A phase 3 clinical trial to confirm efficacy and evaluate safety of twice-daily delgocitinib cream 20 mg/g compared with cream vehicle for a 16-week treatment period in adult subjects with moderate to severe chronic hand eczema (DELTA 2)

CHE is a serious inflammatory skin disorder located anywhere on the hands or
wrists. It is clinically characterised by erythema, infiltration,
hyperkeratosis, oedema, and vesicles.Secondary signs include scaling, fissures,
and erosions, and the condition may be exacerbated
by bacterial infections. Important symptoms include itch and pain, and the
disease is often characterised by chronic 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 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), and the most common subtypes of
CHE are found to be irritant contact dermatitis, atopic hand eczema, and
hyperkeratotic eczema (5). Other subtypes include allergic contact dermatitis,
contact urticaria/protein contact dermatitis, and recurrent vesicular hand
eczema (pompholyx) (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 point 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 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 quality of life, 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 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 can be effective and a necessary
prerequisite for successful therapy on a longer term, but elimination may in
many circumstances be difficult to achieve. Although lacking documented
treatment effect, 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.
Whereas mild CHE to some extent may be managed by elimination of triggers and
general skin care, management of moderate to severe CHE is more cumbersome.
Alitretinoin (24) is the only approved product specifically indicated for
treatment of CHE but is only indicated for severe CHE and only approved in few
countries worldwide (and not approved in the US). Alitretinoin treatment has
various safety limitations and is therefore only indicated for use in adults
who have severe CHE that is unresponsive to treatment with potent TCS.
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 and are restricted to short-term use which is not
suitable in a chronic disorder characterised by relapsing features often
resulting in long-term treatment exposure. 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, 25), 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 the everyday lives of patients with
moderate to severe CHE. Delgocitinib has the potential to address the unmet
medical need associated with this serious disease.

Primary objective:
- To confirm the efficacy of twice-daily applications of delgocitinib cream 20
mg/g compared with cream vehicle in the treatment of adult subjects with
moderate to severe CHE.

Secondary objective:
- To confirm the health-related quality of life and efficacy of twice-daily
applications of delgocitinib cream 20 mg/g compared
with cream vehicle in the treatment of adult subjects with moderate to severe
CHE.
- To evaluate the safety of twice-daily applications of delgocitinib cream 20
mg/g compared with cream vehicle in the treatment of adult subjects with
moderate to severe CHE.

The trial will consist a screening period of 1 to 4 weeks (weeks -4/-1 to 0),
an initial treatment period of 16 weeks (week 0 to week 16) and a follow-up
period (week 16 to week 18)

Screening period:
The screening period has a minimum duration of 1 week and a maximumduration of
4 weeks. At the screening visit, the subjects* eligibility to enter the trial
will be checked, and wash-out of treatments listed as exclusion criteria will
be initiated if applicable. In view of a 28-day wash out for some of these
treatments, the screening period can be extended up to 31 days. The subjects
will receive an eDiary device and training in completion of the eDiary.

Treatment period:
At baseline (Day 1), the subjects* eligibility to enter the trial will be
confirmed.If still eligible, the subjects will be randomised 2:1 to treatment
with
delgocitinib cream 20 mg/g or cream vehicle. The randomisation will be
stratified by the baseline severity of CHE according to IGA-CHE (moderate
and severe) and region (Europe and North America). The first application of IMP
will occur at the trial site at baseline (Day 1). The
subsequent IMP applications will be performed by the subjects at home twice
daily for 16 weeks. During the treatment period, the subjects will be required
to return to the trial site for the visits scheduled at Weeks 1, 2, 4, 8, 12,
and 16. The last IMP application will occur at the subject*s home before the
subject attends the visit scheduled at Week 16.

Follow-up period:
The subjects will attend a follow-up visit (performed via phone, but can be a
site visit if needed) approximately 2 weeks after the last IMP application for
assessment of safety. Eligible subjects who complete the treatment period (i.e.
who do not permanently discontinue IMP prior to Week 16) will be invited to
participate in an open-label LTE trial (LP0133-1403, conducted under a separate
protocol). Subjects who continue in the LTE trial will not be required to
complete the follow-up period, as collection of safety data and safety
surveillance will continue in the LTE trial.

- Name of IMP: delgocitinib cream.
- Active substance: delgocitinib.
- Dosage form: cream.
- Concentration: 20 mg/g and cream vehicle.
- Dose and method of administration: topical application twice daily.

Cream vehicle.
Cream vehicle contains the same excipients in the same concentration only
lacking delgocitinib.

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 the most severe
disease state. Alitretinoin is only approved in few countries worldwide and not
approved in the US.
2 out of 3 subjects in this trial will receive active treatment with
delgocitinib cream 20 mg/g which was shown to be effective in CHE in the phase
2b trial LP0133-1273 (see Section 5.2). 1 out of 3 subjects will receive cream
vehicle. All subjects may receive rescue treatment if required (Section 9.5),
regardless of their treatment allocation. Eligible subjects who complete the
treatment period (i.e. who do not permanently discontinue IMP prior to Week 16)
will be invited to participate in an open-label LTE trial (LP0133-1403,
hereafter referred to as *the LTE trial*).
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 (31).
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 only 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 (32) and FDA (33) 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. 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 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).