This study has been transitioned to CTIS with ID 2024-518844-20-00 check the CTIS register for the current data. Primary Objective:To evaluate the efficacy of dapansutrile as an acute gout flare treatment compared to placebo in reducing joint pain…
ID
Source
Brief title
Condition
- Joint disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary clinical activity outcome measurement will be:
• Change from baseline in the subject-assessed pain intensity score (100-mm
VAS) in the target joint at 72 hours post initial loading dose for dapansutrile
compared to placebo.
Secondary outcome
The secondary clinical activity outcome measurements will be:
• Change from baseline in the subject-assessed pain intensity score (100-mm
VAS) in the target joint at 12, 24, 36, 48, and 60 hours post initial loading
dose, and on Study Day 8 and Study Day 15
• Subject-assessed PGART on Study Day 8
• Change from baseline in the Investigator-assessed Target Joint Score
(tenderness, swelling, erythema, warmth, and range of motion) at scheduled
assessments through Study Day 15
• Investigator-assessed IGART at scheduled assessments through Study Day 8
• Proportion of subjects with a response (defined as a 20%, 50%, or 70%
reduction from baseline without using Rescue Medication or Escape medication)
in the subject-assessed pain intensity score (100-mm VAS) in the target joint
at 48 and 72 hours post initial loading dose, and on Study Day 8 and Study Day
15
• Time to intake of medication taken for non-response from first IMP
administration, e.g., Rescue Medication and/or Escape Medication
• Proportion and number of subjects with Rescue Medication or Escape
Medication use from the first IMP administration up to 12 hours, >12 to 24
hours, >24 to 48 hours, >48 to 72 hours, >72 hours to Day 8, and >Day 8 to Day
15
• Change from baseline in the subject-assessed QoL questionnaire (SF 12v2) at
scheduled assessments through Study Day 15
• Change from baseline in the subject-assessed pain intensity score (100-mm
VAS) in any actively flaring non-target joint(s) on Study Day 4, Study Day 8,
and Study Day 15.
PK will be evaluated as follows:
• Changes in plasma dapansutrile concentrations and population PK parameters.
Safety criteria for evaluation are as follows:
• AEs during the clinical trial
• Physical examinations
• Vital signs (pulse, respiratory rate, resting blood pressure, temperature,
and weight)
• Laboratory measures (chemistry, hematology, and urinalysis)
• ECGs.
Biomarkers will be evaluated as follows:
• Changes in plasma levels of circulating C-reactive protein (CRP),
neutrophils, and relevant inflammatory cytokines (e.g., interleukin [IL] 1β,
IL-6).
Background summary
Gout is the most common inflammatory arthritis, and it has had an increasing
incidence over the past several decades due at least in part to the rise in
medical comorbidities that promote hyperuricemia, including hypertension,
obesity, metabolic syndrome, type-2 diabetes mellitus, and chronic kidney
disease (Punzi et al., 2020). Furthermore, demographic and behavioral trends
suggest that a continued growth in the incidence of gout is likely (Kuo et al.,
2015). Acute gout flares are a primary factor in the decreased health-related
quality of life reported by patients with gout and can be debilitating and
associated with decreased work productivity (Roddy and Doherty, 2010; Khanna et
al., 2012).
Gout is a chronic autoinflammatory disease. Periodically, patients diagnosed
with hyperuricemia and gout have a sudden onset of symptoms, or a *flare*,
characterized by severe pain, joint swelling, redness, and/or warmth in one or
more joints. Recurrent autoinflammatory acute gout flare episodes are driven
by a hyperuricemia-associated activation of the NOD-like receptor family pyrin
domain containing 3 (NLRP3) inflammasome due to deposited monosodium urate
(MSU) crystals in affected joints (Narang and Dalbeth, 2020).
Olatec*s investigational medicinal product (dapansutrile tablets) is in
clinical development for the treatment of acute gout flares. Dapansutrile, a
selective oral NLRP3 inhibitor, prevents the processing of the precursor forms
of IL 1β and IL 18 and secretion of the bioactive forms of these highly
inflammatory cytokines (Marchetti et al., 2018). In an acute gout flare, MSU
crystals activate NLRP3, resulting in the production of active IL 1β in the
affected joints (Martinon et al., 2006). Several studies in humans and mice
have demonstrated that IL 1β is the pivotal cytokine in gouty inflammation and
the causative agent mediating the symptoms of acute gout flares, including
joint pain due to inflammation (Marchetti et al., 2018; Joosten et al., 2010;
Schlesinger et al., 2012; Janssen et al., 2019; Dinarello, 2019). IL-1β
release, in turn, leads to the downstream release of IL-6 and other cytokines
and chemokines. Moreover, in gouty arthritis flares, increased synovial fluid
neutrophils in the affected joints contribute to the intense inflammation. The
neutrophil infiltration during the onset of gouty arthritis is predominantly
mediated by the NLRP3- and IL 1β-dependent IL-8 production.
For prompt and effective control of the clinical signs and symptoms in subjects
with an acute gout flare, oral therapeutic agents that target the
NLRP3-mediated response and inhibit the release of IL 1β, such as dapansutrile,
are well-positioned to rapidly and significantly reduce or eliminate the acute
autoinflammatory response.
The current standard of care for an acute gout flare in the US is to prescribe
non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or colchicine
(FitzGerald et al., 2020). Each of these therapies has limitations in their use
in acute gout flares, such as the risks associated with NSAID use on common
renal and cardiac comorbidities, the risks associated with chronic or recurrent
high-dose steroid use in patients with hypertension and/or Type 1 or Type 2
diabetes, and the narrow therapeutic window with colchicine.
Given the limitations of currently available therapies, the development of new
oral pharmaceutical therapies is warranted. Preferably, these new therapies
should involve novel mechanisms of action or inhibition of new biological
targets in order to achieve efficacy and also have safety and tolerability
profiles that do not negatively impact medical comorbidities associated with
gout. The Sponsor believes that dapansutrile has the potential to be one such
therapy.
This clinical trial is designed to investigate the clinical activity and safety
of dapansutrile tablets compared to placebo in subjects with an acute gout
flare.
Study objective
This study has been transitioned to CTIS with ID 2024-518844-20-00 check the CTIS register for the current data.
Primary Objective:
To evaluate the efficacy of dapansutrile as an acute gout flare treatment
compared to placebo in reducing joint pain at 72 hours post initial loading
dose of Investigational Medicinal Product (IMP)
Secondary Objectives:
1. To further assess the clinical activity of dapansutrile compared to placebo
in reducing joint pain at scheduled time points post initial loading dose of IMP
2. To assess the clinical activity of dapansutrile compared to placebo in
treating signs and symptoms of an acute gout flare other than pain (tenderness,
swelling, erythema, warmth, and range of motion)
3. To assess the use of and time to the first intake of any Rescue Medication
and/or Escape Medication taken for non-response
4. To characterize the population pharmacokinetics (PK) of dapansutrile and
exposure response relationship for efficacy and safety
5. To assess the safety and tolerability of dapansutrile compared to placebo
Exploratory Objective
1. To assess and compare changes in relevant circulating inflammatory
biomarkers between dapansutrile and placebo
Study design
This is a multi-center Phase 2/3 randomized, double-blind, placebo-controlled,
parallel-group safety and efficacy study with a 7-day period of IMP treatment
conducted in subjects with an acute gout flare.
Up to 300 eligible subjects will be randomized (2:1) to one of the following
treatment arms in order to have 255 evaluable subjects:
• Treatment Arm 1 (Dapansutrile): initial loading dose of 2000 mg dapansutrile
on Study Day 1 followed by a maintenance regimen of 1000 mg dapansutrile
starting 12 hours (-4 / +2 hours) later administered BID through the second
dose on Study Day 7, inclusive (N = up to 200 subjects); or
• Treatment Arm 2 (Placebo): initial loading dose of matching placebo (to mimic
dapansutrile dosing) on Study Day 1 followed by a maintenance regimen of
matching placebo starting 12 hours (-4 / +2 hours) later administered BID
through the second dose on Study Day 7, inclusive (N = up to 100 subjects).
Randomization will be stratified based on region (US vs EU).
At the Screening Visit, subjects with a known history of gout will provide
informed consent and then be screened for initial eligibility during the
quiescent phase of gout. When the subject experiences his/her next acute gout
flare, the subject will return to the study site for the Baseline Visit/Study
Day 1 and for confirmation of all eligibility criteria, at which time subject
will be randomized into the study if eligibility criteria are met. Eligible
subjects must have a documented acute gout flare in at least one joint but not
more than three joints at the Baseline Visit/Study Day 1.If only one joint is
affected at the Baseline Visit/Study Day 1, it will be designated as the
*target joint*. If more than one joint is affected, then the currently most
painful (according to the subject), actively flaring joint, among typical
joints affected by gout at the time of the Baseline Visit/Study Day 1, will be
designated as the *target joint* the other affected joint(s) will be designated
as a *non-target joint(s)*. The location of the target joint and any actively
flaring non-target joints at the time of the Baseline Visit/Study Day 1 will be
recorded. Additional (pre-dose) baseline safety and efficacy assessments will
be conducted, and the initial loading dose of IMP (i.e., dapansutrile or
placebo) will be self-administered with water at the clinical site. Following
their initial loading dose of IMP, subjects will remain in the clinic for a
brief safety observation period, and once vital signs and any observed AEs are
recorded 1 hour (± 15 minutes) post initial loading dose of IMP, the subjects
will be released from the clinical site. Subjects will self-administer their
second Study Day 1 dose of IMP at home approximately 12 hours later (with an
allowance for the second Study Day 1 dose to be taken 8 to 14 hours post
initial loading dose). For the remainder of IMP doses, subjects will
self-administer IMP at home BID, with dosing occurring at approximately 12 hour
intervals and at approximately the same time of day across Study Days.
Subjects will return to the clinical site for 3 additional visits (with the
indicated visit windows allowed): Visit 2/Study Day 4 (+ 1 day), Visit 3/Study
Day 8 (+ 2 days), and Visit 4/Study Day 15 (follow-up visit) (± 1 day).
Additionally, all subjects may be contacted by telephone or SMS/text message
for dosing compliance confirmation approximately every 24 - 48 hours during the
Treatment Period. Subjects will be contacted by telephone on Study Day 36 (± 3
days) for additional safety follow up.
Assessments to evaluate safety, clinical activity (for pain and signs and
symptoms other than pain in the target joint [tenderness, swelling, erythema,
warmth, and range of motion]; for pain in the non-target joint[s]), and quality
of life (QoL) will be conducted at study visits. Additionally, target joint
pain assessments, IMP administration and any use of Rescue Medication, Escape
Medication (defined as gout medications taken for non-response) and/or other
prohibited medications taken will be captured through subject entries in an
electronic Clinical Outcome Assessments (eCOA) study diary (eDiary). The eDiary
target joint pain assessments should be completed by the subject prior to
taking their dose of IMP for a given timepoint (e.g., a morning pain assessment
should be completed before a dose of IMP is taken that morning).
Safety and tolerability will be evaluated by monitoring the occurrence of AEs
and changes in physical examination findings, vital signs, clinical safety
laboratory test results (chemistry, hematology, and urinalysis), and ECGs.
Intervention
Treatment arm 1 (Dapansutrile): iinitial loading dose of 2000 mg dapansutrile
on Study Day 1 followed by a maintenance regimen of 1000 mg dapansutrile
starting 12 hours (-4 / +2 hours) later administered BID through the second
dose on Study Day 7
Treatment arm 2 (Placebo): mimics dapansutrile dosing
Study burden and risks
Please refer to the study schedule in the protocol (pg 56 - 58).
Participating in this study is approximately 36 days. Subjects will visit the
hospital 4 times in the first 15 days.
During this study, the following tests and assessments can be done, but not
necessarily during every visit:
- Physical Examination
- Blood test
- Urine sample for safety assessment
- If the subject is a woman of childbearing potential, she will be asked to
provide urine for pregnancy test.
- Fill in the ediary
- Electrocardiogram (ECG)
- Microscopic evaluation of synovial fluid or imaging evidence of urate
deposition may be performed 1 time.
It is also possible for the subject to receive every 24 or 48 hours a text
message to check whether the study drug and/or emergency drug has been taken
appropriately.
800 Fifth Avenue Fl 25D
New York 10065
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Listed location countries
Age
Inclusion criteria
1) Male and female subjects >= 18 years of age
2) Clinical diagnosis of gout according to the 2015 ACR/EULAR Gout
Classification Criteria at the Screening visit or Baseline Visit/Study Day 1
(i.e. subject must have at least 8 points or meet sufficient criterion). In
addition:
a. Newly presenting subjects: Diagnosis of gout must be confirmed in the target
joint as indicated by either the presence of monosodium urate (MSU) crystals by
microscopic evaluation of synovial fluid from the target joint or bursa OR by
imaging evidence of urate deposition in the target joint or bursa at the
Baseline Visit/Study Day 1
b. Previously diagnosed subjects: Confirmation of gout diagnosis as per
criterion 2a; OR history of gout diagnosis per one of the following:
- documented history of the presence of MSU crystals in synovial fluid from the
target joint or bursa; OR
- historical imaging report of urate deposition in the target joint or bursa in
their medical record; OR
- documented history of 2 or more gout flares in the previous 18 months
3) Confirmation of a gout flare in the target joint that began within 96 hours
prior to the Baseline Visit/Study Day 1, based on the presence (at the Baseline
Visit/Study Day 1) of subject-reported target joint pain at rest of >= 50 mm on
a 0 to 100-mm VAS and at least two of the following criteria in the target
joint:
a. Subject-reported flare
b. Subject-reported warm joint
c. Subject-reported swollen joint
4) Acceptable overall medical condition to safely participate in the study and
complete all study procedures (with specific regard to cardiovascular, renal,
and hepatic conditions), in the opinion of the Investigator
5) Able and willing to provide written informed consent prior to initiation of
any study related procedures
6) Ability, in the opinion of the Investigator, to understand and comply with
all the requirements of the study, which includes understanding restrictions
regarding the use of Rescue Medication, Escape Medication and other prohibited
medications, including other pain medications, as outlined in Section 4.10.3 of
the protocol
Exclusion criteria
1) Woman of childbearing potential, or man whose sexual partner(s) is a woman
of childbearing potential, who:
a. Is or intends to become pregnant (including use of fertility drugs) while
participating in the study (through the Study Day 36 Follow-up call)
b. Is lactating/breastfeeding or plans to breastfeed while participating in the
study (female subjects only)
c. Is not willing to use an acceptable, highly effective method of
contraception until all follow-up procedures are complete (see protocol Section
4.10.2 for more details on acceptable forms of contraceptives)
2) Presence of any palpable and visible tophi by physical examination
3) Has >= 4 joints with an acute gout flare at the Baseline Visit/Study Day 1
4) Presence of rheumatoid arthritis or other acute inflammatory arthritis
5) Evidence/suspicion of infectious/septic arthritis
6) Clinically significant general pain or non-gout-related joint pain that
would interfere with the subject*s ability to accurately assess pain in the
target joint, in the opinion of the Investigator
7) Known history of any clinically significant or unstable medical condition or
any other disorder, condition, or circumstance (including secondary pain, or
recreational or medical use of substances that may alter pain perception such
as cannabidiol [CBD]- and
tetrahydrocannabinol [THC]-containing substances, psilocybin, etc.) that, in
the opinion of the Investigator, has the potential to prevent study completion
and/or to have a confounding effect on outcome assessments
8) Any other concomitant medical or psychiatric conditions, diseases, or prior
surgeries that, in the opinion of the Investigator, would impair the subject
from safely participating in the trial and/or completing protocol requirements
9) Use of any prohibited concomitant medications/therapies over the periods
defined in Protocol Section 4.10.3 or planned use of any prohibited concomitant
medications/therapies during the Treatment Period (including the use of
paracetamol/acetaminophen within 4 hours prior to the Baseline Visit/Study Day
1 or other pain medications within 12 hours prior to the Baseline Visit/Study
Day 1)
10) Use of any product containing paracetamol/acetaminophen within 4 hours
prior to the Baseline Visit/Study Day 1 or planned use during the Treatment
Period (with the exception of sponsor-provided Rescue Medication
[paracetamol/acetaminophen], which is permitted after completion of the first
target joint pain assessment on Study Day 4)
11) Meets 2 or more of the criteria for substance use disorder provided in
Appendix 1 within 1 year of the Baseline Visit/Study Day 1
12) History of, or known positive for, human immunodeficiency virus (HIV),
hepatitis B surface antigen (HBsAg), or antibodies to hepatitis C virus (HCV)
with a positive polymerase chain reaction (PCR) result for HCV
13) Known diagnosis of chronic kidney disease or known history of renal
impairment (e.g., estimated glomerular filtration rate [eGFR] < 45 mL/min/1.73
m2)
14) Enrollment in any trial and/or use of any investigational medicinal product
or device within the immediate 1-year period prior to the Baseline Visit/Study
Day 1
15) Enrollment in previous gout studies with dapansutrile
16) Positive test for severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) infection, if tested, within 4 weeks of the Baseline Visit/Study
Day 1
17) Active malignancy or recent malignancy with any systemic anti-cancer
treatment (e.g., immunotherapy or chemotherapy) within the past 6 months
18) Has a serious illness that resulted in hospitalization in the 30 days
preceding the Baseline Visit/Study Day 1
19) Has a hypersensitivity or allergy to dapansutrile or other drugs in its
class and/or the components of the IMP (dapansutrile tablets or placebo tablets)
20) Has a hypersensitivity or allergy to paracetamol/acetaminophen
21) Is an employee, family member, or student of the Investigator or clinical
site
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 | CTIS2024-518844-20-00 |
| EudraCT | EUCTR2019-002717-19-NL |
| ClinicalTrials.gov | NCT05658575 |
| CCMO | NL82797.068.22 |