposition. Dose-dependent, statistically significant reductions in
levels of total
IgG and dose-dependent reductions in levels of IgG subclasses (IgG 1 to 4) were
observed after
rozanolixizumab was administered by intravenous (iv) or sc routes. In study
participants with
generalized MG (gMG), clinically relevant improvements in day-to-day
functioning were
observed following treatment with rozanolixizumab 7mg/kg compared with placebo.
Study objective
• To assess the efficacy of rozanolixizumab as measured by seizure freedom
• To assess the efficacy of ozanolixizumab as measured by change in cognitive
function
• To assess the efficacy of ozanolixizumab as measured by use of rescue
medication
• To assess the efficacy of rozanolixizumab as measured by the onset of seizure
freedom
• To assess the safety and tolerability of rozanolixizumab
Study design
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled,
2-arm, repeat dose
study to evaluate the efficacy, safety, and PK of rozanolixizumab for the
treatment of LGI1 AIE.
Approximately 68 adult study participants with LGI1 AIE with onset of disease
between 0 to
12 months prior to study entry will be randomized to receive rozanolixizumab
560mg or placebo,
administered by subcutaneous (sc) infusion at weekly intervals for 24 weeks. A
Treatment Period
of 24 weeks has been selected to ensure a sufficient time period to evaluate a
difference between
rozanolixizumab and placebo in key symptoms of the disease. The primary
objective of the study
is to assess the efficacy of rozanolixizumab as measured by seizure freedom.
Following screening and completion of the Baseline assessments, treatment will
be initiated in
study participants who are currently considered for treatment with intravenous
methylprednisolone (IVMP) by the investigator, or who have initiated IVMP
treatment within
14 days prior to randomization at a dose of 500 to 1000mg/day. Down titration
of steroids will
begin at the end of the 3 to 5-day (based on the decision of the investigator)
IVMP regimen. If
the study participant has initiated a steroid taper, the study participant
cannot receive oral
steroids at a dose lower than 60mg/day when randomized. Each subsequent
down-titration step
will last for 7 days (±2 days; see Section 1.2).
The study participants will be stratified at randomization by:
• Time from disease onset (<=6 months or >6 months from disease onset)
• Cognitive function (RBANS score of <=85 or >85)
After the initial 5 investigational medicinal product (IMP) administrations
have been performed
at the clinic, the study participant may have the opportunity to be treated at
home by a visiting
healthcare practitioner.
Although the use of rescue medication is allowable at any time during the
study, the use of
rescue medications should be delayed, if clinically appropriate, for at least 4
weeks following the
initiation of study treatment. Study participants who require rescue medication
will discontinue
blinded treatment and complete the assessments for the Early Discontinuation
Visit. Following
this, the selection of an appropriate rescue medication will be made at the
investigators
UCB 04 Dec 2020
Clinical Study Protocol Amendment 1 Rozanolixizumab AIE001
Confidential Page 19 of 126
discretion, and the study participant will enter the Safety Follow-Up (SFU)
Period. Unscheduled
study visits are permitted for any study participant including those study
participants who have
initiated rescue medication.
An Independent Data Monitoring Committee (IDMC) will be established for the
study to
monitor the emerging safety data within the clinical study on a periodic basis.
Intervention
Treatment Groups and Duration
The maximum study duration per study participant is 34 weeks. There are 3 study
periods:
• Screening Period: Eligibility will be assessed during the Screening Period of
up to 14 days. If
a study participant becomes seizure free during the Screening Period as a
result of IVMP
treatment, the participant may be randomized in the study, providing the prior
occurrence of
seizures is well documented. Intravenous methylprednisolone can be initiated
prior to the
start of the Screening Period, however, the study participant must be
randomized within
14 days.
• Treatment Period: Participants who have been confirmed eligible will be
randomized in a
1:1 ratio to receive rozanolixizumab 560mg or placebo at weekly intervals over
a 24-week
Treatment Period.
• Safety Follow-Up Period: Study participants who complete the 24-week
Treatment Period or
prematurely discontinue IMP, as well as study participants who receive rescue
medication
during the 24-week Treatment Period will undergo the End of Treatment (EOT)
Visit/Early
Discontinuation Visit and enter the SFU Period. At 4 weeks after the final
dose, study
participants will undergo a SFU phone call, and at 8 weeks after the final
dose, study
participants will undergo the End of Study (EOS) Visit.
Study burden and risks
The therapy to be investigated may cause side effects or adverse effects.
Your doctor will provide appropriate treatment and may perform further tests
due to side effects but will explain this to you if necessary.
Possible side effects which you might experience when you receive the study
drug, along with how often they are expected to occur are listed below.
• Very Common (occurring in 10% or more of the study participants):
- Headache
- Diarrhea
- Fever
• Common (occurring in 1% to less than 10% of the study participants):
- Vomiting
- Nausea
- Infusion/injection site reactions
- Upper respiratory tract infections (such as sore throat, sinus infection,
common cold, cough)
- Oral herpes
- Joint and muscle ache
- Rash
Infusion re action including hypersensitivity (allergic reaction):
The study drug is a protein substance foreign to your body and like other
proteins of this class (called monoclonal antibodies), it can cause infusion
reactions. Some study participants reported a mild local reaction at the site
where the drug was infused under the skin; in some study participants, it was
accompanied by mild vomiting, mild fever, and/or mild to moderate diarrhea.
Symptoms of hypersensitivity are itching, flushing (redness), hives, swelling
of lips, tongue, eyes or face, headache, feeling dizzy, sweating, feeling sick
(nausea) or being sick (vomiting), feeling out of breath, and heart racing. You
must inform your study doctor or study staff IMMEDIATELY if you have any or
some of these symptoms particularly during the infusion or for the first few
hours following the infusion. Your study doctor and/or site staff will provide
treatment for this side effect if necessary.
There is a small risk that the result of the test for LGI1 does not provide
accurate results. However, this risk would not be different than if you were
tested for LGI1 outside of the study.
Possible side effects based on currently available information are described
below. This information is based on limited study participant numbers at this
stage of the drug development.
Headache:
In previous studies, when the study drug was administered as an infusion under
the skin, some study participants reported headache. In most of the cases, the
headache starts within 1 to 3 days following the study treatment and they are
generally mild to moderate. In few cases, severe headaches were reported. The
majority of these cases resolved spontaneously. In some cases, treatment with
analgesic may be required to reduce the pain. To date, there have been no
observations of any permanent ill effects associated with this side effect. If
you suffer from this side effect, you must immediately inform your study
doctor. Your study doctor will provide appropriate treatment or perform further
tests for these side effects if necessary.
Gastrointestinal Upset:
In the same studies mentioned above, when the study drug was administered as an
infusion under the skin, some study participants reported nausea (feeling sick
or as you are going to throw up), vomiting (actually being sick or throwing
up), and diarrhea. All these cases were mild to moderate, except a few cases of
diarrhea that were severe in intensity. All resolved without any permanent ill
effects on their health. Please let your doctor know if you have had recent
history of inflammatory or ulcerative stomach or intestine diseases. If you
suffer from these or other tummy symptoms, you must immediately inform your
study doctor. Your study doctor will provide appropriate treatment or perform
further tests if necessary.
Increased risk of infections:
Fever, sore throat, influenza and common cold, and cough have been reported in
study participants receiving the study drug. However, in the previous studies,
study participants who received rozanolixizumab were not found to be at a
particularly increased risk of infections compared to study participants who
received dummy drug (placebo). There was no the study drug -related evidence of
infection in animals given this drug. However, the study drug works by reducing
the level of antibodies (substances in your body that help fight off certain
infections) in your body which may put you at increased risk of infections. You
must let your study doctor or study staff know immediately if you have any
symptoms of infections such as but not limited to feeling cold or shivery; your
skin feels hot to touch; stinging or pain when you pass urine, or coughing etc.
Your study doctor will provide appropriate treatment or perform further tests
if necessary.
In some study participants, the study drug may reduce the level of antibodies
too much. In case this happens, your study medication may be temporarily
stopped to decrease the risk of infections. Treatment with study medication
will be restarted once the antibody levels have increased sufficiently.
Effects on your response to vaccines:
The study drug has potential to decrease the immunity against certain diseases
for which you have received vaccines in the past. It can also modify the
necessary response of your body to vaccines that you receive while the study
drug is effective; for example, you may not develop protection against a
disease from the vaccination; or taking a live vaccine may cause you to develop
the illness it was supposed to prevent. You will not be eligible for
participating in this study if you have received a live vaccine within 8 weeks
before the Baseline Visit or you intend to have a live vaccination during the
course of the study or within 8 weeks following the final dose of study
medication. You must tell your study doctor if you have received or plan to
receive any vaccination during this period. Vaccination with non-live vaccines
(including COVID-19 vaccines) is permitted.
Effects on kidneys:
The study drug may have an effect on the kidney based on its mechanism of
action. Results from previous clinical studies did not indicate any ill effects
of the study drug on the kidney. However, your blood and urine samples will be
taken regularly to ensure that your kidneys are in good health. Your study
doctor will monitor you and provide appropriate treatment in case you
experience this side effect. In addition, your doctor may need to change the
dosage of your medications to take into account the health of your kidney at
the time you enter the study.
Immunogenicity:
It is possible that your body develops a natural defense (antibodies) against
the study drug (anti-rozanolixizumab-antibody). Positive
anti-rozanolixizumab-antibody has been detected in animal studies, including in
one animal who developed immune complex formation and an accelerated clearance
of the study drug as the consequence of positive anti-drug antibody. The
anti-rozanolixizumab-antibody can also result in side effects such as allergic
reaction. However, the incidence and/or magnitude of the
anti-rozanolixizumab-antibody response in animals does not predict such effects
in humans. Positive anti-rozanolixizumab-antibody has also been detected in
some patients treated with the study drug. It is not yet known if there are
long-term effects associated with developing these antibodies. Blood samples
will be collected to detect their presence. Your study doctor will monitor any
potential side effects that may be associated with
anti-rozanolixizumab-antibody.
Effects on albumin:
Albumin is a substance (protein) that performs many necessary functions in your
body such as to prevent fluids from leaking out of your body vessels, carrying
vital nutrients and hormones, and providing your body with substances it needs
for maintenance, repair and growth of your body. Hypothetically, the study drug
may decrease the amount of albumin in your body. Mild and short-lived decreases
in albumin were observed in some animals after administration of the study
drug. However, the previous clinical studies did not indi
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Age
Inclusion criteria
Protocol Amd 3 14Jan2022 section 5.1 Inclusion Criteria
-Study participant must be >=18 to <=89 years of age, at the time of signing the
informed consent
-Study participant must be seropositive for leucine-rich glioma inactivated 1
(LGI1) antibody measured by LGI1 serum autoantibody cell-binding assay
-Study participant must have >=2 seizures/week during the Screening Period or
have experienced such seizures that stopped following high dose corticosteroids
(500 to 1000mg MP equivalent/day):
• Either FBDS with or without other focal (partial) seizures including focal to
bilateral tonic clonic
• Or focal (partial) seizures including focal to bilateral tonic clonic and
fulfil the following new-onset AIE criteria:
a. Subacute onset (rapid progression of less than 3 months) of working memory
deficits (short-term memory loss), altered mental status (defined as decreased
or altered level of consciousness, lethargy, or personality change), or
psychiatric symptoms.
AND
b. At least one of the following:
i. New focal CNS finding, as per the investigator's assessment
ii. Seizures not explained by a previously known seizure disorder
iii. CSF pleocytosis (white blood cell count of >5 cells/mm3)
iv. MRI features suggestive of encephalitis (Brain MRI hyperintense signal on
T2- weighted fluid-attenuated inversion recovery sequences highly restricted to
one or both medial temporal lobes [limbic encephalitis], or in multifocal areas
involving grey matter, white matter, or both compatible with demyelination or
inflammation).
AND
c. Reasonable exclusion of alternative causes
-Study participant has initiated or re-initiated corticosteroids at a dose of
500 to 1000 mg MP equivalent/day within 42 days prior to randomization.
Participants re-initiating corticosteroids are eligible only if re-initiation
is due to seizure rebound and within the timeframe outlined in Section 4.1.
If the study participant has initiated a steroid taper, the study participant
cannot receive an
oral steroid dose lower than 40 mg/day when randomized
-Study participant with onset of disease symptom between 0 to 12 months prior
to Screening, per investigator's assessment.
-Study participant weighs at least 35 kg (for males and females) at Screening
*A male participant must agree to use contraception during the treatment period
and for at least 90 days after the final dose of study treatment and refrain
from donating sperm during this period
*A female participant is eligible to participate if she is not pregnant, not
breastfeeding, and at least one of the following conditions applies:
i) Not a woman of childbearing potential (WOCBP)
OR
ii) A WOCBP who agrees to follow the contraceptive guidance during the
treatment period and for at least 90 days after the final dose of study
treatment
8a. Study participant is capable of giving signed informed consent or has a
legal representative to consent for him/her as described in Appendix 1 (Section
10.1.3) which includes compliance with the requirements and restrictions listed
in the informed consent form (ICF) and in this protocol.
9a. Study participant has a reliable caregiver who will be available during the
whole study period, as determined by the investigator.
Exclusion criteria
Protocol Amd 5 09Feb2023 section 5.2 Exclusion Criteria
Medical conditions
1. Study participant has any medical or psychiatric condition that, in the
opinion of the investigator, could jeopardize or would compromise the study
participant*s ability to participate in this study.
2. Study participant has a history of alcohol use disorder or other substance
use disorder (as per Diagnostic and Statistical Manual of Mental Disorders-5)
within the previous 12 months.
3. Study participant has a known hypersensitivity to any components of the
study medication or any other anti-FcRn medications. This includes a known
history of hyperprolinemia, since L proline is a constituent of the
rozanolixizumab formulation.
4a. Study participant has a confirmed prior diagnosis of epilepsy or new onset
seizures that are unrelated to LGI1 AIE or has any known or suspected medical
cause for the onset of seizures other than possible AIE.
5. Study participant has a known active neoplastic disease or history of
neoplastic disease within 5 years of study entry (except for basal or squamous
cell carcinoma of the skin or carcinoma in situ of the uterine cervix which has
been definitively treated with standard of care approaches).
6. Study participant has 12-lead ECG with findings considered clinically
significant by the investigator.
7a. Study participant has renal impairment, defined as glomerular filtration
rate (GFR) <30mL/min/1.73m2 at the Screening Visit.
8a. Study participant has a clinically important active infection (including
unresolved or not adequately treated infection) as assessed by investigator,
including participants with a serious infection within 6 weeks prior to the
first dose of IMP.
9a. Study participant has a history of chronic ongoing infections (eg,
Hepatitis B or C, human immune deficiency virus [HIV], active tuberculosis
[TB]) or who tests positive for HIV, Hepatitis B or C at the Screening Visit.
* Presence of Hepatitis B surface antigen at the Screening Visit.
* Positive Hepatitis C antibody test result at Screening or within 3 months
prior to the IMP dose. NOTE: Study participant with a positive Hepatitis C
antibody due to prior resolved disease can be enrolled only if a confirmatory
negative Hepatitis C RNA test is obtained.
10. Study participant has current unstable liver or biliary disease, per
investigator assessment, defined by the presence of ascites, encephalopathy,
coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent
jaundice, or cirrhosis. Note: An exception is stable chronic hepatobiliary
conditions (including Gilbert*s syndrome, asymptomatic gallstones).
11. Study participant has positive TB test at the Screening Visit unless it is
determined by a TB specialist that the positive result is related to an
adequately treated latent TB infection
12. Study participants met any of the following TB exclusion criteria:
* Known active TB disease
* History of active TB involving any organ system unless adequately treated
according to World Health Organization (WHO)/US Center for Disease Control
therapeutic guidance and proven to be fully recovered upon consult with a TB
specialist
* Latent tuberculosis infection (LTBI) (unless appropriate prophylaxis is
initiated at least 4 weeks prior to IMP dosing and will be continued to
completion of prophylaxis). Prophylaxis should be in accordance with applicable
clinical guidelines and TB specialist judgment based on the origin of infection.
* High risk of exposure to TB infection, as assessed by the investigator
* Current nontuberculous mycobacterial (NTM) infection or history of NTM
infection unless proven to be fully recovered.
For further information relating to definitions of known active TB, past
history of TB, LTBI, high risk of acquiring TB infection see Section 10.12.
13. Study participant has a lifetime history of suicide attempt (including an
active attempt, interrupted attempt, or aborted attempt), or had suicidal
ideation with at least some intent to act in the past 6 months as indicated by
a positive response (Yes) to either Question 4 or Question 5 of the Columbia
Suicide Severity Rating Scale (C-SSRS) at Visit 1.
14. Removed in Protocol Amendment 4.
15. Study participant has a current or medical history of IgA deficiency.
16. Study participant has a history of solid organ transplant or hematopoietic
stem cell transplant.
17. Study participant has undergone a splenectomy.
18. Study participant has a current or medical history of primary immune
deficiency.
Prior/concomitant therapy
19. Study participant has been treated with prohibited immunosuppressants,
biologics, and other therapies within the timeframe specified in Section 6.5.2.
20a. Study participant has received a live vaccination within 4 weeks prior to
the Baseline Visit; or intends to have a live vaccination during the course of
the study or within 8 weeks following the final dose of IMP.
Prior/concurrent clinical study experience
21. Study participant has been previously randomized in this study (rescreening
for screen-failed participants is allowed with prior consultation and
permission of the medical monitor/study physician).
22. Study participant has previously received rozanolixizumab drug product.
23. Study participant has participated in another study of an IMP (and/or an
investigational device) within the previous 3 months or 5 half-lives prior to
Baseline (whichever is longer) or is currently participating in another study
of an IMP (and/or an investigational device).
Diagnostic assessments
24b Alanine transaminase (ALT), aspartate aminotransferase (AST), or alkaline
phosphatase (ALP) are >3x upper limit of normal (ULN).
* If study participant has >ULN for ALT, AST, or ALP that does not meet the
exclusion limit at Screening, the tests must be repeated prior to dosing to
ensure there was no further ongoing clinically relevant increase. In case of a
clinically relevant increase as per the investigator's judgement, the study
participant must be excluded.
* Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit
(>2xULN) may be repeated once for confirmation. This includes rescreening. If
any of the repeated tests (ALT, AST, or ALP) are >2xULN, the study participant
will meet the exclusion criterion #24 and the study participant must be
excluded.
* For randomized study participants with a Baseline result >ULN for ALT, AST,
ALP, or total bilirubin but <1.5xULN, a Baseline diagnosis and/or the cause of
any clinically meaningful elevation will have to be understood and recorded in
the electronic case report form (eCRF).
25. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin
is fractionated and direct bilirubin <35%).
26. Removed in Protocol Amendment 5 as already incorporated in exclusion
criterion #10.
27. Removed in Protocol Amendment 2, and incorporated in exclusion criterion
#24.
28. Removed in Protocol Amendment 2, and incorporated in exclusion criterion
#24.
29. Removed in Protocol Amendment 2, and incorporated in exclusion criterion
#24.
30a. Study participant has a total IgG level <=5.5g/L at the Screening Visit.
31. Study participant has absolute neutrophil count <1500 cells/mm3 at the
Screening Visit.
32. Study participant has a planned major elective surgical procedure for the
duration of their participation in the study.
33. Removed in Protocol Amendment 4.
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 | EUCTR2019-004778-25-NL |
| Other | IND: 146922 |
| CCMO | NL75512.028.21 |