Primary objectiveTo compare the effect on psoriasis symptoms of an adjustable brodalumab dosage regimen to standard brodalumab treatment in subjects with moderate-to-severe psoriasis and a body weight >=120 kg.Secondary objectives:To evaluate the…
ID
Source
Brief title
Condition
- Epidermal and dermal conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint:
• Having at least 90% lower Psoriasis Area and Severity Index (PASI) score
relative to baseline (PASI 90 response) at Week 40.
Secondary outcome
Key secondary endpoint:
• Having static Physician*s Global Assessment (sPGA) score of 0 or 1 at Week 40.
Additional Secondary endpoints:
• Having PASI 90 response at Week 52.
• Having sPGA score of 0 or 1 at Week 52.
• Having sPGAof genitalia (sPGA-G) of 0 or 1 at both Weeks 40 and 52.
• Having sPGA-G of 0 or 1 at Week 40.
• Having sPGA-G of 0 or 1 at Week 52.
• Having PASI 100 response at Week 40.
• Having PASI 100 response at Week 52.
• Change from baseline at Weeks 40 and 52 in PASI score.
• Change from baseline at Weeks 40 and 52 in affected body surface area (BSA).
• Having Dermatology Life Quality Index (DLQI) total score of 0 or 1 at Week 40.
• Having DLQI total score of 0 or 1 at Week 52.
• Change from baseline at Weeks 40 and 52 in DLQI total score.
• Occurrence of adverse events (AEs) up to Week 58.
• AUCtau at Weeks 14-16 and Weeks 40-42.
• Cmax at Weeks 14-16 and Weeks 40-42.
• tmax at Weeks 14-16 and Weeks 40-42.
• Change from baseline in concentration of serum inflammatory biomarkers at
Weeks 16 and 40.
Background summary
Psoriasis is an inflammatory skin disease that occurs in approximately 2% of
the population worldwide . It is a chronic polygenic inherited disease of
uncontrolled cutaneous inflammation that manifests, in the majority of
subjects, as plaque psoriasis, clinically seen as sharply demarcated, elevated,
scaling, erythematous plaques located predominantly on the scalp, extensor
sides of elbows and knees, and the sacral region . The skin lesions can be
painful, pruritic, and may cause significant emotional and physical discomfort
. Psoriatic arthritis is a musculoskeletal inflammatory disease that can be
seen as a manifestation of the psoriatic inflammatory process in up to 30% of
subjects with chronic plaque psoriasis .
In addition, psoriasis is associated with a range of comorbidities that include
cardiovascular disease, traditional cardiovascular risk factors, diabetes
mellitus, and psychiatric conditions such as depression and anxiety . Current
evidence indicate that obesity is bidirectionally associated with psoriasis,
meaning that obesity, through pro-inflammatory pathways, predisposes to the
development of psoriasis and that obesity aggravates existing psoriasis.
Inherently, obesity has been shown to increase the risk of major cardiovascular
events and cardiovascular mortality . Taken together, severe psoriasis in
combination with severe obesity is likely to cause a markedly increased
cardiometabolic burden in obese patients.
Thus, a high prevalence of cardiovascular disease is observed in obese
psoriasis patients. Therefore, an increased prevalence/incidence of
cardiovascular disease is expected in a trial investigating the efficacy and
safety of brodalumab relative to previous trials in the psoriasis
indication.
The majority of patients with psoriasis has mild to moderate disease and can be
treated with topical therapies. In patients with moderate-to-severe psoriasis,
phototherapy or systemic treatment, including biologics, are recommended
(topicals can be used as an adjunct to
biologics) . It is well known that obesity complicates treatment of psoriasis.
Reduced response to systemic and biological treatment has been shown in obese
patients and conditions associated with obesity may pose relative
contraindications to some traditional systemic agents. Thus, there is an unmet
need for effective and safe biological treatment in the population of psoriasis
patients with severe obesity.
Study objective
Primary objective
To compare the effect on psoriasis symptoms of an adjustable brodalumab dosage
regimen to standard brodalumab treatment in subjects with moderate-to-severe
psoriasis and a body weight >=120 kg.
Secondary objectives:
To evaluate the safety of an adjustable brodalumab dosage regimen in subjects
with moderate-to-severe psoriasis and a body weight >=120 kg.
To evaluate pharmacokinetics (PK) of brodalumab in subjects with moderate to
severe psoriasis and a body weight >=120 kg.
To explore the effect of brodalumab on systemic inflammation in subjects with
moderate-to-severe psoriasis and a body weight >=120 kg.
(Substudy is not applicable in the Netherlands)
Study design
This clinical trial is a randomised, double-blind, controlled, parallel group,
multi-centre trial consisting of 3 periods. The individual periods and visit
structure are further described below and overviews of the trial design and
scheduled procedures are displayed in Sections 3 and 4 of the protocol.
Screening period (-4 weeks to -2 weeks)
A screening visit will take place up to a maximum of 4 weeks and minimum of 2
weeks prior to the treatment period. The objective of the screening period is
to enroll eligible and informed subjects. This entails wash-out of specified
prohibited medication and specified laboratory testing.
Before any trial-related procedure is started, the subjects will receive the
necessary written and verbal information and instructions, including the
informed consent form (ICF) and the written subject information sheet. Each
subject will receive a unique subject number and the subject*s eligibility will
be determined by clinical examination and confirmation of the subject selection
criteria.
Treatment period (Week 0 to Week 52)
The start of the treatment period is defined as Week 0 (baseline; Day 1). At
this visit, eligibility will be confirmed by re-checking the criteria in
subjects who were eligible based on previous examinations, review of sufficient
wash-out of prohibited drugs, and review of electrocardiogram (ECG) and central
laboratory results from the screening visit. If still eligible, the subject
will continue in the trial and receive a unique subject ID number that
determines the application scheme of IMP for the individual subject (see
Section 9.3 of the protocol).
From Week 0 up to Week 16, all subjects will follow the standard brodalumab
regimen of 210 mg at Weeks 0, 1, and 2 and then every second week (Q2W+1)
(16-week induction period; see Section 9.2 of the protocol). Including Week 16
and until the last IMP administration at Week 50, the subject will follow an
adjustable treatment regimen with additional exposure (+70 mg brodalumab) or
placebo Q2W if PASI 90 response is not achieved at any visit from Week 16 to
Week 48.
Baseline, efficacy, and safety assessments during the trial are described in
Section 11 of the protocol.
Follow-up period (Week 52 to Week 58)
The safety follow-up visit is scheduled at Week 58, approximately 5 half-lives
after last IMP administration, provided that the last IMP was administered at
Week 50 as per protocol.
In case of early IMP discontinuation, the safety follow-up visit should occur
sooner (8 weeks after last dose of IMP), and then the Week 40 visit (Visit 25)
may become the last scheduled trial visit (i.e., in case of IMP discontinuation
at Week 32 or sooner).
It will be at the discretion of the investigator to ensure the treatment of
subjects who discontinue/complete the trial/treatment or ensuring that the
subjects are referred to other physician(s) according to standard practice.
Intervention
Kyntheum® (brodalumab)is a recombinant fully human monoclonal immunoglobulin
IgG2-antibody that binds with high affinity to human interleukin (IL)-17
receptor A (IL-17RA), thereby blocking the IL-17 pathway. Brodalumab is
approved in EU, UK, Canada, Japan, Taiwan, Thailand, Hongkong, China Brazil and
the USA for the treatment of moderate-to-severe plaque psoriasis in adult
patients who are candidates for systemic therapy.
Kyntheum® (brodalumab): Solution for subcutaneous injection, Brodalumab
formulated at a nominal concentration of 140 mg/mL including the
following excipients: Proline, Glutamate, Polysorbate 20, Water for injections
. Pre-filled syringe with 210 mg brodalumab in 1.5 mL solution.
Kyntheum® (brodalumab) ; Solution for subcutaneous injection, Brodalumab
formulated at a nominal concentration of 140 mg/mL including the
following excipients: Proline, Glutamate, Polysorbate 20, Water for injections
. Pre-filled syringe with 70 mg brodalumab in 0.5 mL solution.
Placebo; Solution for subcutaneous injection, The placebo solution is similar
to the active brodalumab solution except that it does not contain any active
substance. Pre-filled syringe with 0.5 mL solution.
Study burden and risks
A high body weight is associated with increased morbidity and poorer treatment
outcomes in patients with psoriasis . Thus, the subjects included in this trial
are a difficult-to-treat population, as indicated by the lower treatment effect
observed with the standard brodalumab
dosage in subjects with moderate-to-severe psoriasis and a body weight >=120 kg
(see Section 12 of the protocol).
Population PK exposure modelling supports that the adjustable brodalumab dosage
regimen in this trial may be associated with increased efficacy in subjects
with moderate-to-severe psoriasis and a body weight >=120 kg, assuming that a
higher exposure translates into higher efficacy.
The adjustable brodalumab dosage regimen explored in this trial will lead to
increased systemic exposure in subjects where the dosage is adjusted, compared
to subjects where the dose is not adjusted, which may be associated with
increased risk. However, the systemic
exposure in dose-adjusted subjects is expected to be similar to the systemic
exposure previously seen in subjects weighing 80 kg. The benefit/risk profile
is maintained by ensuring that only subjects who achieve suboptimal efficacy
with the standard regimen will receive an increased brodalumab dosage (or
placebo).
The only adverse events (AEs) that showed dose dependency in the phase 3
development programme were infections and neutropenia. These may occur with
increased frequency in patients receiving a higher dose of brodalumab. However,
the expected systemic steady state exposure of brodalumab in subjects >=120 kg
receiving treatment with 280 mg every 2 weeks (Q2W) does not exceed the
exposure predicted in subjects <=80 kg receiving treatment with 210 mg Q2W (see
Panel 20), and therefore no change in the safety profile due to increased
exposure is expected in this trial.
Altogether, the risks associated with participating in this clinical trial are
considered low and outweighed by the benefit of a potentially improved
treatment option for subjects with a body weight >=120 kg.
Industriparken 55
Ballerup 2750 Ballerup
DK
Industriparken 55
Ballerup 2750 Ballerup
DK
Listed location countries
Age
Inclusion criteria
* Signed and dated informed consent has been obtained prior to any
protocol-related procedures.
* Age >=18 to <75 years at the time of screening.
* Diagnosed with chronic plaque psoriasis at least 6 months before
randomisation as determined by the investigator.
* Body weight >=120 kg at the time of screening.
* Moderate-to-severe plaque psoriasis as defined by: BSA >=10% and
PASI >=12 at screening and baseline.
* No evidence of active or latent tuberculosis according to local standard of
care for patients requiring initiation of a biologic treatment
Exclusion criteria
* Diagnosed with erythrodermic psoriasis, pustular psoriasis, guttate
psoriasis, medication-induced psoriasis, or other skin conditions (e.g.,eczema)
that would interfere with evaluations of the effect of theinvestigational
medicinal product (IMP) on subjects with plaque psoriasis.
* Clinically important active infections or infestations, chronic, recurrent or
latent infections or infestations, or is immunocompromised (e.g., human
immunodeficiency virus, hepatitis B, and hepatitis C).
* Any systemic disease considered by the investigator to be uncontrolled
and either immunocompromising the subject and/or placing the subject at
undue risk of intercurrent diseases (including, but not limited to, renal
failure, heart failure, liver disease, diabetes, and anaemia).
* Known history of Crohn*s disease.
* Myocardial infarction or stroke, or unstable angina pectoris within the past
12 months.
* Any active malignancy.
* History of malignancy within 5 years, except for treated and considered
cured cutaneous squamous or basal cell carcinoma, in situ cervical cancer,
or in situ breast ductal carcinoma.
* History of suicidal behaviour (i.e., *actual suicide attempt*, *interrupted
attempt*, *aborted attempt*, or *preparatory acts or behaviour*) based on
the Columbia-Suicide Severity Rating Scale (C-SSRS) questionnaire at
screening or at baseline.
* Any suicidal ideation of category 4 or 5 (*active suicidal ideation with
some intent to act, without specific plan* or * active suicidal ideation with
specific plan and intent*) based on the C-SSRS questionnaire at screening
or at baseline.
* A Patient Health Questionnaire (PHQ)-8 score of >=10 corresponding to
moderate-to-severe depression at screening or at baseline.
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 | EUCTR2017-004998-13-NL |
| ClinicalTrials.gov | NCT04306315 |
| CCMO | NL73011.056.20 |