The primary objective of the study is to evaluate the efficacy of 2 dose regimens of dupilumab compared to placebo, administered with concomitant topical corticosteroids (TCS), in adult patients with severe AD who are not adequately controlled with…
ID
Source
Brief title
Condition
- Epidermal and dermal conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Endpoints
Primary: The primary endpoint in the study is: the proportion of
patients with Eczema Area and Severity Index (EASI) 75 (*75% improvement from
baseline) at week 16.
Secondary outcome
Secondary: The secondary endpoints are:
Efficacy
* Proportion of patients with EASI 75 (*75% improvement from baseline) at week
16 for patients with prior CSA use
* Proportion of patients with IGA 0 or 1 (on a 5-point scale) and a reduction
from baseline of *2 points at week 16
* Percent change from baseline to week 16 in the pruritus numerical rating
scale (NRS)
* Proportion of patients with improvement (reduction) of pruritus NRS *3 at
week 16
* Percent change from baseline to week 16 in the EASI score
* Change from baseline to week 16 in percent body surface area (BSA)
* Percent change from baseline to week 16 in the SCORing Atopic Dermatitis
(SCORAD)
*
* Change from baseline to week 16 in the Dermatology Life Quality Index (DLQI)
*
* Change from baseline to week 16 in the Hospital Anxiety and Depression Scale
(HADS)
* Change from baseline to week 16 in the Patient Oriented Eczema Measure (POEM)
* Percent change from baseline to week 2 in the pruritus NRS
* Topical treatment for AD * medication-free days to week 16
* Mean weekly dose of TCS through week 16
* Proportion of patients with EASI 75 (*75% improvement from baseline) at week
24
* Proportion of patients with EASI 75 (*75% improvement from baseline) at week
24 for patients with prior CSA use
* Proportion of patients with IGA 0 or 1 (on a 5-point scale) and a reduction
from baseline of *2 points at week 24
* Percent change from baseline to week 24 in the pruritus NRS
* Proportion of patients with improvement (reduction) of pruritus NRS *3 at
week 24
* Percent change from baseline to week 24 in the EASI score
* Change from baseline to week 24 in percent BSA
* Percent change from baseline to week 24 in the SCORAD
* Proportion of patients with SCORAD 50 (*50% improvement from baseline) at
week 24
* Change from baseline to week 24 in the DLQI
* Change from baseline to week 24 in the HADS
* Change from baseline to week 24 in the POEM
* Topical treatment for AD * medication-free days to week 24
* Change from baseline to week 24 in the Hospital Anxiety and Depression Scale
(HADS)
* Mean weekly dose of TCS through week 24
Safety and tolerability
* Incidence of skin infection treatment-emergent adverse events (TEAEs)
(excluding herpetic infections) from baseline through the on-treatment period
* Incidence of treatment-emergent serious adverse events (TESAEs) from baseline
through the on-treatment period
* Incidence of TEAEs leading to treatment discontinuation from baseline through
the on-treatment period
* Overall incidence of TEAEs from baseline through the on-treatment period
Background summary
A Phase 3 Study Investigating the Efficacy, Safety, and Tolerability of
Dupilumab Administered to Adult Patients with Severe Atopic Dermatitis who are
not Adequately Controlled with or are Intolerant to Oral Cyclosporine A, or
when this Treatment is not Medically Advisable.
The study will be executed in approximately 125 study sites in countries where
systemic cyclosporine A (CSA) is approved for the treatment of atopic
dermatitis (AD).
The duration of the study for a patient is approximately 40 weeks, including
the screening period.
See also section C4 and section of the protocol: Introduction and Rationale.
Study objective
The primary objective of the study is to evaluate the efficacy of 2 dose
regimens of dupilumab compared to placebo, administered with concomitant
topical corticosteroids (TCS), in adult patients with severe AD who are not
adequately controlled with, or are intolerant to, oral CSA, or when this
treatment is currently not medically advisable.
The secondary objective of the study is to assess the safety and tolerability
of 2 dose regimens of dupilumab compared to placebo, administered with
concomitant TCS, in adult patients with severe AD who are not adequately
controlled with, or are intolerant to, oral CSA, or when this treatment is
currently not medically advisable.
Study design
The study comprises a 2-week screening period, a 2-week medium-potency TCS
standardization period, a 24-week treatment period, and a 12 week safety follow
up period. This study is being done to evaluate dupilumab treatment in these
patients with severe AD who have also previously demonstrated inadequate
response to TCS. All patients will receive concomitant medium-potency TCS as
background concomitant therapy to reflect standard of care treatment of this
severe population.
After providing informed consent, patients will be assessed for study
eligibility at the screening visit. Patients will undergo screening between
day -28 and day -15, prior to randomization. During this 2-week screening
period, TCS treatment is allowed at the discretion of the investigator.
Starting on day -14, all patients will initiate a standardized TCS treatment
regimen, and will continue the standardized medium-potency regimen through the
end of the treatment period (week 24). During the 12 week follow-up period,
they may continue to receive TCS at the discretion of the investigator, for
intolerable AD disease activity.
Patients will also be required to apply moisturizers at least twice daily for
at least the 7 consecutive days immediately before randomization (baseline/day
1) and continue at least twice daily throughout the study.
Patients who continue to meet eligibility criteria at baseline (day 1) will
undergo assessments and will be randomized in a 1:1:1 ratio to receive either
once-weekly (qw) or every 2 week (q2w) subcutaneous (SC) injections of 300 mg
dupilumab (following an SC loading dose of 600 mg on day 1), or matching
injectable placebo, including the placebo for the loading dose. During weeks
in which dupilumab is not administered (in the q2w regimen), patients will
receive injectable placebo. In order to maintain blinding, all patients will
receive an injection (active or placebo) each week from day 1 to week 24
(treatment period).
The patients will be stratified by: 1) Baseline assessment of disease severity
(Investigator*s Global Assessment [IGA] 3 vs IGA 4) and 2) documented history
of no prior CSA exposure and not currently a candidate for CSA treatment or CSA
prior exposure that should not be continued or restarted.
Patients will be followed up for an additional 12 weeks for safety after the
end of the treatment period. Starting at week 24, patients may be rolled over
into an open-label extension (OLE) study, if they are considered eligible.
Patients who discontinued prematurely (ie, patients who did not complete the
protocol-defined end-of-treatment [EOT] visit) cannot enroll into the OLE study
before the date when the EOT visit would have normally occurred.
Intervention
Treatments
Study Drug
Dose/Route/Schedule: Patients will receive either qw SC injections of
300 mg dupilumab (following a loading dose of 600 mg on day 1), or q2w SC
injections of 300 mg dupilumab (following a loading dose of 600 mg on day 1)
during the 24 week treatment period. During weeks in which dupilumab is not
administered (in the q2w regimen), patients will receive injectable placebo.
Placebo
Route/Schedule: Patients will receive weekly injections of matching
placebo (following a placebo *loading dose* on day 1) during the 24-week
treatment period.
Background Treatment
Dose/Route/Schedule: TCS:
Starting on day -14, all patients are required to undergo treatment with TCS
using a standardized regimen according to the following guidelines:
* Apply medium-potency TCS once daily to areas with active lesions
* Low-potency TCS should be used once daily on areas of thin skin (face, neck,
intertriginous, and genital areas, areas of skin atrophy, etc) or for areas
where continued treatment with medium-potency TCS is considered unsafe
* Monitor the patient for signs of local or systemic TCS toxicity and stop
treatment as necessary
During the 24-week placebo-controlled study treatment period, medium potency
TCS dosing frequency will be symptom-based (IGA score) adjusted every 4 weeks
(q4w) as per the protocol-specified tapering algorithm.
Emollients:
All patients are required to apply moisturizers (emollients) at least twice
daily for at least the 7 consecutive days immediately before randomization
(baseline/day 1) and to continue through the end of the follow-up period.
However, to allow adequate assessment of skin dryness, moisturizers should not
be applied on the area(s) of non-lesional skin designated for such assessments
for at least 8 hours before each clinic visit. All types of moisturizers are
permitted, but patients may not initiate treatment with prescription
moisturizers or moisturizers containing additives during the screening period
or during the study. Patients may continue using stable doses of prescription
moisturizers or moisturizers containing additives, if initiated before the
screening visit.
Rescue Treatment
Dose/Route/Schedule: If medically necessary (ie, to control intolerable
AD symptoms), rescue treatment for AD may be provided to study patients at the
discretion of the investigator. If possible, investigators should attempt to
limit the first step of rescue therapy to high-potency TCS, and escalate to
systemic medications only for patients who do not respond adequately after at
least 7 days of topical treatment. Investigators should make every attempt to
conduct efficacy and safety assessments (eg, disease severity scores, safety
labs) immediately before administering any rescue treatment. An unscheduled
visit may be used for this, if necessary.
Study burden and risks
See section E9
Old Saw Mill River Road 777
Tarrytown, NY 10591
US
Old Saw Mill River Road 777
Tarrytown, NY 10591
US
Listed location countries
Age
Inclusion criteria
1. Male or female, 18 years or older ;2. Severe, Chronic AD, (according to American Academy of Dermatology Consensus Criteria [Eichenfield 2014]) ;3. EASI score *20 at the screening and baseline visits ;4. IGA score *3 (on the 0 to 4 IGA scale) at the screening and baseline visits ;5. *10% body surface area (BSA) of AD involvement at the screening and baseline visits ;6. Documented recent history (within 6 months before the screening visit) of inadequate response to treatment with TCS;7. Have applied a stable dose of topical emollient (moisturizer) twice daily for at least the 7 consecutive days immediately before the baseline visit;8. Documented history by a physician of either:;A. No prior CSA exposure and not currently a candidate for CSA treatment due to:;* medical contraindications (eg, uncontrolled hypertension on medication), or;* use of prohibited concomitant medications (eg, statins, digoxin, macrolide;* antibiotics, barbiturates, anti-seizure, nonsteroidal anti-inflammatory drugs,;* diuretics, angiotensin-converting-enzyme inhibitors, St John*s Wort, etc), or;* increased susceptibility to CSA-induced renal damage (elevated creatinine) and;* liver damage (elevated function tests), or;* increased risk of serious infections, or ;* hypersensitivity to CSA active substance or excipients, ;OR;B. Previously exposed to CSA, and CSA treatment should not be continued or restarted due to:;* intolerance and/or unacceptable toxicity (eg, elevated creatinine, elevated liver function tests, uncontrolled hypertension, paraesthesia, headache, nausea, hypertrichosis, etc), or;* inadequate response to CSA (defined as flare of AD on CSA tapering after a maximum of 6 weeks of high dose [5 mg/kg/day] to maintenance dose [2 to 3 mg/kg/day] or a flare after a minimum of 3 months on maintenance dose). Flare is defined as increase in signs and/or symptoms leading to escalation of therapy, which can be an increase in dose, a switch to a higher-potency class of TCS, or the start of another systemic non-steroidal immunosuppressive drug. Or;* requirement for CSA at doses >5 mg/kg/day, or duration beyond those specified in the prescribing information (>1 year).
Exclusion criteria
1. Participation in a prior dupilumab clinical study ;2. Treatment with an investigational drug within 8 weeks or within 5 half-lives (if known), whichever is longer, prior to screening;3. Hypersensitivity and/or intolerance to corticosteroids or to any other ingredients contained in the TCS product used in the study;4. Systemic CSA, systemic corticosteroids, or phototherapy within 4 weeks prior to screening, and azathioprine (AZA), methotrexate (MTX), mycophenolate mofetil (MMF), or Janus Kinase (JAK) inhibitors within 8 weeks prior to screening.;5. Treatment with TCI within 1 week prior to screening visit ;6. Treatment with biologics as follows:;* Any cell-depleting agents including but not limited to rituximab: within 6 months before the screening visit, or until lymphocyte count returns to normal, whichever is longer;* Other biologics: within 5 half-lives (if known) or 16 weeks prior to the screening visit, whichever is longer;7. Regular use (more than 2 visits per week) of a tanning booth/parlor within 4 weeks of the screening visit ;8. Treatment with a live (attenuated) vaccine within 12 weeks before the screening visit;9. Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals within 2 weeks before the screening visit;or superficial skin infections within 1 week before the screening visit. NOTE: patients may be rescreened no sooner than 2 weeks after infection resolves. ;10. Known or suspected history of immunosuppression, including history of invasive opportunistic infections (eg, tuberculosis [TB], histoplasmosis, Listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis) despite infection resolution; or unusually frequent, recurrent, or prolonged infections, per investigator judgment;11. Presence of any 1 of the following TB criteria: ;a. A positive tuberculin skin test at the screening visit;b. A positive blood QuantiFERON®-TB or T-Spot test at the screening visit;c. Chest x-ray (posterior-anterior and lateral views) at screening or within 3 months before the screening visit (radiology report must be available) with results consistent with prior TB infection (including but not limited to apical scarring, apical fibrosis, or multiple calcified granuloma). This does not include non-caseating granulomata.;NOTE: Any of these 3 TB tests will be performed on a country-by-country basis according to local guidelines only if required by regulatory authorities or ethics boards.;12. History of human immunodeficiency virus (HIV) infection or positive HIV serology at screening;13. Positive hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBc Ab), or hepatitis C antibody (HCV Ab) at the screening visit.
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 | EUCTR2015-002653-35-NL |
| CCMO | NL55127.028.15 |