The History of Collagenase Clostridium Histolyticum

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The History of Collagenase Clostridium Histolyticum Kevin K. Yang, MD and Nelson Bennett, MD, FACS Lahey Hospital and Medical Center, Institute of Urology, Burlington, MA, USA DOI: 10.1002/smrj.54

ABSTRACT

Introduction. After its U.S. FDA approval in 2013, Collagenase Clostridium histolyticum (CCh) has seen increasing use as a nonoperative treatment for Peyronie’s disease (PD). We review the history of CCh and trials that led to its adoption. Aim. To provide a historical and contemporary context for the evolution of Collagenase Clostridium histolyticum as a treatment modality for Peyronie’s disease. Methods. A comprehensive search of peer-reviewed literature was performed pertaining to CCh and its biochemical and clinical significance. Main Outcome Measure. The main outcome studied was the efficacy and safety profile of CCh in PD. CCh use in other diseases processes and its associated outcomes are also described. Results. CCh injection yields objective improvement in penile curvature across multiple trials in PD patients. Recently, level 1 strength of evidence has emerged supporting its widespread use. As such, CCh stands as the only FDA-approved injectable therapy for PD. Adverse events were namely limited to local reactions. Serious systemic complications and need for intervention were rare. Conclusions. CCh is a safe and effective treatment for PD patients with deformities and plaque configuration amenable to injectable therapy. Multiple trials have demonstrated improvements in objective and subjective metrics such as penile curvature and bother scores. However, multiyear follow-up is needed to assess durability and its sustained clinical significance. Currently, refinement in dosing and technique has established a niche for CCh in PD patients who are affected by their symptoms but are not yet committed to surgical intervention. Yang KK and Bennett N. The history of collagenase clostridium histolyticum. Sex Med Rev 2015;3:289–297. Key Words. Peyronie’s Disease; Collagenase Clostridium Histolyticum; Xiaflex

Introduction

P

eyronie’s disease (PD) is a progressive wound healing disorder highlighted by an inelastic fibrous scar in the tunica albuginea. Its etiology has been linked to a history of penile trauma and subsequent microvascular insults followed by extravascular activation of the fibrotic cascade [1,2]. Histologically, tunical collagen display abnormal distributions of type I, III, and V subtypes instead of a typical fibrillary type I pattern neatly interweaved by elastin fibers [3,4]. Pathologic extracellular remodeling is highlighted by inappropriate fibrin deposition, decreased elastin content and infiltration by fibroblasts, glycoproteins and proteoglycans [2,4,5]. Transforming growth factor beta 1 (TGFβ1) has been implicated for the

© 2015 International Society for Sexual Medicine

molecular upregulation of myofibroblast activity, nitric oxide dysregulation, and subsequent oxidative stress [6]. Indeed, inappropriate extracellular matrix propagation may be due to the observed downregulation of tissue inhibitors of matrix metalloproteinases (TIMPs) by TGFβ1 [7]. In addition, endogenous collagenase expression is also downregulated, thereby hindering degradation of the pathological collagen complexes [8]. The most common clinical manifestation is a dorsal curvature and an associated palpable plaque. Subjective symptoms include painful erections, sexual dysfunction, and significant psychosocial burden [9–11]. The disease process is recognized to occur in two phases. The acute phase of PD is marked by ongoing inflammation causing pain and a dynamic penile curvature. Twelve to 18 months Sex Med Rev 2015;3:289–297

290 after initial presentation, patients progress to the chronic phase and stabilization into a painless deformity of the shaft [12]. For PD patients in the chronic phase, the historical gold standard for the definitive correction of penile curvature has been surgical management [13]. Tunical shortening and tunical lengthening procedures with or without concomitant placement of an inflatable penile prosthesis have been extensively described [14]. The complete breadth of operative options available for PD is beyond the scope of this review and is described elsewhere. Options for nonsurgical management of PD are plentiful, but none have definitely shown to halt the fibrotic disease process. Oral medications have hypothetical effects in hindering the inflammatory and fibrotic cascade of PD. Systemic antioxidants such as vitamin E (tocopherol), anti-fibrotic agents such as potassium aminobenzoate, pentoxifyllinem tamoxifen, colchicine, and PDE-5 inhibitors demonstrate an efficacy profile ranging from no benefit to modest improvement in curvature, plaque size, and pain [15]. Although there is a potential for oral medications as adjunct therapy in the acute PD phase, the lack of confirmatory, large-scale, placebo-controlled randomized trials have precluded oral monotherapy as the standard of care for PD [16]. Injectable therapy for PD was first carried out with corticosteroids in 1954 with a reported decrease in plaque size, penile pain, and curvature [17]. However, these results were not reproducible in subsequent series and placebo-controlled trials [18,19]. Antioxidizing enzymes such as orgotein, a superoxide dismutase variant have shown therapeutic benefits in curvature correction and pain when injected in the region of penile induration [20–22]. Yet, all published studies lacked placebotreated controls and had limited sample sizes thus curtailing its widespread adoption for PD. Intraplaque interferon injections for PD have been relatively well described since its in vitro demonstration of fibroblast inhibition and collagenase upregulation [23]. Subsequent clinical applications showed mixed results ranging from no therapeutic benefit to modest improvements in curvature while systemic flu-like symptoms were common side effects [24,25]. In the largest trial to date, Hellstrom et al. confirmed improved objective parameters from interferon alpha-2b (INFα-2b) in a prospective, single-blinded, placebo-controlled trial [26]. The reported 13.5° decrease in curvature for INFα-2b compared to 4.5° in placebo was statistically significant compared to placebo, but its Sex Med Rev 2015;3:289–297

Yang and Bennett clinical consequence may be blunted as patients did not show comparable improvement in their International Index of Erectile Function (IIEF) questionnaire. First reported in 1994 by Levine et al., intralesional verapamil posed an inexpensive and safe injectable therapy for PD [27]. Its mechanism appears to involve extracellular matrix regulation with reduced myofibroblast activity and upregulation of collagenase leading to collagenogenesis regulation [28,29]. Similar to the aforementioned therapies, large-scale and well-controlled trials have been lacking despite promising results for limited patient cohort sizes in both the acute/early and chronic/mature PD populations [30–32]. Intralesional verapamil has also been used in combination with oral antioxidant therapy with objective responses in penile curvature reduction, plaque size lessening, and erectile function improvement [33,34]. Other combinations with iontophoresis and topical therapy have been reported with favorable results [35,36]. Nonetheless, these observations suffer limitations in not having a placebo-controlled arm. In addition, the optimal combination, selection of patients, and sequence of treatment remain questions to be addressed. Clostridial Collagenase Application Outside of Peyronie’s Disease

The activity of Clostridial collagenase was first observed by Maschmann as a major virulence factor for the bacteria, Clostridium perfringens during the digestion of the host’s tissues [37]. This enzyme was subsequently isolated in the 1940s, but initial purity was rudimentary involving precipitation from crude filtrates [38]. Mandl et al. later reported better lysis and greater specificity in purified samples of collagenase from a related species, Clostridium histolyticum [39,40]. Later, with successful mass production of the enzyme by gene recombination, collagenase Clostridium histolyticum (CCh) was adopted as the therapeutic model for future in vitro and clinical studies [41]. Collagenase belongs to a family of metalloproteases and has a collagenolytic function. Unlike mammalian collagenase, bacterial collagenase cleaves the collagen triple helix at multiple sites. Ensuing peptidase activity of CCh fragments the unwound collagen into smaller peptides [42]. Collagenase from Clostridium histolyticum has two subtypes, class I and class II, which are products of two distinct genes. Class I collagenase has an endopeptidase activity cleaving internal seg-

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The History of Collagenase Clostridium Histolyticum ments while class II behaves as a tripeptidylcarboxypeptidase, cleaving the carboxyl terminal moiety [43]. Commercialization of CCh as Xiaflex (Auxilium Pharmaceuticals, USA) achieves a fixed class I to class II ratio for optimal collagenolysis and aids reproducibility in clinical applications. In vitro studies suggest induced fibroblast necrosis by Xiaflex in Dupuytren’s disease, whereas unformulated collagenase A nonspecifically triggers both apoptosis and necrosis in fibroblasts [44]. The clinical ramifications of such a difference are currently unknown. In an in vitro environment, CCh assists in isolation of pancreatic islet cells to be transplanted in type I diabetics [45]. Donor pancreases are digested with CCh, which hydrolyzes the extracellular matrix freeing up the islet cells. Therapeutic benefits of direct CCh application were first described in burns and dermatological ulcers as a form of enzymatic debridement to promote wound healing [46,47]. Subsequently, limited applications of CCh in herniated disks, plantar fibromatosis, and keloids were reported [48–50]. Ophthalmological literature even describes utilizing CCh as an adjunct to vitrectomies by digesting vitreous scar tissue as early as 1980 [51]. The breadth of clinical literature outside of PD is provided by Dupuytren’s disease (DD), an analogous pathological fibrosis of the palmar aponeurosis causing nodules, cords, and joint contraction. As with PD, DD involves fibroproliferation instigated by TGFβ1 and myofibroblast infiltration with abnormal collagen deposition [52,53]. Consensus guidelines have historically favored a surgical approach with palmodigital fasciectomies and needle or open fasciotomies [54]. Enzymatic fasciotomy was initially described with nonspecific hydrolytic agents against protein and extracellular matrix contents [55]. CCh was investigated to rupture DD cords in vitro and then in a prospective pilot study for DD patients with metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joint contractures with promising results [56,57]. A multicentered, placebo-controlled phase 2 trial later confirmed a dose-dependent improvement of joint contractures with local and self-resolving adverse events [58]. In 2009, Hurst et al. published a phase 3 clinical trial of 308 patients comparing CCh injections with finger extension manipulation to placebo [59]. The former group saw a clinical resolution of their joint contractures to 0 to 5° in 76.7% of MCP and 40% of PIP joints compared to 7.2% and 5.9%, respectively, for placebo. Range of motion was also mark-

edly improved over placebo. Two instances of tendon rupture requiring surgical intervention were reported. In February of 2010, the U.S. FDA approved Xiaflex for DD. Recently, large-scale post-approval surveillance of the previously studied population over 3 years of follow-up revealed recurrence rates of 35% [60,61]. Nonetheless, relatively few of this group reached their preoperative curvature levels, and patient satisfaction remained decidedly in favor of the treatment arm. A decreased number of doses for therapeutic cord rupture and reduced incidence of tendon injuries were attributed to refined technique and greater experience in practitioners [62]. As of currently, expert consensus and guidelines have not yet adopted CCh as a standardized recommendation for the treatment of DD [54]. Clostridial Collagenase for Peyronie’s Disease Historical Data

Gelbard et al. are credited with the first application of CCh in PD [63]. In vitro studies in the 1980s demonstrated dose-dependent dissolution of PD plaques by CCh although normal tunical collagen was also nonspecifically targeted [64]. The same group published the first series of intralesional CCh administered to PD patients in 1985 [65]. Thirty-one patients with mean duration of PD symptoms for 22 months underwent a dosetitrated injection of CCh without matching placebo controls. Adjuvant β-aminopropionitrile (oral or topical) was administrated in 25 patients. After a follow-up of 9.8 months on average, 20 (65%) of the subjects demonstrated objective improvements in either plaque size or penile curvature. Thirteen out of 14 patients reported elimination of penile pain, three out of four patients who were unable to have intercourse prior to treatment regained the ability. Twenty-one out of 31 patients had injection site ecchymosis that was self-resolving. One patient experienced a small corporal rupture during intercourse that was managed conservatively. Another patient experienced a hypersensitivity reaction but was attributed to β-aminopropionitrile and not CCh. Subsequent studies investigated the systemic concerns of introducing bacterial collagenase, a compound that was considered immunologically foreign by the body. Most patients exhibited increased titers of IgG to CCh after treatment while only one patient out of the 44 treated demonstrated detectable IgE levels. No anaphylactic reactions were reported [66]. Sex Med Rev 2015;3:289–297

292 In 1993, Gelbard et al. reported the first placebo-controlled, double-blinded study of CCh for PD in 49 patients [67]. After only 3 months of follow-up, eight out of 22 (36%) of CCh treated patients had a positive response in curvature reduction compared to one out of 27 (4%) who received placebo. Subsequent crossover retreatment of placebo yielded a qualitative response in 13 out of 23 (56%) patients. A positive response was defined as an objective improvement of plaque size, extent, and penile bending that correlated with subjective improvement of sexual function. Patients were also stratified according to plaque size and penile curvature: less than 30° and 2 cm, 30 to 60° and 2–4 cm or more than 60° and 4 cm. Subset analysis showed as pretreatment curvature and plaque size increased, CCh was less effective; the positive response for the respective groups were three out of three (100%), four out of 11 (36%), and one out of eight (13%) for CCh compared to one out of four (25%), 0 out of 13 (0%), and 0 out of 10 (0%) for placebo. Quantitative measurements of curvature reductions yielded maximal improvements of only 15–20°. Like the previous study, all adverse events were local and self-resolving including one tunical tear during intercourse. In 2008, Jordan provided a prospective, singlecenter series of 25 PD patients undergoing three intralesional injections of CCh. Baseline curvature and plaque size were 52.8° and 5.8 cm, respectively. Mean duration of illness prior to CCh treatment was 43.6 months suggesting that most patients had chronic/stable disease. After 9 months, 19 patients completed all treatment courses with a follow-up visit every 3 months. There was a statistically significant reduction in curvature at 3 and 6 months (12.7° and 11.1° reduction, respectively) but not at 9 months. In fact, 64.7% of patients were classified as treatment failures at 9 months (curvature reduction less than 25° compared to pretreatment baseline). The authors attributed this to the withdrawal before all 9 months of follow-up of three patients who had initially achieved measurable curvature and plaque size reduction. Adverse events were recorded in 72% of patients reporting local symptoms of post-injection pain or ecchymosis that resolved with observation. Of note, this was the first independent validation of CCh efficacy to the aforementioned Gelbard trials. In addition, more concentrated CCh with smaller volume was used, and a formal treatment cycle with repeat injections was employed. Sex Med Rev 2015;3:289–297

Yang and Bennett Clostridial Collagenase for Peyronie’s Disease Contemporary Data

In 2012, Gelbard et al.’s group performed a phase 2b, double-blind, placebo-controlled trial with CCh for PD [68]. This study was sponsored by Auxilium Pharmaceuticals and was the first to use the proprietary Xiaflex formulation. One hundred forty-seven patients from 12 sites were randomized 3:1 in CCh to placebo arms. Three treatments cycles 6 weeks apart were performed with each cycle consisting of two injections 24–72 hours apart. There was also a 1:1 randomization of penile modeling after the second injection. This entailed “gradual, gentle stretching of the flaccid penis in the opposite direction of the curvature” for 30 seconds repeated three times. Inclusion criteria selected patients with 30° to 90° penile curvatures in a dorsal, lateral, or dorsolateral direction. Patients with curvatures of less than 30° and over 90° were excluded along with any with ventral curvatures or isolated hourglass configurations. Also excluded were patients with extensively calcified plaques determined by radiography and those with previous PD treatments within 2 to 12 weeks depending on the mode of intervention. Baseline enrollment age was 56.6 years with an average reported PD history of 2.8 years and penile curvatures of 53.5° determined by pharmacologically induced erections. Subjective outcomes were measured by IIEF questionnaire involving erectile and orgasmic function. Disease-specific questions were presented as the Peyronie’s Disease Questionnaire (PDQ), a 15-question externally validated survey that categorized symptoms into domains of sexual function, pain, and bother [69,70]. After 137 of 147 patients completed all three cycles of injections, an intention-to-treat analysis showed mean curvature reduction in the CCh treated arm of 16.3° (29.7%) vs. 5.4° (11%) after 36 weeks. In subset analyses, CCh treatment with penile modeling (54 patients) demonstrated a curvature reduction of 17.5° (32.4%) vs. a 0.6° (2.5%) worsening for placebo with modeling (20 patients). CCh treatment without modeling (57 patients) showed a mean curvature reduction of 15° (27.1%) while having no statistical difference from that of placebo without modeling (16 patients) at 13° (27.9%). The authors reasoned that this unexpected outcome in the placebo without modeling arm was affected by relatively few patients (16) and a skewed proportion of patients with PD less than 1 year (four, 25%).

The History of Collagenase Clostridium Histolyticum Regarding subjective outcomes, only the bother domain of the PDQ demonstrated a significant difference for the CCh treatment over placebo (mean score reduction of 2.55 compared to 0.76, respectively). This difference was maintained in the CCh treatment with modeling arm compared to placebo with modeling arm (mean score reduction of 3.6 compared to 0.1, respectively). PDQ domains of sexual function and pain along with the IIEF questionnaire demonstrated no statistically significant disparity in all arms. With a standardized injection protocol, there was no reported treatment-related serious adverse events. Injection site bruising was the most common treatment emergent adverse event (TEAE) occurring in 86.5% of CCh treated patients compared to 52.8% of placebo. No corporal rupture or need for surgical intervention was reported. No systemic immunological events occurred. While the phase 2b study was at that time the largest for a CCh-related trial, patient numbers limited certain interpretations as they were required to power four intervention arms. Addressing this concern, Gelbard et al. presented data from two parallel phase 3 trials, the Investigation for Maximal Peyronie’s Reduction Efficacy and Safety Studies I and II (IMPRESS I and II) [71]. Enrolled were 832 patients from 64 sites across the United States and Australia. Treatment was conducted in a double-blind, placebo-controlled fashion. Major protocol differences from the phase 2b included penile modeling at home by all patients three times daily for 6 weeks after each treatment cycle. Treatment cycles were extended to up to 4 cycles 6 weeks apart with each cycle consisting of two injections 24–72 hours apart. Patients were required to halt injection cycles if their penile curvature was reduced to less than 15° at any point or if treatment was not further indicated. Inclusion and exclusion criteria slightly changed from the phase 2b trial as only patients with stable PD over 12 months were enrolled, while anyone with erectile dysfunction refractory to PDE5 inhibitors was excluded. Post-randomization participants of 220 were excluded out of the original 832 (26.4%) in a modified intention-to-treat analysis. The most commonly reported reason for exclusion was voluntary patient withdrawal (6.4%). Mean reduction in penile curvature was more in the CCh treated arm at 17° (34% decrease) compared to placebo at 9.3° (18.2% decrease). PDQ bother score was also lower in the CCh arm vs. placebo (−2.8 to −1.8). Unique from the phase 2b trial, the IMPRESS studies showed combined PDQ scores and greater

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IIEF overall satisfaction scores in favor of CCh over placebo although individual psychological and physical domain results were not reported. All of the abovementioned comparisons were statistically significant at P < 0.05. The authors delineated a patient with combined improved subjective and objective outcomes as a composite responder, which entailed an improvement of the PDQ bother score of one or greater or a change from reporting no sexual activity prior to treatment to successful sexual activity in addition to an objective 20% or greater reduction in penile curvature. Identified were 46.6% of CCh-treated patients as composite responders compared to 28% of placebo. Of note, CCh has not been shown in this trial or any previous literature to alter penile length nor has it demonstrated any enhancement of indentation defects. As with the earlier phase 2b trial, more TEAEs were attributed due to CCh over placebo (84.2% vs. 36.3%). Most of these were at the local injection site (ecchymosis, swelling, pain) and resolved within one injection cycle without intervention. However, three instances of corporal ruptures during intercourse in the CCh arm were reported requiring surgical repair. Three penile hematomas also developed after CCh treatment, two of which required either aspiration or surgical exploration. The authors noted that one case of corporal rupture was during intercourse within 14 days of last injection cycle while another case was at 14 days. Per patient instructions, intercourse was prohibited for at least 14 days after the last treatment cycle. The methodologies and findings of the contemporary Phase 2b and Phase 3 trials are summarized in Table 1. Given the results and level 1b strength of evidence posed by the IMPRESS trials, the FDA approved Xiaflex for PD patients with at least 30° of penile curvature in December of 2013. The medication is currently undergoing postmarket analysis and is currently only available through the FDA-regulated Risk Evaluation and Mitigation Strategy program. Discussion

As it stands, CCh has emerged as the most studied intralesional injectable therapy for PD as the only mode of treatment with a phase 3 study to its name. Since its inception for clinical use in PD patients, CCh has produced modest but consistent responses in penile curvature and bother symptoms. However, compared to other injectable Sex Med Rev 2015;3:289–297

294 Table 1

Yang and Bennett Comparison of contemporary CCh trials

Trials

Number of patients

Intervention

Phase 2b Trial (Gelbard 2012)

Reduction in penile curvature Adverse events

Total of 147 stratified to: Three treatments cycles 6 weeks 16.3° (29.7%) CCh with penile modeling (n = 54) apart with two injections in each CCh vs. 5.4° Placebo with penile modeling (n = 20) cycle (0.58 mg CCh), Penile (11.0%) CCh without penile modeling (n = 57) modeling x 3 after second placebo Placebo without penile modeling injection of each cycle if in (n = 16) modeling group 17.0° (34.0%) Phase 3 Trials Total of 832 patients: Up to four treatment cycles 6 (IMPRESS I + II, CCh (n = 551) weeks apart with two injections CCh vs. 9.3° Gelbard 2013) Placebo (n = 281) in each cycle (0.58 mg CCh), (18.2%) mandatory penile modeling x 3 placebo after second injection of each cycle followed by three times daily at home by patient

therapies such as INFα-2b and verapamil, one must wonder if CCh holds a true clinical advantage over them or if the disparity is due to a lack of robust and large-scale trials in the former agents. It has been shown, albeit in trials with weaker strength of evidence and different outcome metrics, that both INFα-2b and verapamil led to comparable decreases in penile curvature compared to CCh’s reported 17° improvement in the latest phase 3 trial [71]. In the largest respective trials for these agents, Hellstrom et al. demonstrated a 13.5° decrease in penile curvature after a treatment cycle of INFα-2b, while Levine et al. described a 31° curvature reduction in 62% of the men treated with intra-plaque verapamil [26,32]. With INFα-2b and verapamil potentially being a fraction of the cost of CCh and demonstrating a comparable safety profile, further, well-controlled trials directly comparing all three injectable compounds are needed. The scientific progression of CCh in Peyronie’s disease has mirrored of that in Dupuytren’s disease with an almost parallel evolution of clinical series to large-scale phase 3 studies to subsequent FDA approval of Xiaflex in both conditions. Recently, post-approval surveillance of the CCh in DD has shown optimization of technique and dosing while maintaining efficacy and a comparable safety profile to clinical trials [60]. With more than 3 years of follow-up, a 35% recurrence rate across all joints has been reported in the original phase 3 study population [61]. Although the DD differs from PD in disease progression and definition of recurrence, it may be prudent to await long-term post-approval data before declaring CCh for PD a definitive, durable treatment. Further trials must also address adjunct therapies with CCh in PD. Gelbard et al.’s phase 2b Sex Med Rev 2015;3:289–297

Treatment emergent adverse events (TEAE) limited to injection site bruising; no serious adverse events (SAE) 84.2% TEAE for CCh vs. 36.3% TEAE for placebo, 6 SAE for CCh (3 corporal ruptures, 3 penile hematomas)

study suggests that penile modeling offered a synergistic effect to CCh treatment [68]. However, one of the control arms (placebo injection without modeling) included a disproportionate number of patients with active disease 1 year or less so an adequate conclusion could not be made about the precise effect of penile modeling. The subsequent phase 3 trial included penile modeling as a standard procedure in all arms, thus precluding any conclusions about its role. Finally, it is currently not clear which PD patient would best respond to CCh. Although Xiaflex was approved by the FDA for penile curvatures over 30°, Gelbard et al. had shown in 1993 that CCh was more effective in patients with smaller baseline penile curvatures and plaque sizes [67]. These findings may establish ideal niches for CCh in the PD patient and grounds for further stratification in future studies. Additionally, CCh has been used for both acute and chronic PD, but data comparing its effectiveness in both phases is lacking. The results from the 2012 phase 2b trial imply that CCh was less effective over placebo in patients with less than 1 year history of PD, but the subsequent phase 3 excluded patients with acute disease thus precluding any further analysis [65]. Current guidelines have not yet reflected the most up to date data from as the European Association of Urology (EAU), in 2012, offered a grade of recommendation “C” for CCh use in PD [72]. Nonetheless, it is apparent now that CCh provides a safe and effective treatment for PD for patients who are symptomatic from their disease but are not yet committed to surgical intervention. Increased adoption, post-approval data, and provider experience will present valuable insight about the extent of CCh’s niche for this debilitating disease.

The History of Collagenase Clostridium Histolyticum Corresponding Author: Nelson Bennett, MD, FACS, Institute of Urology, Lahey Clinic, 41 Mall Road, Burlington, MA 01805, USA. Tel: (781) 7441590; Fax: (781) 744-2780; E-mail: nbennettjrmd@ gmail.com Conflict of Interest: The authors report no conflicts of interest. Statement of Authorship

Category 1 (a) Conception and Design Kevin K. Yang; Nelson Bennett (b) Acquisition of Data Kevin K. Yang (c) Analysis and Interpretation of Data Kevin K. Yang; Nelson Bennett

Category 2 (a) Drafting the Article Kevin K. Yang (b) Revising It for Intellectual Content Nelson Bennett

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