Alexa B. Kimball, MD, MPH; Francisco Kerdel, MD; David Adams, MD, PharmD; Ulrich Mrowietz, MD; Joel M. Gelfand, MD, MSCE; Robert Gniadecki, MD; Errol P. Prens, MD, PhD; Joel Schlessinger, MD; Christos C. Zouboulis, MD, PhD; Hessel H. van der Zee, MD, PhD; Marie Rosenfeld, BA; Parvez Mulani, PhD; Yihua Gu, MS; Susan Paulson, PhD; Martin Okun, MD, PhD; Gregor B.E. Jemec, MD, DMSc
Disclaimer: All authors had unrestricted access to printouts of the data and to the analyses, were involved in the writing and review of the manuscript and the decision to submit it for publication, and vouch for the accuracy and completeness of the data analyses and results presented.
Acknowledgment: The authors thank Amy Gamelli, PhD, of Abbott Laboratories, for providing medical writing support during the development and writing of this manuscript; Ke Chen, formerly of Abbott Laboratories, for her support in statistical analysis; and Thomas Harris, RPh, formerly of Abbott Laboratories, for his scientific contributions to the development of the study protocol.
Financial Support: By Abbott Laboratories.
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-2529.
Reproducible Research Statement: Study protocol and data set: Not available. Statistical code: Available from Dr. Okun (e-mail, firstname.lastname@example.org).
Requests for Single Reprints: Alexa B. Kimball, MD, MPH, Clinical Unit for Research Trials and Outcomes in Skin, Massachusetts General Hospital, Harvard Medical School, 50 Staniford Street, No. 246, Boston, MA 02114; e-mail, email@example.com.
Current Author Addresses: Dr. Kimball: Clinical Unit for Research Trials and Outcomes in Skin, Massachusetts General Hospital, Harvard Medical School, 50 Staniford Street, No. 246, Boston, MA 02114.
Dr. Kerdel: Florida Academic Dermatology Centers, 1400 NW 12 Avenue, Suite 4, Miami, FL 33136.
Dr. Adams: Penn State Milton S. Hershey Medical Center, Department of Dermatology, 500 University Drive, Hershey, PA 17033.
Dr. Mrowietz: Department of Dermatology, University Medical Center Schleswig-Holstein, Schittenhelmstraße 7, 24105 Kiel, Germany.
Dr. Gelfand: University of Pennsylvania, 1471 Penn Tower, 1 Convention Avenue, Philadelphia, PA 19104.
Dr. Gniadecki: Bispebjerg Hospital, Department of Dermatology, Bispebjerg bakke 23, 2400 Copenhagen, Denmark.
Drs. Prens and van der Zee: Erasmus Medical Center, Dr. Molewaterplein 50, 3015 GE Rotterdam, the Netherlands.
Dr. Schlessinger: Skin Specialists P.C., 2802 Oak View Drive, Suite 100, Omaha, NE 68144.
Dr. Zouboulis: Departments of Dermatology, Venereology, Allergology, and Immunology, Dessau Medical Center, Auenweg 38, 06847 Dessau, Germany.
Ms. Rosenfeld; Drs. Mulani, Paulson, and Okun; and Ms. Gu: Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064.
Dr. Jemec: University of Copenhagen, Department of Neurology, Psychiatry, and Sensory Sciences, Roskilde Sygehus, Køgevej 7-13, 4000 Roskilde, Denmark.
Author Contributions: Conception and design: A.B. Kimball, U. Mrowietz, E.P. Prens, J. Schlessinger, H.H. van der Zee, M. Rosenfeld, Y. Gu, S. Paulson, M. Okun, G.B.E. Jemec.
Analysis and interpretation of the data: A.B. Kimball, U. Mrowietz, J.M. Gelfand, R. Gniadecki, J. Schlessinger, C.C. Zouboulis, P. Mulani, Y. Gu, S. Paulson, M. Okun, G.B.E. Jemec.
Drafting of the article: A.B. Kimball, E.P. Prens, J. Schlessinger, C.C. Zouboulis, H.H. van der Zee, P. Mulani, Y. Gu, M. Okun, G.B.E. Jemec.
Critical revision of the article for important intellectual content: A.B. Kimball, D. Adams, U. Mrowietz, J.M. Gelfand, R. Gniadecki, E.P. Prens, J. Schlessinger, C.C. Zouboulis, P. Mulani, Y. Gu, M. Okun, G.B.E. Jemec.
Final approval of the article: A.B. Kimball, F. Kerdel, D. Adams, U. Mrowietz, J.M. Gelfand, R. Gniadecki, E.P. Prens, J. Schlessinger, C.C. Zouboulis, H.H. van der Zee, M. Rosenfeld, P. Mulani, Y. Gu, M. Okun, G.B.E. Jemec.
Provision of study materials or patients: A.B. Kimball, F. Kerdel, U. Mrowietz, J.M. Gelfand, R. Gniadecki, E.P. Prens, J. Schlessinger, C.C. Zouboulis, G.B.E. Jemec.
Statistical expertise: J.M. Gelfand, P. Mulani, Y. Gu.
Administrative, technical, or logistic support: M. Rosenfeld.
Collection and assembly of data: A.B. Kimball, U. Mrowietz, J.M. Gelfand, R. Gniadecki, E.P. Prens, J. Schlessinger, H.H. van der Zee, M. Rosenfeld, Y. Gu, G.B.E. Jemec.
Kimball A., Kerdel F., Adams D., Mrowietz U., Gelfand J., Gniadecki R., Prens E., Schlessinger J., Zouboulis C., van der Zee H., Rosenfeld M., Mulani P., Gu Y., Paulson S., Okun M., Jemec G.; Adalimumab for the Treatment of Moderate to Severe Hidradenitis Suppurativa: A Parallel Randomized Trial. Ann Intern Med. 2012;157:846-855. doi: 10.7326/0003-4819-157-12-201212180-00004
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Published: Ann Intern Med. 2012;157(12):846-855.
Hidradenitis suppurativa (HS) is a chronic, painful skin disease characterized by abscesses, nodules, and draining fistulas in the axilla and groin of young adults.
To evaluate the efficacy and safety of adalimumab, an anti–tumor necrosis factor-α antibody, in patients with moderate to severe HS.
Phase 2, parallel, randomized, placebo-controlled trial consisting of a blinded 16-week period (period 1) and an open-label 36-week period (period 2). All study personnel, investigators, and patients remained blinded to treatment group throughout the study. (ClinicalTrials.gov: NCT00918255)
26 academic and private practice medical centers in the United States and Europe.
154 adult patients with moderate to severe HS who were unresponsive or intolerant to oral antibiotics.
Patients were assigned in a 1:1:1 ratio to adalimumab, 40 mg/wk; adalimumab, 40 mg every other week (EOW); or placebo. All patients received adalimumab, 40 mg EOW, at the beginning of period 2 but switched to weekly dosing if the response was suboptimal (HS Physician's Global Assessment [PGA] score of moderate or worse) at weeks 28 or 31.
The primary outcome measure (clinical response) was the proportion of patients achieving an HS-PGA score of clear, minimal, or mild with at least a 2-grade improvement relative to baseline at week 16.
At week 16, 3.9% of placebo patients (2 of 51), 9.6% of EOW patients (5 of 52), and 17.6% of weekly patients (9 of 51) achieved clinical response (EOW vs. placebo strata-adjusted difference, 5.6% [95% CI, −4.0% to 15.3%]; P = 0.25; weekly vs. placebo strata-adjusted difference, 13.7% [CI, 1.7% to 25.7%]; P = 0.025). Serious adverse event rates were 3.9%, 5.8%, and 7.8% for placebo, EOW, and weekly patients, respectively (EOW vs. placebo difference, 1.8% [CI, −6.4% to 10.1%]; weekly vs. placebo difference, 3.9% [CI, −5.2% to 13.0%]). Significantly greater improvements in patient-reported outcomes and pain were seen in the weekly dosing group than in the placebo group. A decrease in response was seen after the switch from weekly to EOW dosing in period 2.
Weeks 16 to 52 of the study were open-label. The study was not powered to assess the risk for known serious adverse effects of adalimumab, such as tuberculosis, other serious infections, and demyelinating disorders.
Adalimumab dosed once per week alleviates moderate to severe HS.
National Cancer Institute/ National Institutes of Health
December 23, 2012
The phase II randomized trial by Kimball, et al , which claims a benefit of Adalimumab (Humira, Abbott) in hydradenitis suppuritiva raises a number of questions regarding its methodology history . First, while the authors state the primary outcome was “prespecified,” the trial’s history of changes on clinicaltrials.gov notes significant alterations on May, 7, 2011, over two years after the trial began . Specifically, the primary outcome was altered on that date from an undefined “Physician’s Global Assessment” to “Percentage of Participants Achieving Clinical Response at Week 16”. Another primary outcome of “Adverse events,” at a time point of week 52, was changed to “Percent Change From Baseline in Number of All Inflammatory Nodules and Plaques at Week 16.” A secondary endpoint of Physician’s Global Assessment at week 52, was changed to “Percentage of Participants Achieving Clinical Response at Week 8.” A secondary outcome of “Nodule, Fistula and Abcess [sic] Improvement,” which was not significantly improved (see Appendix Table 5) was changed to, “Percentage of Participants Achieving Clinical Response at Week 12.” There are other alterations, but my question is the same: do the authors have any explanation for these excessive, late changes?Additionally, on 11-12-2009, the authors changed the dosing of arm 2 from “40 mg eow (end of week) through Week 15” to “40 mg eow (every other week) through Week 15,”  preserving the abbreviation EOW, while changing its meaning. Admittedly, I don’t understand the original language, as I am not sure how end of week would be different than Arm 1: weekly. Can the authors clarify this as well?In short, in the absence of a satisfying explanation, the study by Kimball, et al. is an underpowered, randomized phase II trial with multiple, subjective and shifting endpoints. I count at least 7 scales used as primary or secondary endpoints. Multiplied by 3 arms, and several time points yields at a minimum of 40 possible comparisons that could be made. It should not be surprising that some are unsurprising . It may be worth noting that of 16 authors, 13 disclose conflicts of interest (81%), while one author’s ICMJE form was inaccessible to me. And finally, the authors note that the study protocol and data set are not available. I urge the authors to post this information publically.
1. Kimball AB, Kerdel F, Adams D, et al. Adalimumab for the Treatment of Moderate to Severe Hidradenitis SuppurativaA Parallel Randomized Trial. Annals of internal medicine 2012;157:846-55.
2. Krumholz HM. Documenting the Methods History: Would It Improve the Interpretability of Studies? Circulation: Cardiovascular Quality and Outcomes 2012;5:418-9.
3. Clinicaltrials.gov 05-07-2011 changes. (Accessed December 23, 2012, at http://clinicaltrials.gov/archive/NCT00918255/2011_05_07/changes.)
4. Clinicaltrials.gov 11-12-2009 changes. (Accessed December 23, 2012, at http://clinicaltrials.gov/archive/NCT00918255/2009_11_12/changes.)
5. Ioannidis JP. The importance of potential studies that have not existed and registration of observational data sets. JAMA : the journal of the American Medical Association 2012;308:575-6.
Alexa Kimball, MD, MPH
Harvard Medical School
February 8, 2013
Prasad unfortunately misinterprets clarifications and a correction of prespecified endpoint descriptions in ClinicalTrials.gov to be "shifting" of the endpoints themselves in the study reported by Kimball et al demonstrating the effectiveness of adalimumab in the treatment of moderate-severe hidradenitis suppurativa (1). These clarifications and correction do not reflect any deviation of study conduct or reporting from good clinical practice, and in fact, some were requested by ClinicalTrials.gov itself.
The authors affirm that the Physician’s Global Assessment was the prespecified instrument utilized to assess the degree of severity of HS study patients. The protocol-defined prespecified primary endpoint has always been the percentage of patients achieving Clinical Response at Week 16. The authors further affirm that Clinical Response was assessed using the Physician’s Global Assessment instrument and was defined as a PGA score of clear, minimal or mild with at least a 2-grade improvement relative to baseline score.
The change in the ClinicalTrials.gov posting that Prasad alludes to was done to provide more detail about the primary endpoint, which remained unchanged, in the posting, Similarly, the description of the secondary endpoints in ClinicalTrials.gov was expanded to clarify the protocol-defined prespecified endpoints and to include the timepoint information, per requests from ClinicalTrials.gov.The change in the description of dosing in Arm 2 from "40 mg eow (end of week) to "40 mg eow (every other week)" was a correction of a mistake in the original entry. The error was identified and corrected in two weeks. The dosing itself in arm 2 was prespecified in the protocol, did not change during study conduct, and is accurately described in the publication.
The study was powered only for the prespecified primary endpoint (as stated in the Methods section of the publication), not for secondary endpoints, and success for this study was assessed utilizing the primary endpoint. Evaluation of the primary endpoint depends on the count of different types of inflammatory lesions as assessed by the study physicians, and is therefore not subjective. As mentioned above, the endpoint did not shift during the study.
The results from the secondary endpoints, which measure different dimensions of disease severity than was captured by the primary endpoint, provide further support for the effectiveness of adalimumab in the treatment of moderate to severe hidradenitis suppurativa; these secondary endpoints were prespecified to aid in validation and improvement of the scoring system for the primary endpoint.
ICMJE forms for conflicts of interest were provided directly to Annals of Internal Medicine by each author, and we refer you back to the journal for any that are currently inaccessible to interested readers. Annals of Internal Medicine does not currently have a requirement for public posting of study protocols or datasets; however, substantial information, as has been noted, is currently available at the ClinicalTrials.gov website.
Alexa B. Kimball, MD, MPH
Massachusetts General Hospital
Harvard Medical School
Martin Okun, MD, PhD
1. Kimball AB, Kerdel F, Adams D, et al. Adalimumab for the Treatment of Moderate to Severe Hidradenitis Suppurativa: A Parallel Randomized Trial. Annals of Internal Medicine 2012;157:846-55.
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