Primary Objective: To assess the safety of rVA576 in adult subjects with mild to moderate bullous pemphigoid (BP).Secondary Objectives: To assess the efficacy of rVA576 and its effect on the quality of life in adult subjects with mild to moderate…
ID
Source
Brief title
Condition
- Skin and subcutaneous tissue disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Proportion of participants reporting grade 3, 4 and 5 adverse events, which are
related/possibly related to rVA576 during the treatment period.
The Common Terminology Criteria for Adverse Events (CTCAE v4.03) will be used
to grade adverse events by the investigator. At each study visit, participants
will be questioned about adverse events they have experienced since the last
study visit.
Secondary outcome
* Mean absolute change in BPDAI activity scores between baseline (Day 1) and
Day 42.
* Proportion of patients whose BPDAI activity score decreases by 4 or more
points between baseline (Day 1) and Day 42.
* Proportion of patients whose BPDAI activity score increases by 3 or more
points between baseline (Day 1) and Day 42.
* Mean absolute change in BPDAI pruritus index between Day 1(baseline) and Day
42
* Mean change in Dermatology Life Quality Index (DLQI) between baseline (Day 1)
and Day 42
* Mean change in Treatment of Autoimmune Bullous Disease Quality of Life
(TABQOL) between baseline (Day 1) and Day 42
Background summary
Bullous pemphigoid (BP) is the most common of the autoimmune blistering skin
diseases in Western Europe.
BP is a serious condition with a significant associated morbidity and mortality
rate. Widespread tense and haemorrhagic blisters, skin erosions and severe
itching cause patients a great deal of distress and pain. It occurs mainly in
the elderly (>65 years).
Untreated, BP may be a self-limiting disease in a proportion of patients with
periods of spontaneous remissions and exacerbations. In most patients who are
treated, BP remits within 1.5-5 years but may recur once medication is stopped.
Patients are often admitted to hospital for initial treatment. The estimates
of admission rates vary, but they are generally high, thus representing a
significant burden and cost to the healthcare systems, as well to the patients*
and their families / carers. The severity of symptoms and lesions in bullous
pemphigoid make treatment mandatory corticosteroids and frequent hospital
visits are needed for dose adjustments.
During the active stage, the disease is associated with significant morbidity
and a mortality twice that of the general elderly population. Older age at
onset and frail general condition are poor prognostic factors.
Many available treatments are associated with toxicity and may be poorly
tolerated in patients with BP. Mortality during the first year is significantly
higher in patients treated with high doses of systemic corticosteroids
(prednisolone equivalent >40 mg daily).
Treatment should aim to control symptoms with minimum adverse effects where
possible. Options are broadly divided into anti-inflammatory drugs,
immunosuppressive or immunomodulating drugs, and procedures aiming to remove
circulating pathogenic antibodies and inflammatory mediators .
Corticosteroids are the most commonly used anti-inflammatory drugs used for
treatment of BP. They are administered systemically, for example prednisolone,
or by whole-body application of very potent steroids such as clobetasol.
Anti-inflammatory antibiotics such a tetracyclines are used as well. Long term
use is associated with several adverse effects such as severe skin atrophy,
osteoporosis, diabetes, glaucoma, cataract formation, weight gain, and
psychologic disturbances.
Azathioprine and methotrexate are still a commonly used drug in BP. Intravenous
immunoglobulins have been used as immunomodulatory agents in BP as well as
other auto immune blistering skin diseases.
The choice of treatment depends on the individual patient*s circumstances
especially the severity of the BP and presence of comorbidities. All of these
treatment options have limited applicability due to reasons associated with
efficacy, safety or both. And thus, there exists a need for a safe and
effective therapy for bullous pemphigoid patients
A Cochrane systematic review addressed the treatment of BP and highlighted the
lack of the evidence informing current treatment paradigms as well as the unmet
need and the need for better evidence based therapies.
The mortality rate in treated patients is estimated to range from 20% - 40% at
one year. It is thought that in this susceptible elderly population,
corticosteroid treatment contributes to the high mortality rate. This is due,
at least in part, to the significant adverse events associated with the use of
steroids, such as hypertension, diabetes, infections and osteoporosis.
Management of these conditions can be difficult and their treatment represents
a significant burden. Therefore, the avoidance of systemic corticosteroids in
this vulnerable group of patients is highly desirable and a safer, and
effective, evidence based alternative is needed.
As seen in the recent BLISTER study there is now evidence that tetracyclines
may be effective in treating BP. Tetracyclines are readily available
broad-spectrum antibiotics which have other anti-inflammatory non-antibiotic
properties. In this study mometasone was allowed as background steroid therapy
in the doses of up to 30 grams per week
This early proof of concept study will try to estimate the safety and efficacy
of rVA576 as a complement C5 and LTB4 inhibitor for the treatment of mild to
moderate bullous pemphigoid patients.
A significant obstacle in guiding evidence-based management of bullous
pemphigoid (BP) has been a lack of a standardised, validated scoring system for
the condition. This had led to difficulties in sharing multicentre-based
evidences for therapeutic efforts as there was a lack of generally accepted
definitions for the clinical evaluation of patients with BP.
Common terms and end points of BP were needed so that experts in the field can
accurately measure and assess disease extent, activity, severity, and
therapeutic response, and thus facilitate and advance clinical trials.
Therefore, the recently published recommendations from the International
Pemphigoid Committee that represent 2 years of collaborative efforts to attain
mutually acceptable common definitions for BP and proposes a disease extent
score, the BP Disease Area Index. (BPDAI)
As this index is still new, there is paucity of data on cut offs to be used for
differentiating between mild, moderate and severe disease. Also, various
definitions of response and remission will develop over time.
The current study aims to use BPDAI for identification of mild to moderate BP
patients. Based on research by Levy-Sitbon et al a BPDAI cut off of 56 has been
used to exclude severe bullous pemphigoid.
A reduction of 4 points in BPDAI as a minimal clinically important difference (
MCID) for improvement and an increase of 3 points as an MCID for disease
worsening. We will be using these cut offs for assessment in this study
A BPDAI score of 10 as minimal entry criteria has been chosen based on
consultation with the experts in the field.
As this is a study of short duration, a single arm study and a first study of
rVA576 in Bullous pemphigoid, change from baseline will be used as efficacy
criteria.
This study will not only help the sponsors to design further clinical studies
in BP if appropriate but will provide important data to help use of BPDAI in
management of BP for the experts and other researchers.
The BPDAI tool computes 2 scores: total BPDAI activity and total BPDAI damage.
The total BPDAI activity score is the arithmetic sum of the 3 subcomponents *
cutaneous blisters/ erosions, cutaneous urticaria/erythema, and mucosal
blisters/ erosions.
The total BPDAI damage score is the arithmetic sum of the items rated
regionally for damage caused by more permanent features such as
post-inflammatory hyperpigmentation, scarring and other. BPDAI quantifies
lesion number and size thresholds.
Lesions are rated based on the regions affected. BPDAI gives additional
weighting to areas of the skin primarily affected in BP, such as the limbs, and
less emphasis to scalp and face, to better differentiate clinical response in
BP.
Scores can range from 0 to 360 for BPDAI total activity (maximum 240 for total
skin activity and 120 for mucosal activity), and 0 to 12 for BPDAI damage, with
higher scores indicating greater disease activity or damage. BPDAI also has a
separate subjective measure known as BPDAI-pruritus.
Study objective
Primary Objective: To assess the safety of rVA576 in adult subjects with mild
to moderate bullous pemphigoid (BP).
Secondary Objectives: To assess the efficacy of rVA576 and its effect on the
quality of life in adult subjects with mild to moderate bullous pemphigoid
(BP).
Study design
Open-label single arm study.
Bullous Pemphigoid subjects will be treated with 30 mg once daily rVA576 regime
for 6 weeks.
Intervention
Open-label single arm study.
Bullous Pemphigoid subjects will be treated with 30 mg once daily rVA576 regime
for 6 weeks.
Study burden and risks
Although there has been limited clinical experience with rVA576 to date, the
clinical implications of complement C5 blockade can be deduced from a
combination of genetic and epidemiological studies, animal studies and
experience with eculizumab (Soliris®). Complement C5 deficiency in humans is a
rare, familial condition caused by a variety of genetic defects including
mutations in the C5 exons. Those affected have a predisposition to gram
negative infections, particularly meningococcal meningitis [Densen, 1989].
rVA576 has been to date, 2 November, 2017, administered to approximately 42
subjects, 32 healthy volunteers and 10 patients. In these, rVA576 has generally
been found to be well tolerated.
In the single ascending dose trial (VA576) the drug was well tolerated, there
were no serious or severe adverse reactions and only mild injection site
reactions. A total of three adverse reactions were reported in 2 of 16 healthy
subjects who received the active drug and in 1 of 8 subjects who received
placebo. There was no dose relationship, three of the four AEs occurring at the
lowest dose and one in the third of four ascending doses. The AEs were mild and
self-limiting and consisted of light headedness (1), symptoms of a cold (1),
pain in the arm related to the injection site (1) and intolerance to bright
light (1).
In the multi-dose Phase I b study (AK577) there was a subject in Cohort 1 who
received 3 doses of rVA576 and 4 doses of ciprofloxacin and experienced a
significantly raised creatinine kinase (CK) and serum myoglobin level on Day 2.
The subject was clinically stable and troponin was negative. The PI decided to
stop rVA576 and ciprofloxacin and withdraw the subject. The subject did not
experience any symptoms relating to the raised CK and myoglobin levels. The CK
level dropped significantly by Day 6 and had returned to normal by Day 28. The
investigator considered that this AE was related to the administration of
ciprofloxacin as it is a known but rare side effect of the drug. He did not
consider that it was related to rVA576. Cohort 4 (comprising 4 active subjects
only) received the same ablating dose as Cohorts 1, 2 and 3 and a maintenance
dose of 22.5mg once a day for 19 days. Cohort 4 subjects were followed during a
7 day recovery period from Day 21 to 28.
In the currently on-going Phase II study in PNH patients (AK579), five patients
have completed the study and all experienced adverse events that were treatment
related. Most treatment-related adverse events observed were injection site
reactions which accounted for 92% of all adverse events. A skin rash was
observed in one patient and hypophosphataemia, hypoproteinuria in another
patient on two separate occasions along with aggravation of osteoarthritis. A
further patient experienced a headache and upper abdominal discomfort.
In a retrospective review of PNH patients on long term treatment with
eculizumab (Soliris®), two of ninety-six patients developed meningococcal
meningitis [Hillmen et al, 2013]. Currently subjects taking eculizumab are
advised to maintain prophylaxis against Neisseria meningitidis either by active
immunization or by taking long term antibiotics or both [Dmytrijuk et al,
2008]. In this study, the anti-meningococcal measures employed in individual
cases will be at the discretion of the Investigators and in accordance with
local practice. In limited duration, toxicological studies with both
eculizumab (Soliris®) and rVA576, no AEs or findings attributable to C5
blockade have been reported but Investigators are advised to be alert for
possible infectious events, even in subjects who have received meningococcal
immunisation.
GLP-compliant daily s.c. repeat dose studies in mice (1, 3 and 6 months) and
cynomolgus monkeys (1 month) have been completed. In the 3-month mouse study
(high dose group 5mg/kg) no drug related affects were detected other than an
increase in the incidence and severity of microscopic signs of inflammation
detected by histopathology at the site of injection (scapular region only in
mice) that were considered related to rVA576. In the 6-month mouse study (high
dose 6.5 mg/kg) was determined to be the NOAEL but histopathological
inflammatory changes were observed at the site of administration. Minor
immunostimulation in local lymph nodes in both sexes were observed at 6.5 mg/kg
and in the spleen in males
Because rVA576 is a xenologous protein (derived from a tick salivary protein),
there is a possibility that its chronic use may be associated with the
formation of antibodies which could neutralise the effect of the drug or cause
untoward adverse reactions. The immunogenicity study in mice and 58-day dosing
of the 4-year-old child described above and the ongoing treatment of the Dutch
PNH patient resistant to eculizumab (Soliris®) and 6 months or more data in the
4 PNH patients who completed the Phase 2 trial (AK579) has gone some way to
mitigating this risk. Experience with other parasite derived therapeutic
molecules such as the leech-derived anticoagulant lepirudin also support long
term therapeutic use of xenologous proteins.
The potential of rVA576 to induce phototoxicity is at present unknown. For this
reason, patients taking rVA576 should be advised to avoid excessive exposure to
sunlight or UV light (e.g. sunbeds) for the duration of the study and for five
half-lives after the last administration of rVA576 (6 hours).
Wimpole Street 75-76
London W1G 9RT
GB
Wimpole Street 75-76
London W1G 9RT
GB
Listed location countries
Age
Inclusion criteria
1. Adult male or female *18-year-old patients
2. Subject with newly presenting mild to moderate cutaneous bullous pemphigoid (BP) not on any current systemic corticosteroid or immunomodulator treatment. (Subjects on topical corticosteroids will stop use of these on or before Day1)
3. BPDAI global score at screening of 10-56 (* 10 but <56)
4. Subjects with a relapse of mild to moderate bullous pemphigoid are eligible if their disease was quiescent without any systemic treatment for at least 2 months before the current relapse.
5. Cutaneous bullous pemphigoid (BP) per standard diagnostic criteria:
a. Clinical presentation (cutaneous blistering and/or itchy dermatosis), AND
b. Direct immunofluorescence (DIF) studies performed on perilesional skin collected approximately 1 cm away from a fresh blister, an erosion or papule showing linear (n-serrated) deposition of IgG and/or C3 along the epidermal basement membrane zone, ;AND/OR;Indirect immunofluorescence (IIF) studies performed with patient serum on 1.0M NaCl human salt split skin, showing IgG along the roof of the blister.;6. Karnofsky performance status > 60%
7. Adequate cardiac, renal, hepatic, neurological and psychiatric function as determined by the Investigator and demonstrated by screening laboratory evaluations, vital sign measurement, ECG recording and physical examination results.
8. Women of childbearing potential (WOCBP) must agree to use effective contraception consistently throughout the study and have a negative serum pregnancy test at screening and a negative urine pregnancy test per the schedule of visits. Women are considered post-menopausal and not of childbearing potential if they have had 12 months of amenorrhea or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks previously.
9. Males with a childbearing potential partner must agree to use effective contraception consistently OR have had a vasectomy
10. Willing and able to adhere to the study visit schedule and other protocol requirements including self-injection.
11. Willing and able to provide voluntary written informed consent
12. Willing to receive immunisation against Neisseria meningitidis and antibiotic prophylaxis in accordance with applicable guidelines and local standard of care of the PI at the trial site
Exclusion criteria
Exclusion criteria:
Bullous Pemphigoid Exclusion criteria
1. Patients with severe BP. Severe disease to defined as global BPDAI * 56.
2. Patients with refractory BP. Refractory BP may be defined as failure or loss of response to maximal topical or oral steroids.
3. Suspected drug induced BP
4. Concomitant skin conditions preventing physical evaluation of BP.
rVA576 and mometasone related exclusion criteria
5. Participation in a clinical trial of an investigational product within 6 weeks of screening.
6. Known hypersensitivity to tick or to rVA576 and any of its excipients.
7. BP patients on systemic corticosteroid or systemic immunomodulator treatment (including azathioprine, dapsone, rituximab etc.).
8. Treatment with biologics (e.g. etanercept, adalimumab, ustekinumab, infliximab, intravenous immunoglobulin (IVIG) and rituximab or other anti-CD20 therapies) within 5 half-lives of the drugs prior to screening. ;9. Known hypersensitivity to mometasone furoate or to other corticosteroids or to any excipients in mometasone furoate
10. Received rVA576 or other recognised systemic medications for the treatment of the current episode of BP prior to study entry. Prior topical treatment with corticosteroids is permitted. This must be discontinued and study medications started on Day 1
General Exclusion Criteria
11. Patients with severe medical or surgical conditions at screening or Day 1 including, but not limited to cardiac, respiratory, renal, hepatic, haematological, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, cerebral, psychiatric, or any other severe acute or chronic medical condition that may increase the risk associated with study participation/treatment or may interfere with the interpretation of study results and, in the Investigator's opinion, would make the patient inappropriate for study entry.
12. Presence of any malignancy that has been under active treatment or in previous 5 years except for patients with removal of uncomplicated basal cell carcinoma or cutaneous squamous cell carcinoma, who may take part in the study.
13. Congenital or acquired immunodeficiency (e.g. common variable immunodeficiency, organ transplantation).
14. Clinically significant vital sign measurements or ECG findings as determined by the Investigator.
15. Clinically significant abnormal laboratory test results including but not limited to:
* Haemoglobin level <10.0 g/dL
* White blood cell count < 3 x 103/*L
* Lymphocyte count < 0.5 x 103/*L
* Platelet count <100 x 10*9 /L or >1200 x 10*9/L
* Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 times the upper limit of normal (ULN)
* Alkaline phosphatase >3x ULN
* Serum creatinine (S.Cr) >2x ULN
16. Active or recent history of clinically significant infection within 1 month of Screening.
17. Pregnant or breast-feeding, or planning to become pregnant during the study.
18. Evidence of an active disease of hepatitis B (HBsAg positive or HBcAg positive) or hepatitis C (HCV ab positive), CMV (IgM positive) or human immunodeficiency virus (HIV) infection (HIV1/2 Ab positive)
19. Active abuse of alcohol or drugs.
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 | EUCTR2017-002836-18-NL |
| CCMO | NL63900.042.17 |