A phase 3 extension trial of DELTA 1 and DELTA 2 to evaluate the long-term safety of a twice-daily treatment with delgocitinib cream 20 mg/g as needed for up to 36 weeks in adult subjects with chronic hand eczema (DELTA 3)

Chronic hand eczema (CHE) is a serious inflammatory skin disorder located
anywhere on the hands or wrists. In the acute stage, it is clinically
characterised by erythema, infiltration,oedema, or vesicles, and in the chronic
stage by scaling, fissures, and hyperkeratosis, and the condition may be
exacerbated by bacterial infections. Important symptoms include itch and pain,
and the disease is often characterised by relapses and a poor prognosis. CHE
refers to hand eczema which persists for more than 3 months or returns twice or
more often within 12 months (1).
Hand eczema aetiology is usually multifactorial, and it is generally agreed
that no simple relationships exist between clinical patterns and aetiological
diagnoses (2). Several different classifications have been proposed (1, 3, 4),
however it is generally agreed that the most
common subtypes of CHE are contact dermatitis (irritant and allergic), atopic
hand eczema, and hyperkeratotic eczema (5). Other subtypes include acute
recurrent vesicular hand eczema, and contact urticaria/protein contact
dermatitis (1).
The reported prevalence and incidence rates of hand eczema vary considerably,
depending on the methodology in the collection of data. In a review of data
available from 1964 to 2007, the prevalence of hand eczema in the general
population was approximately 4%, 1-year prevalence about 10%, and life-time
prevalence approached 15% (6). In another study by Thyssen et al. (7),
approximately 7-10% of patients with hand eczema reported symptoms *nearly all
the time*, implying a chronic state of the disease. Based on data from 7
studies, the incidence rate of hand eczema was 5.5 cases/1000 person-years with
a higher median incidence rate among women (1). Several risk factors, such as
pre-existing atopic dermatitis (AD), female sex, wet work, and contact allergy
have been identified (6, 8). The prevalence of hand eczema is different across
age groups (6) with a mean/median first onset in the early or mid-20*ies
(9-11). However, approximately one-third of men and women report their first
hand eczema before the age of 20 (12). The socioeconomic burden of CHE is
significant. 5 studies from 4 countries have found that total societal costs
(direct and indirect) ranged between USD $1,924 and USD $8,212 (inflated to
2017 cost) per patient per year (1, 13-16). CHE is associated with increased
sick leave (17, 18) as well as job loss and change in jobs (5, 19, 20).
Overall, CHE has a significant detrimental effect on health-related quality of
life (HRQoL), work productivity, daily activities, and health care costs (13).
Although the molecular mechanisms underlying CHE are not fully understood, a
large panel of cytokine-mediated signalling cascades have been identified as
part of the pathophysiology, including cytokine responses representing Th2
pathway (IL-4, IL-13), Th22 pathway (IL-22), Th17 pathway (IL-17), Th1 pathway
(interferon-γ), and the JAK/STAT (janus kinase/signal transducer and activator
of transcription) pathway. As the JAK proteins are required for signalling of
most cytokines, blocking of JAKs reduces cytokine signalling and thereby
abrogates the vicious cycle that leads to the development of CHE (21-23).
CHE is generally difficult to treat and presents with periods of flares and
periods of remissions. Long-term disease control of CHE may require reactive
treatment of flares and proactive treatment for the prevention of flares.
Treatment of CHE involves different disease management strategies such as
elimination of triggers, general skin care, and anti-inflammatory therapy in a
step-wise approach. General skin care in terms of emollients is widely used and
recommended by physicians, but evidence of efficacy is sparse (1). Elimination
of triggers such as allergens and irritants is a necessary prerequisite for
successful therapy on a longer term. Topical corticosteroids (TCS) remain the
mainstay of topical anti-inflammatory therapy for hand eczema. However,
long-term use of TCS is restricted due to side effects such as skin atrophy and
potential inhibition of skin barrier repair (24). Whereas mild CHE to some
extent may be managed by elimination of triggers, general skin care, and TCS,
management of moderate to severe CHE is more cumbersome. Alitretinoin (25) is
the only approved product specifically indicated for treatment of CHE but is
only indicated for severe CHE unresponsive to treatment with potent TCS, and
only approved in Europe and a few other countries worldwide.
Considering the paucity of approved therapies for the treatment of CHE, other
therapeutic options are limited to those approved for other skin diseases with
an inflammatory pathophysiology. These applied treatments lack the clinical
documentation for use in CHE.
As the currently available treatment options either lack documented treatment
effect or are limited by restrictions of long-term use due to safety concerns
(1, 26), there is a high unmet medical need for new topical treatment of
moderate to severe CHE with high efficacy in combination with a good safety
profile especially for long-term use. New and better treatments would
potentially improve HRQoL of patients with moderate to severe CHE.Delgocitinib
has the potential to address the unmet medical need associated with this
burdensome disease.

Primary objective:
To evaluate the long-term safety of an as-needed treatment with twice-daily
applications of delgocitinib cream 20 mg/g.

Secondary objective:
To evaluate the long-term efficacy of an as-needed treatment with twice-daily
applications of delgocitinib cream 20 mg/g.

Other/exploratory objectives:
To explore efficacy, health-related quality of life, and work productivity for
an as needed treatment with twice-daily applications of delgocitinib cream 20
mg/g.

This trial is a phase 3, open-label, multi-site, extension trial. The trial is
designed to evaluate the long-term safety of twice-daily applications of
delgocitinib cream 20 mg/g as needed in eligible subjects with CHE who
completed one of the 2 pivotal phase 3 trials with delgocitinib cream 20 mg/g
or cream vehicle (parent trials - LP0133-1401 or LP0133-1402). The trial will
include a screening period of up to 4 weeks (Week -4 to Week 0) and a treatment
period of 36 weeks during which subjects will be treated with delgocitinib
cream 20 mg/g twice daily as needed. During the treatment period, subjects will
attend site visits every 4 weeks; if needed, unscheduled visits will be
performed to initiate or stop treatment with delgocitinib cream 20 mg/g twice
daily. Subjects will attend an end-of-treatment visit at Week 36 and a safety
follow-up will be performed by phone approximately 2 weeks after the end-of
treatment visit to assess any AEs.

Screening period (Week -4 to Week 0)

Eligibility will be assessed at screening and at the baseline visit. To
facilitate a smooth transition between completing treatment in the parent trial
and commencing participation in the extension trial, potentially eligible
subjects will be offered participation in the extension trial preferably at the
Week 12 visit (prior to the end-of-treatment visit at Week 16) in the parent
trial. Hence, the screening period is expected to overlap with the last 4 weeks
of the treatment period in the parent trial. Any assessment from the Week 12
visit performed in the parent trials may be used to confirm
eligibility for this extension trial. However, if for any reason, assessments
from the Week 12 visit are not evaluable, the Week 16 assessments from the
parent trials may be used as screening results for this trial, without
precluding the initial enrolment of the subject in this extension trial. The
end-of-treatment visit in the parent trial will coincide with the baseline
visit of the extension trial. For subjects meeting the eligibility criteria
(those which can be evaluated prior to the end-of-treatment visit [Week 16] in
the parent trials), assessments performed at the end-of-treatment visit in the
parent trial may be re-used without being repeated for this extension trial.
The subjects will have their eDiary from the parent trial updated to record
PROs, treatment compliance, and local tolerability in this extension trial.
Completion of the eDiary will be initiated from the baseline visit (Day 1).

Treatment period (Week 0 up to Week 36)

Definition of terms:
Response is defined as IGA-CHE score of 0 (clear) or 1 (almost clear).
Treatment re-initiation is triggered by an IGA-CHE score of >=2 after having
achieved
IGA-CHE 0 (clear) or 1 (almost clear) in this trial.

At baseline (Day 1), subjects will be evaluated by the investigator to
determine the severity of their CHE. Subjects with IGA-CHE score of 0 (clear)
or 1 (almost clear) will not be assigned treatment with delgocitinib cream 20
mg/g; they will however continue to use their routine skin care emollient, if
applicable. Subjects with IGA-CHE score >=2 will start treatment with
twice-daily delgocitinib cream 20 mg/g. Treatment will continue until IGA-CHE
score of 0 (clear) or 1 (almost clear) is achieved.

If a subject experiences worsening of CHE signs and symptoms while
off-treatment, the subject should contact the trial site. If a scheduled visit
is not planned within a reasonable timeframe, an unscheduled visit should be
planned as soon as possible. If an IGA-CHE score >=2 is attested, the subject
will be dispensed delgocitinib cream 20 mg/g and the investigator will instruct
the subject to start treatment with twice-daily applications. The minimal set
of assessments to be performed at an unscheduled visit to decide if treatment
with delgocitinib cream 20 mg/g should be re-initiated is IGA-CHE and
collection of AEs.

While on treatment with delgocitinib cream 20 mg/g, if the subject observes
that CHE signs and symptoms are resolved, they should contact the trial site.
If a scheduled visit is not planned within a reasonable timeframe, an
unscheduled visit should be planned as soon as possible. If IGA-CHE score of 0
(clear) or 1 (almost clear) is achieved, the subject will be instructed to stop
treatment and return all opened and unopened tubes to the site. The minimal set
of assessments to be performed at an unscheduled visit to decide if treatment
with delgocitinib cream 20 mg/g should be stopped is IGA-CHE, collection of
AEs, and investigator*s assessment of local tolerability.

For all subjects, regardless if on- or off-treatment, IGA-CHE will be evaluated
by the investigator at visits to the trial site every 4 weeks from baseline up
to Week 36.

If no improvement is observed after a continuous treatment period of 16 weeks
with twice-daily delgocitinib cream 20 mg/g, it will be at the discretion of
the investigator to evaluate if the subject will benefit from further treatment
with delgocitinib cream 20 mg/g.

If CHE becomes *intolerable*, the subject should contact the investigator for
an unscheduled visit. Rescue treatment for CHE may be provided to subjects at
the discretion of the investigator. In this case, delgocitinib cream 20 mg/g
will be discontinued immediately and the subject will be withdrawn from the
trial.

At Week 36, subjects will attend an end-of-treatment visit. If treatment for
CHE is required beyond the end-of-treatment visit, subjects will be referred to
standard of care treatment at the discretion of the investigator.

Follow-up period (Week 36 to Week 38)

All subjects will complete a 2-week off-treatment follow-up period for the
assessment of safety. The safety follow-up period will start after the Week 36
visit (end-of-treatment). Note that for subjects who permanently discontinue
delgocitinib cream 20 mg/g, the 2-week follow-up period will start at the time
of the early termination visit. The safety follow-up visit will be performed
via phone, but can be a site visit if needed.

Name of IMP: delgocitinib cream
Active substance: delgocitinib
Dosage form: cream
Concentration: 20 mg / g
Dose and method of administration: apply topically twice daily

There is a clear unmet medical need for new long-term therapies for subjects
with moderate to severe CHE. The only currently approved treatment option
indicated for patients with CHE is alitretinoin, which is associated with
significant safety precautions and is only indicated for severe CHE.
Alitretinoin is only approved in Europe and a few countries worldwide.
Delgocitinib is a topically applied JAK inhibitor. Systemic JAK inhibitors are
associated with potential adverse reactions and a black box warning concerning
the risk of serious infections, malignancy, and thrombosis. These risks are not
considered relevant for delgocitinib cream due to the very low systemic
exposure observed in previous trials with topically applied
delgocitinib. No important identified risks of delgocitinib have been
documented during the overall nonclinical and clinical development to date. A
detailed overview of nonclinical and clinical data on delgocitinib is available
in the current investigator*s brochure (33). The risk to subjects in this trial
will be minimised by fulfilment of all eligibility criteria and by close
clinical monitoring. To ensure the safety and wellbeing of subjects
participating in this trial, safety will be monitored during the trial, and
stopping criteria have been defined (Section 10.2).
The blood sampling procedure poses the same low risk as normally associated
with this procedure (i.e. infection, bleeding into the surrounding tissue, and,
very rarely, inflammation of the vein or formation of blood clots). Blood
sampling will be conducted by qualified medical personnel.
Altogether, the risks associated with participating in this clinical trial are
considered low and are expected to be outweighed by the benefit of a potential
future treatment option for CHE.Participation in clinical trials may currently
be associated with increased risk and added challenges due to the COVID-19
pandemic caused by SARS-CoV-2. The proposed trial and treatment with
delgocitinib cream 20 mg/g are not believed to put subjects with CHE at an
increased risk for viral infections including SARS-CoV-2. However, a risk of
exposure to infected people cannot be excluded as the trial subjects may enter
public areas (e.g. commute to the trial site) and have additional human contact
(e.g. with trial site staff). Appropriate risk assessments and mitigation
measures must be considered to protect the subjects and trial site staff and to
ensure the integrity of the trial data. Both EMA (34) and FDA (35) as well as
national health authorities in Europe have issued new guidelines that aim to
provide recommendations for conduct of clinical trials during the COVID-19
pandemic. Given the circumstances of the potentially relapsing pandemic
situation with regard to the spread of COVID-19 in the future, special
attention will be paid to protecting subjects participating in the trial and
site staff involved in the investigations against infection with SARS-CoV-2 as
requested by the newly issued EMA guideline. During the trial, the
investigators will be trusted to take appropriate actions to ensure the safety
of the individual subjects according to local authority-issued preventive
measures. As these can differ across countries and regions, no general
instruction from the sponsor can be provided concerning subject safety and the
need for postponing trial visits. In case of local authority-issued preventive
measures, the investigator can convert on-site visits into phone or
video consultations. At phone/video visits, no investigator assessments of
efficacy can be done. Therefore, if and only if subjects are prevented from
attending on-site visits due to local authority-issued preventive measures, a
decision to start or stop treatment with delgocitinib 20 mg/g can be taken
based on a phone or video visit. Safety monitoring remains an obligation to LEO
Pharma, and it is considered feasible to collect safety data remotely (via
electronic communication) where on-site visits are not possible. Other
mitigating measures include collecting patient-reported outcome (PRO) data via
a web-based solution and ensuring supply of IMP to the subjects to overcome
local authority-issued preventive
measures due to the COVID-19 pandemic (see Appendix 7 for details).