The primary objective of this study is to determine the clinical safety and efficacy of adalimumab compared to placebo in subjects with moderate to severe HS after 12 weeks of treatment. A secondary objective is to evaluate safety and explore…
ID
Source
Brief title
Condition
- Skin and subcutaneous tissue disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy variable is the proportion of subjects achieving
Hidradenitis Suppurativa Clinical Response (HiSCR) at Week 12.
Secondary outcome
The following secondary efficacy variables will be analyzed according to the
rank order as follows:
1. Proportion of subjects achieving AN count of 0, 1, or 2 at Week 12, among
subjects with Hurley Stage II at Baseline
2. Proportion of subjects achieving at least 30% reduction and at least 1 unit
reduction from Baseline in Patient's Global Assessment of Skin Pain (NRS30) *
at worst at Week 12 among subjects with baseline NRS * 1
3. Change in modified Sartorius scale from Baseline to Week 12.
Other efficacy variables to be analyzed at each scheduled visit in Period A,
except for the ones included as primary or ranked secondary variables which
will be analyzed for visits other than Week 12.
* Proportion of subject achieving HiSCR
* Proportion of subjects achieving AN count of 0, 1, or 2, among subjects with
Hurley Stage II at Baseline
* Proportion of subjects achieving NRS30 * at worst, among subjects with
baseline Patient's Global Assessment of Skin Pain (NRS) * 1
* Proportion of subjects achieving NRS30 * on average, among subjects with
baseline Patient's Global Assessment of Skin Pain (NRS) * 1
* Change in modified Sartorius scale from Baseline
* Proportion of subjects achieving complete elimination of abscesses at each
visit, among subjects who have any abscess at Baseline
* Percentage change from Baseline in number of abscesses, among subjects who
have at least one abscess at Baseline
* Change from Baseline in number of abscesses
* Proportion of subjects achieving complete elimination of draining fistulas at
each visit, among subjects who have any draining fistulas at Baseline
* Percentage change from Baseline in number of draining fistulas, among
subjects who have at least one draining fistula at Baseline
* Change from Baseline in number of draining fistulas
* Percentage change from Baseline in number of inflammatory nodules, among
subjects who have at least one inflammatory nodule at Baseline
* Proportion of subjects achieving complete elimination of inflammatory nodules
at each visit, among subjects who have any inflammatory nodules at Baseline
* Change from Baseline in number of inflammatory nodules
* Number of interventions during Period A
* Proportion of subjects with DLQI=0
* Proportion of subjects with DLQI=0 or 1
* Change from Baseline in DLQI
* Change from Baseline in WPAI:SHP
* Percentage change from Baseline in Patient's Global Assessment of Skin Pain
(NRS) * at worst, among subjects who have baseline NRS * 1
* Percentage change from Baseline in Patient's Global Assessment of Skin Pain
(NRS) * on average, among subjects who have baseline NRS * 1
* Change from Baseline in Patient's Global Assessment of Skin Pain (NRS) * at
worst
* Change from Baseline in Patient's Global Assessment of Skin Pain (NRS) * on
average
* Proportion of subjects achieving AN50 (at least 50% reduction in the AN count
relative to Baseline)
* Proportion of subjects achieving AN75 (at least 75% reduction in the AN count
relative to Baseline)
* Proportion of subjects achieving AN100 (100% reduction in the AN count
relative to Baseline)
* Absolute and percentage change from Baseline in AN count
* Proportion of subjects achieving erythema score of 1 or 0 in all affected
anatomic regions among subjects who have erythema score of 2 or more in at
least one anatomic region at Baseline
* Proportion of subjects who experience worsening by at least one Hurley Stage
in at least 1 affected anatomic region
* Proportion of subjects who experience improvement by at least one Hurley
Stage in at least 1 affected anatomic region
* Change from baseline in TSQM (Treatment Satisfaction Questionnaire -
Medication)
* Change from baseline in EQ-5D index
* Change from baseline in EQ-5D VAS
* Proportion of subjects who experience flare, defined as an at least 25%
increase in AN counts with a minimum increase of 2 relative to Baseline
* Number of days on flare, calculated from the day when flare is observed to
the day prior to the observation that flare is no long present. Of note, there
could be multiple periods that flares are observed, in which case, the total
days from the multiple periods will be used
* Proportion of subjects who experience at least 25% increase in abscess counts
with a minimum increase of 2 relative to Baseline
* Proportion of subjects who experience at least 25% increase in inflammatory
nodule counts with a minimum increase of 2 relative to Baseline
* Proportion of subjects who experience at least 25% increase in draining
fistula counts with a minimum increase of 2 relative to Baseline
Background summary
HS is a painful, chronic, skin disease characterized by recurrent inflamed
nodules and abscesses, which may rupture to form fistulas and subsequent
scarring. The most commonly involved anatomic locations are the inguino-crural
and axillary folds, with sub-mammary folds (in women) and the perineal area
less commonly involved.
Hidradenitis Suppurativa has a severely negative effect on patients' quality of
life. It typically presents with painful, deep-seated nodules, which either
resolve spontaneously, persist as non-tender nodules, or progress to form
abscesses. Abscesses typically rupture and release purulent drainage. Abscesses
and nodules may heal with scarring and the formation of fistulas or sinus
tracts. Thus, many patients with HS develop permanent sequelae of past
inflammation that are only remediable through surgical excision of the involved
skin areas. The physical and psycho-social morbidity associated with en bloc
excision of scarred axillary, inguinal, or groin skin is substantial. Rare
complications of
HS include fistula formation into urethra, bladder, rectum, or peritoneum,
lymphedema of the limbs or scrotal elephantiasis, and squamous cell carcinomas
of the skin originating from HS lesions.
Hidradenitis Suppurativa affects approximately 1% of the general population.
Disease onset is typically after puberty. Disease prevalence decreases from
1.5% in those < 25 years of age to 0.5% in those older than 55 years of age. It
affects women from 2 to 5 times more commonly than men. Several factors may
predispose a person to HS, including genetics, cigarette smoking, and obesity.
The histopathologic characteristics of HS include a dense inflammatory cell
infiltrate of neutrophils, lymphocytes, and histiocytes. Tumor necrosis
factor-alpha (TNF-*), which induces pro-inflammatory cytokines and activates
neutrophils and lymphocytes, may have a pathogenic role.
Study objective
The primary objective of this study is to determine the clinical safety and
efficacy of adalimumab compared to placebo in subjects with moderate to severe
HS after 12 weeks of treatment. A secondary objective is to evaluate safety and
explore efficacy for continuous weekly dosing versus dose reduction versus
maintenance of response off therapy from Week 12 to Week 36. The
pharmacokinetics and immunogenicity of adalimumab following subcutaneous (SC)
injection will also be assessed.
Study design
A randomised, double-blind, placebo-controlled multicenter study.
Intervention
The study was designed to enroll 300 subjects to meet scientific and regulatory
objectives without enrolling an undue number of subjects in alignment with
ethical considerations. Therefore, if the target number of subjects has been
enrolled, there is a possibility that additional subjects in screening will not
be enrolled.
The study duration will include a 7 to 30-day Screening Period, an initial
12-week double-blind treatment period (Period A), and a subsequent 24-week
double-blind treatment period (Period B), plus a Day 70 follow-up phone call 70
days after the last dose of study drug administration.
Period A:
A 12-week double-blind, placebo-controlled treatment period during which
subjects are randomized at Day 1, in a 1:1 ratio to receive blinded adalimumab
40 mg every week (ew) or matching placebo for an evaluation of safety and
efficacy. The randomization will be stratified by baseline Hurley Stage (II
versus III) and baseline concomitant antibiotic use (Yes versus No). A
subject's Hurley Stage is determined by
the worst Hurley Stage across all affected anatomic regions.
All subjects enrolled in this study who complete Period A are eligible to
participate in Period B.
Period B:
A 24-week double-blind, placebo-controlled treatment period. All subjects
continuing to Period B, regardless of the treatment in Period A, will be
re-randomized at Week 12 to maintain the blind. Subjects randomized to
adalimumab in Period A are re-randomized in a 1:1:1 ratio to receive blinded
adalimumab 40 mg ew, adalimumab 40 mg every-other-week (eow), or placebo from
Week 12 to Week 35. The re-randomization will be stratified by Week 12 HiSCR
response (responder versus non-responder) (See Section 1.2 for definition of
term) and by baseline Hurley Stage (II versus III). Subjects from the placebo
arm in Period A (Arm 2) will continue on blinded placebo from Week 12 to Week
35.
All subjects (Arm 1 and Arm 2) who achieve HiSCR at Week 12 will continue in
Period B through Week 36. Subjects who experience a loss of response (LOR),
defined as an AN count that is greater than the average of AN counts at
Baseline and Week 12, will be discontinued from the study and have the
opportunity to enter the open-label extension (OLE) Study M12-555 to receive
open-label adalimumab 40 mg ew.
All subjects (Arm 1 and Arm 2) who do not achieve HiSCR at Week 12 will
continue in Period B through Week 36. Starting at or after Week 16, subjects
who experience a Worsening or Absence of Improvement, defined as an AN count
that is greater than or equal to the AN count at Baseline on two consecutive
visits (excluding Week 12) occurring at least 14 days apart, they may be
discontinued from the study and have the opportunity to enter the OLE Study
M12-555 to receive open-label adalimumab 40 mg ew.
At Week 36, all subjects will have the opportunity to enter in the OLE Study
M12-555 where they will receive adalimumab 40 mg ew.
Study visits will occur at Baseline, Week 2, Week 4, Week 8, Week 12, Week 14,
Week 16, Week 20, Week 24, Week 28, Week 32, Week 36, and at the Premature
Discontinuation visit if the subject discontinues prior to Week 36.
Additionally, all subjects will be contacted by phone 1 week following the
Baseline visit to ensure daily pain assessments are being recorded, and at
Weeks 6 and 10 to monitor whether any signs or symptoms of infection are
present at or near an HS lesion.
Study burden and risks
The subjects will participate in the study for 36 weeks. During this period,
all subjects will visit the hospital 13 times. 70 Days after the last
adalimumab injection, the subject will get a follow-up telephone call. During
the screening visit, an ECG will be made, and an X-ray of the thorax.
For the X-ray of the thorax, the subject will be exposed to a small amount of
radiation. This amount of radiation is not considered a significant risk.
Furthermore, a PPD (Mantoux) or QuantiFERON test will be done. A physical exam
will be done during all visits. In total, blood will be withdrawn 13 times,
between 6-13 times (in total 310 ml). The drawing of blood can leas to
fainting, infection of the artery, pain, bruising, and infections. also
bleeding can occur on the site of puncture. The subject has to complete
questionnaires. Some of these have to be completed on 8 visits, others 3 or 4
times. All subjects need to take a urine sample to 9 of the visits. Women who
can become pregnant need to take a urine sample to all visits.
The subject can have adverse events when using the study medication. Most
frequent adverse events are injection site reactions. Subjects can have
redness, itching, bruising pain and/or swelling of the injection site. Most
reactions are considered mild or moderate, and most reactions disappeared
without stopping the treatment with adalimumab. The following adverse events
have been reported frequently: upper respiratory tract infection, headache,
skin rash, sinusitis, bronchitis, nausea, diarrhea, abdominal pain, joint pain,
backpain, urinary tract infections, hypertension and influenza. Women of
fertile age have to use a reliable method of contraception as described in the
protocol. The use of some medication is not allowed during the study. This is
described in the protocol. (Page 34-39, section 5.2.3 Protocol version 25
august 2011)
Wegalaan 9
Hoofddorp 2132 JD
NL
Wegalaan 9
Hoofddorp 2132 JD
NL
Listed location countries
Age
Inclusion criteria
* Adult subjects must have a diagnosis of HS for at least 1 year (365 days) prior to Baseline;;* HS lesions must be present in at least two distinct anatomic areas, one of which must be at least Hurley Stage II or Hurley Stage III;;* Subject must have stable HS for at least 2 months (60 days) prior to Screening and also at the Baseline visit as determined by the investigator through subject interview and review of medical history; ;* Subject must have had an inadequate response to at least a 3-month (90 days) trial of an oral antibiotic for treatment of HS (or demonstrated intolerance to, or have a contraindication to, oral antibiotics for treatment of their HS);;* Subject must have an AN count of greater than or equal to 3 at the Baseline visit;;* Subject has a negative TB screening assessment (including a PPD test and/or Quantiferon-TB Gold test, or equivalent) and negative chest x-ray (CXR) (posterior-anterior [PA] and lateral view) at Screening;;* Subject must agree to daily use (and throughout the entirety of the study) of one of the following over-the-counter topical antiseptics on their HS lesions: chlorhexidine gluconate, triclosan, benzoyl peroxide, or dilute bleach in bathwater;;* Subject is judged to be in good general health, as determined by the Principal Investigator based upon the results of a medical history, physical examination, laboratory profile, CXR and a 12 lead ECG performed during the Screening period and confirmed at Baseline.
Exclusion criteria
* Prior treatment with adalimumab or other anti-TNF therapy (e.g., infliximab or etanercept), or participation in an adalimumab trial;;* Subjects on permitted oral antibiotic treatment (doxcycline or minocycline only) for HS who have not been on a stable dose for at least 28 days prior to the Baseline visit; ;* Subject received oral concomitant analgesics (including opioids) for HS-related pain within 14 days prior to the Baseline visit; ;* If entering the study on concomitant oral analgesics for non-HS-related pain:;* Subject on opioid analgesics within 14 days prior to Baseline visit;;* Subject not on a stable dose of non-opioid oral analgesics for at least 14 days prior to the Baseline visit (PRN is not considered a stable dose).;* Subject requires, or is expected to require, opioid analgesics for any reason (excluding tramadol);;* Subject received prescription topical therapies for the treatment of HS within 14 days prior to the Baseline visit;;* Subject received systemic non-biologic therapies for HS with potential therapeutic impact for HS less than 28 days prior to Baseline visit (other than permitted oral antibiotics);;* Subject has a draining fistula count of greater than 20 at the Baseline visit;;* Infection(s) requiring treatment with intravenous (IV) anti-infectives (antibiotics, antivirals, antifungals) within 30 days prior to Baseline or oral anti-infectives (antibiotics, antivirals, antifungals) within 14 days prior to Baseline, except as required as part of an anti-TB regimen;;* Any other active skin disease or condition (e.g., bacterial, fungal or viral infection) that may interfere with assessment of HS;;* History of demyelinating disease (including myeleitis) or neurologic symptoms suggestive of demyelinating disease;;* History of invasive infection (e.g., listeriosis, histoplasmosis), human immunodeficiency virus (HIV);;* Subject has an active systemic viral infection or any active viral infection that based on the investigator's clinical assessment make the subject an unsuitable candidate for the study;;* Hepatitis B: HBsAg positive (+) or detected sensitivity on the HBV-DNA PCR qualitative test for HBc Ab/HBsAb positive subjects;;* Chronic recurring infections or active TB;;* History of moderate to severe congestive heart failure (NYHA class III or IV), recent cerebrovascular accident and any other condition which, in the opinion of the investigator, would put the subject at risk by participation in the protocol;;* Evidence of dysplasia or history of malignancy (including lymphoma and leukemia) other than a successfully treated non-metastatic cutaneous squamous cell carcinoma, basal cell carcinoma or localized carcinoma in situ of the cervix;;* Pregnant or lactating females.
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 | EUCTR2011-003406-24-NL |
| ClinicalTrials.gov | NCT01468233 |
| CCMO | NL38118.018.12 |