Primary: (part 3) Potential of BPR277 1% ointment b.i.d. to improve the clinical severity of lesional skin in the majority of NS patients at end of treatment versus baseline of >= 2 points, dose range and regimen relationship on clinical severity…
ID
Source
Brief title
Condition
- Skin and subcutaneous tissue disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Total lesional sign score
Secondary outcome
Lesional itch VAS, investigator and patient global assessment, safety.
Background summary
This study is designed as a First-in-Human study with subsequent parts for
proof of concept of BPR277 in adult atopic dermatitis (AD) and Netherton
Syndrome (NS) patients. The purpose of this exploratory study is to investigate
tolerability, PK in subjects and patients as well as determine preliminary
efficacy of BPR277 1% ointment, when applied topically. This study consists of
3 parts: in healthy subjects (1), patients with AD (2) and patients with NS
(3). In the Netherlands only part 3 (cohort AA and AB) will be performed.
NS is a rare autosomal recessive disease with an estimated incidence of 1-9/100
000 births and characterized by congenital ichthyosiform erythroderma and hair
shaft defects. The large majority of NS patients develop atopic manifestations.
In NS the activity of proteases in the upper layers of the skin, including
Klk7, is increased. Augmented Klk7 activity ultimately results in barrier
breakdown and disease manifestations. Treatment is symptomatic (emollients).
Use of topical steroids and topical immunomodulators has been described as
beneficial in some cases, but these agents are not indicated for long-term use
or treatment of large surface areas as the skin barrier defect allows increased
systemic drug absorption.
BPR277 is a naturally occurring depsipeptide isolated from myxobacteria and a
highly potent Klk7 inhibitor with favorable skin penetration properties.
Pharmacological models in pigs and mice have shown that BPR277 is able to
enhance repair of a disturbed skin barrier and exhibits anti-inflammatory
activities after topical application in both acute and subchronic models of
skin inflammation. Thus, the potential clinical utility of BPR277 includes the
topical treatment of various skin diseases with impaired barrier function where
dysregulated Klk7 activity has been demonstrated.
Study objective
Primary: (part 3) Potential of BPR277 1% ointment b.i.d. to improve the
clinical severity of lesional skin in the majority of NS patients at end of
treatment versus baseline of >= 2 points, dose range and regimen relationship on
clinical severity of lesional skin (TLSS-NS) in NS patients of two regimens of
BPR277 (BPR277 1% ointment, applied b.i.d. and q.d.), safety and tolerability.
Secondary: Systemic steady state PK, BPR277 concentrations in the skin and the
urinary excretion of BPR277 after repeated topical administration.
Study design
Multicenter open-label first-in-human study.
This study consists of 3 parts: in healthy subjects (1), patients with AD (2)
and patients with NS (3). In the Netherlands only part 3 (cohorts AA and AB)
will be performed.
The remaining information is focused on part 3.
• Cohort A: Patients (n=7) enrolled in Part 3 Cohort A (which was conducted in
parallel to Part 2) received treatment with 1% BPR277 ointment and 0% vehicle
administered b.i.d. over a 250 cm2 treatment area for 4 weeks.
• Cohort AA: Patients in Part 3AA will receive 1% BPR277 ointment and 0%
vehicle administered b.i.d. over approximately 100 cm2 to up to 500 cm2
treatment area for 4 weeks. Between 4-10 patients are expected to be enrolled.
• Cohort AB: Patients in Part 3AB will receive 1% BPR277 ointment and 0%
vehicle administered q.d. (preferentially in the evening) over approximately
100cm2 to up to a 500 cm2 treatment area for 4 weeks. Between 4-10 patients are
also expected to be enrolled.
Intervention
Treatment with BPR277.
Study burden and risks
Risk: Adverse effects of study medication.
Burden: Study duration approx. 7 weeks. 6 visits. Duration 2-3 h.
Physical examination 4 times.
Blood draw during 5 visits, 5-20 ml per occasion.
Optional pharmacogenetic blood testing (10 ml).
Pregnancy test (if relevant) 3 times.
Skin tests (tape) 4x
Skin pH measurement 4x.
Skin biopsy 2x + 2 optional (pharmacokinetic substudy).
Stratum corneum sample (each treatment area) 2 times.
Photogrphs of skin lesions 5 times.
ECG 4 times.
Medication diary daily.
Questionnaires severity of symptoms (5x), quality of life (2x), satisfaction
with end result (1x).
Raapopseweg 1
Arnhem 6824 DP
NL
Raapopseweg 1
Arnhem 6824 DP
NL
Listed location countries
Age
Inclusion criteria
• Male and female patients with Netherton syndrome, 18 to 65 years of age inclusive.
• Confirmed diagnosis of Netherton syndrome (SPINK5 mutation and/or LEKTI deficiency in the skin).
• Total lesional sign score NS (TLSS-NS) of 5-9 for each selected treatment area at baseline.
• Each treatment area must have a minimum of approximately 250 cm2 of lesional skin within a maximum of approximately 1500 cm2. The TLSS-NS values of both treatment areas need to be similar and, if possible, should not differ (±) by more than 1 point between the two areas at baseline.
Exclusion criteria
• History of abnormal skin reactivity to UV light. Unusual exposure to UV light in the previous 3 weeks to study start (screening), including tanning and sun beds.
• Pregnant or nursing (lactating) women.
• Women of child-bearing potential not using acceptable contraceptive methods.
• Recent previous treatment with phototherapy, biological therapy, immunosuppressive agents (see protocol page 62 for details).
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 |
|---|---|
| Other | clinicaltrials.gov;NCT01428297 |
| EudraCT | EUCTR2011-000917-38-NL |
| CCMO | NL42450.041.12 |