Primary:To provide access to abrocitinib to adolescent and adult patients with or without background topical therapy who have inadequate treatment options due to inadequate response or intolerance to available approved medicated topical and systemic…
ID
Source
Brief title
Condition
- Epidermal and dermal conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Not applicable.
Secondary outcome
• Incidence of treatment-emergent adverse events (AEs) and serious adverse
events (SAEs).
• Incidence of serious adverse events (SAEs) and AEs leading to discontinuation.
• Incidence of serious infections, defined as any infection (viral, bacterial,
and fungal) requiring hospitalization or parenteral antimicrobials.
Background summary
2.2.1. Atopic Dermatitis
Atopic dermatitis (AD), also known as atopic eczema, is a common, chronic,
inflammatory skin disorder characterized by flaky skin lesions, intense
pruritus, and a general deterioration in quality of life. Over the past 50
years, AD has become more prevalent, especially in industrialized, temperate
countries such as the United States (US).1,2 AD is one of the most common,
chronic, relapsing childhood dermatoses, impacting 15-30% of all children in
the US, and many have disease that persists into adulthood with a lifetime
prevalence of those affected in childhood reported to be 34%.3 Earlier reports
indicated that, in up to 70% of cases, the disease greatly improves or resolves
by late childhood, however more recent findings suggest that disease activity
remains manifest for a prolonged period of time. Based on a total of 7,157
patients enrolled in the Pediatric Eczema Elective Registry (PEER) study,
comprising a total of 22,550 person years, it was concluded that symptoms
associated with AD seem to persist well into the second decade of life and
likely longer.4 At every age, more than 80% of PEER study patients had symptoms
of AD and/or were using medication to treat their AD.
Of the currently available therapies, none offers a cure; therefore, the main
aims of existing treatments are to reduce skin lesions, reduce the occurrence
of acute flares, to increase the time between relapses, and to reduce pruritus
and the resulting sleep disturbance.5,6
Non medicated topical therapies include emollients. Medicated topical therapies
for moderate to severe AD include topical corticosteroids (TCS) (eg,
betamethasone, clobetasol, fluocinonide), topical calcineurin inhibitors (TCI)
(eg, pimecrolimus, tacrolimus), and coal tar preparations. TCS are limited in
terms of the treatment duration (eg, corticosteroid use is limited to 2 to 4
weeks) and the body region of treatment due to consistent skin toxicities as
well as having risks associated with their broad immunosuppressive actions. TCI
have a limited role as a second line treatment due to their limitations in the
duration and the body region of treatment.
There are a limited number of approved systemic treatments for moderate to
severe AD, and in the US the only approved systemic drugs are corticosteroids
and dupilumab. Per the American Academy of Dermatology (AAD) guidelines, the
use of steroids should be avoided for the treatment of AD and should be
exclusively reserved for acute, severe exacerbations and as a short-term bridge
therapy to other systemic, steroid-sparing therapies.7
Dupilumab, an injectable human monoclonal antibody targeting IL 4 and IL 13,
was approved by the FDA in March 2017 and received marketing authorization in
Europe in September 2017 for the treatment of moderate to severe AD. Treatment
with systemic corticosteroids has known and well documented adverse effects.
Treatment with dupilumab has the risk of injection site reactions, allergic
reactions, eye and eyelid inflammations and cold sores. Another potential
limitation of dupilumab is the possibility for the development of antidrug
antibodies, which may result in loss of efficacy over time and the development
of safety concerns such as serum sickness like reactions. Furthermore,
dupilumab is delivered via subcutaneous injection, which may not be a method of
administration tolerated well by all patients. During a 1 year, randomized,
double blinded study with dupilumab, in the dupilumab 300 mg every 2 weeks
(marketed maintenance dose) plus TCS group, the estimated difference from
placebo of the Investigator's Global Assessment (IGA) response rate and Eczema
Area and Severity Index (EASI) 75 response rate (>=75% improvement from Baseline
in EASI score) were 26% and 46%, respectively. The placebo response rate for
IGA and EASI 75 was 12% and 23%, respectively.8 There is a need for therapies
for those patients who do not respond to dupilumab or who after responding,
fail to improve with dupilumab. The development of potential treatments with
further improvements in efficacy remains desirable.
In Europe, cyclosporine is approved for use in patients with severe AD when
systemic therapy is required. Cyclosporine use is associated with several
undesirable side effects and due to its narrow therapeutic index, occasional
therapeutic drug monitoring is recommended. Known adverse effects include
infections, renal toxicity, hepatotoxicity, skin malignancies, lymphoma, and
other malignancies.
The predominant unmet medical need is for a conveniently administered therapy
with an acceptable safety profile, for continuous and intermittent use, which
is effective for moderate to severe AD and effective in patients who have
failed other approved medicated topical or systemic treatments. Patients with
moderate to severe AD require other systemic treatment options beyond those
which are currently approved.
2.2.2. Clinical Overview
Abrocitinib is being developed as an oral treatment for patients with moderate
to severe AD based on the existing unmet need in AD, its novel mechanism of
action, and the clinical results obtained in Phase 1, Phase 2, and Phase 3
studies. The clinical development program for abrocitinib includes healthy
participants as well as participants with psoriasis and with AD.
Abrocitinib is an oral tablet providing a more convenient route of
administration compared with the subcutaneous injection required for dupilumab,
and so it does not have the potential risk of injection site reactions. Unlike
dupilumab, abrocitinib is a small molecule and there is no anticipated
immunogenicity to abrocitinib, and so it is unlikely to generate neutralizing
antidrug antibodies and may be used intermittently.
Rationale
Abrocitinib is a Janus kinase 1 (JAK1) inhibitor that has been in Phase 3
development since December 2017 treating patients with moderate to severe
atopic dermatitis (AD) with or without topical treatment. Recently completed
Phase 3 studies B7451012 and B7451013 which evaluated 100 mg once daily (QD)
and 200 mg QD abrocitinib in patients aged 12 years and older with moderate to
severe AD reported statistically significant improvement in efficacy endpoints
in both treatment groups compared to the placebo group with an acceptable
safety profile. Based on these data, Pfizer Inc., is filing for marketing
authorization for abrocitinib for the treatment of moderate to severe AD in
adolescent and adult patients.
This expanded access protocol will provide access to abrocitinib until it
becomes commercially available to patients who have inadequate treatment
options due to inadequate response or intolerance to available approved
medicated topical and systemic therapies, underlying conditions that preclude
use of available approved medicated topical and systemic therapies, or lack of
availability or access to approved medicated topical and systemic therapies and
need abrocitinib as a possible treatment regimen for moderate to severe AD.
Study objective
Primary:
To provide access to abrocitinib to adolescent and adult patients with or
without background topical therapy who have inadequate treatment options due to
inadequate response or intolerance to available approved medicated topical and
systemic therapies, underlying conditions that preclude use of available
approved medicated topical and systemic therapies, or lack of availability or
access to approved medicated topical and systemic therapies and need
abrocitinib as a possible treatment regimen for moderate to severe AD.
Secondary:
To gain additional safety and tolerability data for abrocitinib 100 mg and 200
mg once daily (QD) with or without background topical therapy in adolescent and
adult participants with moderate to severe AD in a *real world* clinical
setting.
Study design
• This is an open label, non-comparative, multi-center, expanded access study
of abrocitinib in adolescents and adults with moderate to severe AD who have
inadequate therapeutic options. The study will be conducted in countries where
there is an intent to register abrocitinib for a marketing authorization.
• Participants who meet eligibility criteria at Baseline will undergo Day 1
assessments and be assigned to receive abrocitinib 100 mg QD or 200 mg QD at
the investigator*s discretion. Participants may have their dose up- or
down-titrated by the investigator during the course of the study (minimum 100
mg QD, maximum 200 mg QD) for efficacy or safety reasons. Participants may also
have dosing temporarily interrupted for safety reasons for up to 30 consecutive
days.
• Medicated and non-medicated topical treatments for AD are permitted
throughout the study and should be administered in accordance with local
practice and regulations. Concomitant systemic treatments for AD are not
permitted except as part of rescue therapy (Refer to Rescue Therapy for Atopic
Dermatitis section). Concomitant medication for AEs or other non-AD concomitant
medical conditions are permitted throughout the study, unless listed as a
prohibited medication.
• Laboratory tests will be performed throughout this study as detailed in the
SoA. Investigators will follow the instructions for more frequent monitoring
detailed in the Monitoring and Discontinuation Criteria appendix if the
specified laboratory values reach the listed thresholds.
Intervention
• Abrocitinib 100 mg (1 x 100 mg tablet) or 200 mg (2 x 100 mg tablet) will be
administered orally QD at the investigator*s discretion pursuant to
instructions in the protocol. Refer to Section 6 Study Intervention of the main
protocol for complete information on abrocitinib administration instructions
and guidance.
• The maximum total treatment duration for individual participants may differ,
as a participant may continue to receive abrocitinib until availability of
commercial product in his/her country or until the sponsor terminates the study
in that country.
• The study will be comprised of 1) a Screening period of up to 28 days, 2) a
Study Intervention period during which participants will complete scheduled
onsite visits at Baseline, Week 4, Week 12, and every 12 weeks thereafter until
the End of Treatment visit, and a 4-week Follow-up period.
Study burden and risks
Benefit/Risk Assessment
There was clinically meaningful benefit demonstrated with abrocitinib in the
Phase 2b POC study in adult patients with moderate to severe AD and the
completed Phase 3 B7451012 and B7451013 studies. The potential risks of
treatment include those that were noted in Phase 2b and Phase 3 studies and
those based on the pharmacology of JAK inhibitors and include viral
reactivation, serious and opportunistic infections, hematopoietic effects
(including reduced platelet count), and malignancy and immunoproliferative
disorders. The most common events were gastrointestinal disorders, nervous
system disorders, and skin/subcutaneous tissue disorders. Appropriate risk
evaluation and mitigation strategies have been incorporated into this protocol.
Overall, there is a favorable benefit-risk profile to support the continued
development of abrocitinib in the treatment of adolescent and adult
participants with AD for both the 100 mg and 200 mg doses.
More detailed information about the known and expected benefits and risks and
reasonably expected adverse events (AEs) of abrocitinib may be found in the
Abrocitinib (PF-04965842) Investigator*s Brochure.
Benefit Assessment
Participation in study B7451064 will provide adolescent and adult patients with
moderate to severe AD who have inadequate treatment options for their moderate
to severe AD with the potential benefit of receiving early access treatment
with abrocitinib (100 mg and 200 mg) which has demonstrated efficacy and an
acceptable safety profile in Phase 3 studies. While it is possible that a
study participant*s AD symptoms may improve during treatment with abrocitinib,
there is no guarantee of benefit. Participants may also benefit from protocol
participation by gaining knowledge about their health status through study
tests (eg, physical examinations, laboratory assessments, vital sign
measurements) conducted at regular intervals during the trial.
Overall Benefit/Risk Conclusion
Taking into account the measures taken to minimize risk to participants in this
study, the potential risks identified in association with abrocitinib are
justified by the anticipated benefits that may be afforded to participants with
moderate to severe AD who have inadequate treatment options. The study will
also collect safety data and exploratory efficacy data in a population
representative of those who will receive the drug if approved by regulatory
authorities.
East 42nd street 235
New York 10017
US
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US
Listed location countries
Age
Inclusion criteria
Participants are eligible to be included in the study only if all of the
following criteria apply:
Age:
1. Participants 12 years of age or older at the time of signing the informed
consent. Adolescent participants below the age of 18 years(or country -specific
age of majority) will only be enrolled if approved by the country
regulatory/health authority. If these approvals have not been granted, only
participants 18 years of age (or country-specific age of majority) or older at
the time of signing of informed consent may be enrolled.
2. Participants who meet all of the following atopic dermatitis criteria:
- Clinical diagnosis of chronic atopic dermatitis (also known as atopic eczema)
for at least 6months prior to Day 1 and has confirmed atopic dermatitis at the
Screening and Baseline visits according to Hanifin and Rajka criteria for AD.10
Refer to protocol. -Inadequate treatment options for moderate to severe AD due
to history of inadequate response or intolerance to treatment with available
approved medicated topical and systemic therapies for the treatment of AD,
underlying conditions that preclude use of available approved medicated topical
and systemic therapies for the treatment of AD, or lack of availability or
access to approved medicated topical and systemic therapies for the treatment
of AD.
NOTE: Medicated topical therapy is defined as a topical product that contains
an active pharmaceutical ingredient indicated for the treatment of AD
(irrespective of whether it is an over the counter [OTC] or prescribed product).
- Moderate to severe AD as indicated by meeting at least 1of the following on
the day of the baseline visit: IGA >=3; EASI >=16.
3. Participants who are ineligible for participation in any ongoing clinical
trial of abrocitinib, including lack of access due to geographical limitations.
4. Participants and, as applicable, parents/legal guardians of age of minority
participants who are willing and able to comply with all scheduled visits,
treatment plan, laboratory tests, lifestyle considerations, and other study
procedures.
Sex:
5. Male or Female
Contraceptive use by men or women should be consistent with local regulations
regarding the methods of contraception for those participating in clinical
studies. Refer to protocol.
a. Male participants: No contraceptive measures are required.
b. Female participants: A female participant is eligible to participate if she
is not pregnant or breastfeeding, and at least one of the following conditions
applies:
- Is not a woman of childbearing potential (WOCBP) (Refer to the definition in
the Contraceptive Guidance appendix).
OR
- Is a WOCBP.A WOCBP who is sexually active must use a contraceptive method
that is highly effective, with a failure rate of <1%, as described in
Contraceptive Guidance appendix during the intervention period and for at least
28 days after the last dose of abrocitinib. The investigator should evaluate
the effectiveness of the contraceptive method in relationship to the first dose
of abrocitinib.
- A WOCBP must have a negative highly sensitive(refer to the Clinical
Laboratory Tests appendix)serum pregnancy test at the Screening visit. A urine
pregnancy test with a sensitivity of at least 25 mIU/mL, will be performed
before the first dose of abrocitinib and at every site visit including the EOT
and Follow-up/EOS visits to confirm the participant has not become pregnant. If
a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum
pregnancy test is required. In such cases, the participant must be excluded
from participation if the serum pregnancy result is positive.
- The investigator is responsible for review of medical history, menstrual
history, and recent sexual activity to decrease the risk for inclusion of a
woman with an early undetected pregnancy.
Please refer to section 5.1 of the protocol for a complete list of inclusion
criteria
Exclusion criteria
Medical Conditions:
1. Other medical or psychiatric condition including recent(within the past
year)or active suicidal ideation/behavior or laboratory abnormality that may
increase the risk of study participation or, in the investigator*s judgment,
make the participant inappropriate for the study.
2. The participant must have a risk assessment done by a qualified mental
health professional (MHP) to assess whether it is safe to participate in the
trial if the participant*s responses on any of the screening instruments or
other information from the screening period indicate:
- Suicidal ideation associated with actual intent and a method or plan in the
past year for adults or at any time in their lifetime for adolescents ages >=12
and <18years: *Yes* answers on items 4 or 5 of the Columbia Suicide Severity
Rating Scale (C-SSRS).
- Previous history of suicidal behaviors in the past 5 years for adults or at
any time in their lifetime for adolescents ages >=12 and <18 years: *Yes* answer
(in the past 5 years for adults or at any time in their lifetime for
adolescents) to any of the suicidal behavior items of the C-SSRS.
- Any lifetime history of serious or recurrent suicidal behavior (non-suicidal
self-injurious behavior is not a trigger for a risk assessment unless in the
investigator*s judgement it is indicated).
- Clinically significant depression: Patient Health Questionnaire 8 items
(PHQ-8) when the total score is>=15 for adults or>=10for adolescents ages >=12 and
<18years.
- The presence of any current major psychiatric disorder that is not explicitly
permitted in the inclusion/exclusion criteria.
- In the investigator*s judgment a risk assessment or exclusion is required.
3. Have increased risk of developing venous thromboembolism, eg, deep vein
thrombosis or pulmonary embolism:
- History of venous thromboembolism, or
- First-degree relative with unprovoked venous thromboembolism (ie, without
known underlying cause such as trauma, surgery, immobilization, prolonged
travel, pregnancy, hormone use, or plaster cast), that would suggest
participant is at increased risk of inherited coagulation disorder (eg,Factor V
Leiden).
4. A current or past medical history of conditions associated with
thrombocytopenia, coagulopathy, or platelet dysfunction.
5. Receiving anti-coagulants or medications known to cause thrombocytopenia
(unless considered safe to stop and washout for the duration of the study).
6. Have a history of any lymphoproliferative disorder such as Epstein Barr
virus (EBV), related lymphoproliferative disorder, history of lymphoma,
leukemia, or signs or symptoms suggestive of current lymphatic or lymphoid
disease.
7. Infection history:
- Have a history of systemic infection requiring hospitalization, parenteral
antimicrobial therapy, or as otherwise judged clinically significant by the
investigator within 6months prior to Day1;
- Have active chronic or acute skin infection requiring treatment with systemic
antimicrobials within 2weeks prior to Day1, or superficial skin infections
within 1week prior to Day1;
- A participant known to be infected with human immunodeficiency virus (HIV),
Hepatitis B, or Hepatitis C.
• Screening for Hepatitis B will include testing for hepatitis B surface
antigen (HBsAg) and hepatitis B core antibody (HBcAb). Participants who are
HBsAg negative and HBcAb positive will have testing for HBsAb. Participants who
are HBsAg negative, HBcAb positive, and HBsAb positive at Screening will have
testing for hepatitis B Virus (HBV) deoxyribonucleic acid (DNA). Participants
who have HBV DNA above the lower limit of quantification (LLQ) are excluded.
Participants who have HBV DNA negative or below LLQ may be assigned to
abrocitinib on Study Day 1 but will have HBV DNA testing repeated at the Q12
week visits, at the End of Treatment (EOT) visit, and at the Follow-up/End of
Study visit
8. Have a history (single episode) of disseminated herpes zoster or
disseminated herpes simplex, or a recurrent (more than one episode of)
localized, dermatomal herpes zoster.
9. Have a known immunodeficiency disorder.
10. Have a history of alcohol or substance abuse within 6 months prior to Day 1
that in the opinion of the investigator will preclude participation in the
study.
Please refer to section 5.2 of the protocol for a complete list of exclusion
criteria.
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 | EUCTR2020-003610-12-NL |
| ClinicalTrials.gov | NCT04564755 |
| CCMO | NL76952.100.21 |