Infection-free Clinical Response Among Patients With Hidradenitis Suppurativa Who Were Treated With Adalimumab: Results from Two Phase 3 Studies

Objective. The objective of this study is to assess the rates of infection-free achievement of hidradenitis suppurativa clinical response (HiSCR) using integrated data from 2 phase 3, placebo-controlled trials, PIONEER I and II. Materials and Methods. Analyses from the first 12 weeks of both studies were examined. Patients were randomized to receive adalimumab (ADA) or placebo, and they then were assessed in the clinic at weeks 0, 2, 4, 8, and 12. All reports of an adverse or serious adverse event and infection were classified as treatment-emergent adverse events (TEAEs). The HiSCR was evaluated as the primary endpoint; infection-free HiSCR was also evaluated. Results. Treatment-emergent adverse events were observed in 55.4% of the ADA group and 64.4% of the placebo (P < .023). The rates of serious TEAEs and infection-related TEAEs were slightly less in the ADA group compared with the placebo group. A significantly higher percentage of ADA-treated patients achieved HiSCR at week 12 compared with placebo (P < .001). At each visit during the study’s 12 weeks, a greater proportion of ADA-treated patients achieved infection-free HiSCR compared with patients treated with placebo (P < .001). Mean durations of HiSCR and infection-free HiSCR were significantly longer in ADA-treated patients when compared with placebo-treated patients (P < .001). Conclusions. Results of this integrated analysis indicate that patients with hidradenitis suppurativa who received a short duration of ADA treatment experienced better combined efficacy and similar safety compared with placebo. Further studies investigating longer ADA treatment may demonstrate further improvements in duration of infection-free clinical response.

Hidradenitis suppurativa (HS) is a chronic skin condition characterized by flares of painful, inflammatory cutaneous nodules, abscesses, sinus tracts, and fistulae.^1–4 Although HS is a systemic inflammatory disease, bacterial colonization of lesions may elicit the inflammatory immune response observed in HS.⁵ Systemic antibiotics are commonly used to manage secondary infection and inflammation, but effectiveness is limited in patients with more severe disease.³ Furthermore, bacteria found in HS lesions are resistant to many commonly used antimicrobial drugs.⁵

Originator adalimumab (ADA, Humira; AbbVie Inc, North Chicago, IL) is an anti-tumor necrosis factor (TNF) alpha monoclonal antibody approved for the treatment of moderate-to-severe HS.⁶ Results from 2 phase 3, placebo-controlled trials, PIONEER I and PIONEER II, demonstrated the efficacy and safety of ADA.⁷ The analysis herein uses integrated data from PIONEER I and II to assess the rate of infection-free achievement of HS clinical response (HiSCR).

Participants
Patients included in the studies were adults with ≥ 1-year history of stable, moderate to severe HS. Baseline count for the sum of abscesses and inflammatory nodules (AN counts) was determined as ≥ 3 and HS lesions in ≥ 2 body areas, with ≥ 1 at Hurley stage II or III. Patients who received previous treatment with ADA or other anti-TNF therapy were excluded from participation. Those patients with other active skin diseases or conditions (eg, bacterial, fungal, or viral infection) that could interfere with assessment of HS or those who had a draining fistula count > 20 at baseline visit also were excluded. Participants could not have taken oral antibiotics for HS within 28 days of baseline visit (except for PIONEER II subjects who were only on stable doxycycline or minocycline) or analgesics or prescription topical treatment for HS within 14 days of baseline visit.

Study design and treatment
Integrated data from 2 phase 3 trials, PIONEER I and II, were used, and this analysis includes data from the first 12 weeks of the studies (Period A). In both studies, patients were randomized (1:1) to receive ADA or matching placebo (Figure 1). All patients received 4 injections of ADA (40 mg each for a total of 160 mg) or placebo at week 0, two injections at week 2 (for a total of 80 mg), and 1 injection of 40 mg weekly from weeks 4 to 11. 

In PIONEER II, concomitant doxycycline or minocycline was permitted if patients took the antibiotic for > 28 days before baseline and maintained a consistent dosing regimen during the study. Up to 100 mg doxycycline twice daily or 100 mg minocycline twice daily was permitted. Concomitant antibiotic use was not permitted in PIONEER I.

Assessments
Patients were assessed in clinic at weeks 0, 2, 4, 8, and 12. All reports of an adverse event or a serious adverse event and infection were classified as treatment-emergent adverse events (TEAEs); TEAEs of special interest included infection, serious infection, opportunistic infection (excluding oral candidiasis and tuberculosis), and latent or active tuberculosis.

The primary endpoint in both studies was HiSCR, defined as ≥ 50% reduction in AN count with no increase in abscess or draining fistula counts relative to baseline.⁸ Infection-free HiSCR was defined as achievement of HiSCR without a reported TEAE of infection.

Statistical analyses
All randomized patients were included in the integrated efficacy analyses. Treatment difference for the proportion of patients achieving infection-free HiSCR was calculated using the Cochran-Mantel-Haenszel test (2-tailed, α = .05). Analyses were stratified by study, baseline Hurley stage, and antibiotic use. Mean duration of infection-free HiSCR was compared using analysis of covariance (ANCOVA; α = .05).

Participants
This integrated analysis included 633 randomized patients (Table). Of these, 596 patients completed the first 12 weeks of the study (ADA, n = 300; placebo, n = 296). Two patients (0.63%) in the placebo group discontinued without receiving a dose. Of 633 patients, 35 (5.5%) discontinued the study during Period A, before reaching week 12. The most frequent primary reasons for discontinuation were due to patient withdrawal consent (1.4%) or adverse events (2.4%). At baseline, 53% of patients had Hurley stage II disease and 47% had Hurley stage III disease. 

Treatment-emergent adverse events and serious adverse events
At least 1 TEAE was reported in 55.4% (175/316) of ADA-treated patients and in 64% (203/317) of placebo-treated patients (P < .023). At least 1 serious TEAE was reported in 1.9% (6/316) and 3.5% (11/315) of ADA-treated and placebo-treated patients, respectively.

Treatment-emergent infection
A TEAE of any infection was reported in 25% (79/316) of ADA-treated patients and in 30.3% (96/317) of placebo-treated patients. Serious infection was reported in 2 (0.6%) patients in each treatment group. No patients experienced an opportunistic infection or tuberculosis.

Achievement of infection-free HiSCR
Overall, 51% (160/316) of patients who received ADA achieved HiSCR at week 12 compared with 27% (85/317) of patients who received placebo (P < .001). At each visit during the first 12 weeks of the study, a greater proportion of patients treated with ADA achieved infection-free HiSCR than patients treated with placebo (P < .001 for each; Figure 2). The proportion of patients who achieved infection-free HiSCR with ADA treatment was greater at 2 weeks than at any study visit among patients who received placebo. The same treatment effect was observed when results were stratified by baseline antibiotic use and Hurley stage (Figure 3).

Duration of infection-free HiSCR
Of patients who achieved HiSCR, those who received ADA had a mean duration of HiSCR of 34.2 days compared with 16.8 days for those patients who received placebo (P < .001). The mean duration of infection-free HiSCR was significantly longer for patients who received ADA than for patients who received placebo (P < .001; Figure 4). 

A limitation of this study was the short, 12-week duration of ADA therapy, which makes it difficult to determine the potential benefit in prolonging the interval between infections.

Patients with moderate to severe HS who received 12 weeks of treatment with ADA experienced better combined efficacy and similar safety compared with patients who received a placebo, as indicated by TEAEs and rates of infection-free HiSCR. Even though ADA-treated patients experienced significantly fewer TEAEs when compared with placebo-treated patients, there were just slight differences between treatment groups in both serious TEAEs and treatment-emergent infection rates.  A greater proportion of patients who received ADA achieved infection-free HiSCR, regardless of baseline antibiotic use or Hurley stage, compared with placebo. Interestingly, although the duration of infection-free HiSCR was significantly longer with ADA treatment compared with placebo, the duration of infection-free HiSCR was just 17 days longer with 12 weeks of ADA treatment, which suggests that a short duration of ADA therapy may provide limited benefit in prolonging the interval between infections. The duration of clinical response without concomitant infection was longer with ADA treatment than with placebo. Studies investigating longer treatment with ADA may demonstrate further improvements in duration of infection-free clinical response.

Affiliations: 4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece; Department of Dermatology, Tufts University School of Medicine, Boston, MA; Department of Dermatology, St. Vincent’s University Hospital, Dublin, Ireland; AP-HP, Département de Dermatologie, UPEC, Hôpitaux Universitaires Henri Mondor, Créteil, France; and AbbVie Inc, North Chicago, IL

Correspondence:
Evangelos J Giamarellos-Bourboulis, MD, PhD
4th Department of Internal Medicine
Attikon University Hospital
National and Kapodistrian University of Athens, Medical School
1 Rimini Str
12462 Athens, Greece
egiamarel@med.uoa.gr

Disclosure: This study was funded by AbbVie Inc (North Chicago, IL). Dr. Giamarellos-Bourboulis received honoraria and independent educational grants (paid to the University of Athens) from AbbVie. Dr. Sobell received honoraria and research grants as a consultant, speaker, and/or investigator from AbbVie. Dr. Ryan has acted as a consultant or speaker for AbbVie. Dr. Wolkenstein received honoraria from AbbVie as a consultant. Drs. Geng and Mulder are full-time employees of AbbVie and may own stock and/or stock options. Editorial assistance was funded by AbbVie and provided by Shelly Asiala-Heckner, PharmD, CMPP, and Kristy A. Grabowski, PhD, of JB Ashtin (Plymouth, MI).This paper was presented as a poster at the SAWC Spring 2017.