The primary objective of the study is to evaluate a dose-response signal of IFX-1 in subjects with HS according to the HiSCR at Week 16. The secondary objectives of the study are:* To assess the efficacy of IFX-1 using additional outcome measures*…
ID
Source
Brief title
Condition
- Skin and subcutaneous tissue disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy endpoint is the percentage of subjects with a response, as
measured by HiSCR at Week 16.
Secondary outcome
Secondary efficacy endpoints:
1. Percentage of subjects with a response on the basis of the HiSCR
determined at Week 12, before administration of IMP
2. Number of subjects with flares analyzed in terms of * 25% increase in
AN count among subjects with a minimum increase of 2 in AN count
relative to Day 1
3. Absolute values and absolute and relative change in modified
Sartorius Score (mSS) from Day 1 by time point
4. Absolute value and absolute and relative change in Patient's Global
Assessment of Skin Pain (Numeric Rating Scale [NRS]) from Day 1 by
time point
5. Percentage of subjects achieving, by time point:
- At least a 30% reduction and at least 1 unit reduction from Day 1
among subjects with baseline NRS * 3 in Patient's Global Assessment of
Skin Pain (NRS30)
- At least a 50% reduction and at least 2 units reduction from Day 1
among subjects with baseline NRS * 3 in Patient's Global Assessment of
Skin Pain (NRS50)
6. Absolute values and absolute and relative change in Dermatology Life
Quality Index (DLQI) score from Day 1 by time point
Safety endpoints:
7. The number and percentage of subjects who had a treatmentemergent
adverse event (TEAE) as well as the number of TEAEs will be
assessed for all TEAEs and serious adverse events (SAEs).
Background summary
Hidradenitis suppurativa (HS) is diagnosed by its clinical features and its
chronicity. It is recognized by the presence of recurrent, painful,
deep-seated, rounded nodules usually ending in abscesses and sinus tracts with
suppuration and hypertrophic scarring of apocrine gland bearing skin [20].
The wide range of possible pathogenic mechanisms suggested by different studies
may imply that HS is associated with host mechanisms rather than exogenous
factors. Taking into account the paradox that both anti-infectious
(antibiotics) and pro-infectious (anti-TNF, corticosteroids, immunosuppressive
drugs) therapies may be helpful, HS may appear as an auto-inflammatory disease
based on a defect in the hair follicle innate immunity [20]. Supported by the
fact that pro-inflammatory cytokines such as interleukin (IL)-1*, and tumor
necrosis factor-* (TNF-*) are markedly increased in lesional and perilesional
skin [28].
As complement C5a is also involved in the underlying acute inflammatory
responses, this study is set up based on the hypothesis that IFX-1 might be
able to block C5a induced pro inflammatory effects such as neutrophil
activation and cytokine generation, potentially contributing to the local skin
inflammation and tissue damage. In addition, C5a blockade in different disease
models has been found to re-establish T-cell balance by increasing T regulatory
cells and reducing TH1 and TH17 responses, which may positively influence the
cause of a chronic autoimmune driven disease such as HS.
IFX-1 is a monoclonal antibody which specifically binds to the soluble human
complement split product C5a. Nonclinical studies have demonstrated that IFX-1
binds to its target, human C5a, rapidly and is capable of a practically
complete blockade of C5a-induced biological effects while not disturbing
cleavage of C5 and formation of the complement membrane attack complex.
Single and repeated iv administration of IFX-1 at doses of up to 50 mg/kg body
weight (bw) over 6 months in cynomolgus monkeys resulted in no related or
relevant toxicological or adverse findings within an extended core battery of
safety pharmacology assessments.
Various nonclinical studies have been conducted to assess pharmacological and
toxicological aspects of IFX-1, none of which revealed any obvious
toxicological or safety concerns for IFX 1. IFX-1 was well tolerated and did
not reveal any toxicity with any of the doses tested. Therefore, the NOAEL
level was defined as the highest administered dose of 50 mg/kg bw
(corresponding to a human equivalent dose of 16.13 mg/kg bw).
Study objective
The primary objective of the study is to evaluate a dose-response signal of
IFX-1 in subjects with HS according to the HiSCR at Week 16.
The secondary objectives of the study are:
* To assess the efficacy of IFX-1 using additional outcome measures
* To assess the safety and tolerability of IFX-1
* To generate data for PK/PD modelling
* To assess patient reported outcomes
* To evaluate the long-term efficacy and safety of IFX-1
Study design
This is a prospective, randomized, 2-period, double-blind, placebo-controlled,
double-dummy, and open-label multicenter study.
Main Period
After Screening, 175 subjects are planned to be randomized to receive
double-blind treatment in 1 of 5 treatment cohorts in a ratio of 1:1:1:1:1, for
a total of 15 weeks. For each cohort, the Main Period consists of a 2-week
Induction Phase followed by a 14-week Maintenance Phase through Week 16, during
which IFX-1 or placebo are administered as follows:
* Cohort 1 (placebo):
o Induction phase: Infusion of placebo at Weeks 0 (Days 1 and 4), 1, and 2
o Maintenance phase: Infusion of placebo at Week 4 and every other week for 12
weeks through Week 14
* Cohort 2 (IFX-1 400 mg q4w):
o Induction phase: Infusion of IFX-1 400 mg at Week 0 (Days 1 and 4), followed
by infusions of placebo in Weeks 1 and 2
o Maintenance phase: Infusion of IFX-1 400 mg at Week 4 followed by alternating
infusions every other week of placebo or IFX-1 400 mg for 12 weeks through Week
14
* Cohort 3 (IFX-1 800 mg q4w):
o Induction phase: Infusion of IFX-1 800 mg at Weeks 0 (Days 1 and 4) and 1,
followed by infusion of placebo at Week 2
o Maintenance phase: Infusion of IFX-1 800 mg at Week 4 followed by alternating
infusions every other week of placebo or IFX-1 800 mg for 12 weeks through Week
14
* Cohort 4 (IFX-1 800 mg q2w):
o Induction phase: Infusion of IFX-1 800 mg at Weeks 0 (Days 1 and 4), 1, and 2
o Maintenance phase: Infusion of IFX-1 800 mg at Week 4 followed by infusion of
IFX-1 800 mg every other week for 12 weeks through Week 14
* Cohort 5 (IFX-1 1200 mg q2w):
o Induction phase: Infusions of IFX-1 800 mg at Weeks 0 (Days 1 and 4) and 1,
followed by infusion of IFX-1 1200 mg at Week 2
o Maintenance phase: Infusion of IFX-1 1200 mg at Week 4 followed by infusion
of IFX-1 800 mg every other week for 12 weeks through Week 14
The primary efficacy endpoint will be the percentage of subjects with a
response, as measured by HiSCR at Week 16 (Section 8.2.2.2). At this time, the
cumulative dose of IFX-1 will be as follows:
* Cohort 1: 0 mg
* Cohort 2: 1600 mg
* Cohort 3: 4000 mg
* Cohort 4: 6400 mg
* Cohort 5: 8400 mg
A PK substudy will be conducted in 36 to 45 of the 175 subjects participating
in the Main Period.
Extension Period
After completing treatment in the double-blind Main Period, subjects will enter
the 28-week Extension Period. Starting at Week 16, the Extension Period for
each cohort consists of a 1-week Induction Phase (double-blind) followed by a
27-week Maintenance Phase (open-label), during which IFX-1 or placebo are
administered as follows (see also Table 2):
* Cohort 1:
o Induction phase: Infusion of IFX-1 800 mg at Weeks 16 (Days 113 and 116) and
17
o Maintenance phase: Infusions of IFX-1 800 mg at Week 20 and every 4 weeks for
24 weeks through Week 40
* Cohort 2:
o Induction phase: Infusion of IFX-1 800 mg at Week 16 (Day 113), followed by
infusion of placebo at Week 16 (Day 116), followed by infusion of IFX-1 800 mg
at Week 17
o Maintenance phase: Infusions of IFX-1 800 mg at Week 20 and every 4 weeks for
24 weeks through Week 40
* Cohorts 3, 4, and 5:
o Induction phase: Infusion of IFX-1 800 mg at Week 16 (Day 113), followed by
infusion of placebo at Weeks 16 (Day 116) and 17
o Maintenance phase: Infusions of IFX-1 800 mg at Week 20 and every 4 weeks for
24 weeks through Week 40
For subjects with worsening, or loss of, response (response on the basis of
HiSCR is defined in Section 8.2.2.2), the dosing regimen for IFX-1 during the
Maintenance Phase will be switched to 800 mg q2w.
Intervention
Patients should visit the clinics and be willing to receive their study drug or
placebo according to the dosing schema.
Furthermore their data of Medical history and demographic data will be
collected They must undergo physicial and vital signs examinations. An
electrocardiogram will be made. Blood and urine will be collected. Several
Questionnaires need to be filled in at different timepoints.
Study burden and risks
IFX-1 has been successfully investigated in an open-label Phase IIa study in
subjects with moderate to severe HS. Further, considerations on
risk-benefit-related aspects are derived from nonclinical data and clinical
Phase I data in healthy subjects as well as from clinical data in 2 other Phase
II studies conducted in subjects suffering from early, newly developing
abdominal or pulmonary derived septic organ dysfunction, and in subjects
undergoing complex cardiac surgery.
The subjects participating in this study who are treated with IFX-1 may benefit
from an improvement in HS-related symptoms.
No obvious findings relevant to the safety of IFX-1 were detected during the
extensive nonclinical in vitro / ex vivo and in vivo testing. In addition,
IFX-1 has been demonstrated to be safe and well tolerated in healthy human
subjects administered IFX-1 intravenously at single doses of up to 4 mg/kg bw.
Furthermore, the safety of IFX-1 has been investigated in 3 Phase II studies,
conducted in 48 subjects with early septic organ dysfunction treated with IFX-1
up to a dose of 3 x 4 mg/kg bw given over 4 days, in 81 subjects undergoing
complex cardiac surgery treated with single doses of IFX-1 up to a dose of 8
mg/kg bw, and in 12 subjects with moderate to severe HS treated with IFX-1 at a
weekly dose of 800 mg for 8 weeks. Overall, IFX-1 was safe and well tolerated
in all these studies, and no additional risks associated with the
administration of IFX-1 were observed.
Thus, it has been demonstrated that IFX-1 was generally well tolerated when
administered to subjects with HS.
Because IFX-1 is an antibody/protein, a general risk for anaphylactic reactions
exists. Subjects who are included in this study are treated with IFX 1 at the
study site so that adequate treatment and care is available in case of an
anaphylactic reaction. To date, no anaphylactic reactions have been reported
after administration of IFX-1 in clinical Phase I and II studies.
The hypothesized benefit of treatment with IFX-1, therefore, outweighs the
potential risks for the subjects participating in this study.
Winzerlaer Str. 2
Jena 07745
DE
Winzerlaer Str. 2
Jena 07745
DE
Listed location countries
Age
Inclusion criteria
1. Male or female, * 18 years of age
2. Written informed consent obtained from subject
3. Diagnosis of Hidradentis Suppurativa (HS) for at least 1 year
4. Moderate or severe HS, as indicated by HS lesions in at least 2 distinct
areas, 1 of which must be at least Hurley Stage II or Stage III
5. Stable HS for at least 2 months before Screening, as determined by
the investigator through subject interview and review of medical history
6. Inadequate response to at least 3 months of oral antibiotics, or
intolerance to antibiotics
7. Total abscess and inflammatory nodule count of * 3
Exclusion criteria
1. Body weight < 60 or > 130 kg
2. Any other skin disease that may interfere with assessment of HS
3. More than 20 draining fistulas
4. Prior treatment with adalimumab or another biologic product during
the 24 weeks before Screening
5. Prior treatment with IFX-1
6. Subjects on permitted oral antibiotic treatment for HS (doxycycline or
minocycline only) who have not been on a stable dose during the 28
days before Screening
7. Subject received systemic non-biologic therapy for HS with potential
therapeutic impact for HS during the 28 days before Screening (other
than permitted oral antibiotics)
8. Prior treatment with any of the following medications during the 28
days before Screening:
a. Any other systemic therapy for HS
b. Any iv anti-infective therapy
c. Phototherapy (UVB or psoralen and UVA)
9. Prior treatment with any of the following medications during the 14
days before IMP administration:
a. Analgesics (including opioids) for HS related pain
b. Prescription-only topical therapies for HS
c. Oral anti-infectives for infections other than HS
10. History of moderate to severe heart failure (New York Heart
Association Class III or IV), cerebrovascular accident during the 24
weeks before Screening, history of malignancy except for successfully
treated non-metastatic basal cell or squamous cell carcinoma or in situ
carcinoma of the cervix
11. One of the following abnormal laboratory findings:
a. White blood cell count (WBC) < 2500/mm3
b. Neutrophil count < 1000/mm3
c. Serum creatinine > 3 × UNL
d. Total bilirubin > 3 × UNL
e. Alanine aminotransferase > 5 × UNL
f. Aspartate aminotransferase > 5 × UNL
g. Positive Screening test for HIV-1 or 2, or hepatitis B or C virus
12. Chronic and/or recurring systemic infections, history of invasive
infections with atypical pathogens (i.e., which normally do not cause
invasive infection, such as listeriosis), or known primary
immunodeficiency, as described in guidance provided to investigator
13. Subject is judged to be in poor general health, as determined by the
investigator based upon medical history, physical examination,
laboratory safety and, a 12 lead ECG
14. Female subjects of childbearing potential unwilling or unable to use
a highly effective method of contraception (pearl index < 1%) such as
complete sexual abstinence, combined oral contraceptive, vaginal
hormone ring, transdermal contraceptive patch, contraceptive implant,
or depot contraceptive injection in combination with a second method of
contraception such as condom, cervical cap, or diaphragm with
spermicide during the study and for at least 1 month after last
administration of IMP
15. History of drug or alcohol abuse during the 24 weeks before
Screening
16. Pregnancy, as verified by a positive pregnancy test, or nursing
woman
17. Evidence or suspicion that the subject might not comply with the
requirements of the study protocol
18. Any other factor which, in the investigator's opinion, is likely to
compromise the subject's ability to participate in the study
19. The subject is an employee or direct relative of an employee at the
study site or sponsor
20. The subject is imprisoned or lawfully kept in an institution
21. The subject has participated in a clinical study during the 3 months
before Screening, or plans to participate in a clinical study
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 | EUCTR2017-004501-40-NL |
| CCMO | NL64746.056.18 |