Intralesional Injection Of Collagenase Clostridium Histolyticum Research Articles

(162) Safety and Feasibility of Platelet-Rich Plasma Injections for Peyronie’s Disease: A Randomized Double-blind Placebo-controlled Cross-over Study

Abstract Introduction Peyronie’s Disease (PD) is prevalent in approximately 7.1% of the general population. Current treatment approaches include medical therapy and surgical intervention, and intervention only occurs once the disease process has entered the chronic, stable phase. The only FDA-approved medical therapy involves use of intralesional collagenase clostridium histolyticum injection and surgical interventions include tunica albuginea plication, plaque excision without grafting, or placement of penile prothesis. Autologous platelet rich plasma (PRP) may prove to be a viable treatment for this patient population due to its ability to facilitate tissue repair and wound healing via various growth factors. Objective We hypothesized that PRP can be safely utilized in patients with PD, with minimal adverse events. Methods We reviewed data for an initial series of men recruited into an ongoing randomized double-blind placebo-controlled cross-over study at the University of Miami from April 2021 to June 2022. Patients received a total of two injections of PRP or placebo directly into the dominant plaque, separated by two weeks. Patients were observed immediately post-injection and assessed with Visual Analogue Pain Scale, and at follow-up for complications and tolerability. Patients are followed three- and six-months post-injection, of which then the patient crosses over into the other treatment / placebo arm. The patient undergoes goniometer measurement with an artificial erection, IIEF-15 and PDQ questionnaire assessment prior to crossover and at the end of the study. ClinicalTrials.gov Identifier: NCT04512287. Results We report data from 24 men who completed two injections for Arm 1 (PRP or placebo) and 15 men who completed two injections (PRP or placebo) after cross-over. No post-procedural minor adverse events were seen in any of the men. None of the participants reported adverse effects such as penile bruising, swelling, edema, allergy, penile fracture, or mild pain at injection site. Six men completed 6-month follow-up and no complications were reported. No worsening curvature was observed in men completing pre/post evaluations. Conclusions PRP appears to be a safe and feasible treatment modality in patients with PD from our limited data accumulated thus far in our ongoing randomized placebo-controlled trial with PRP for PD. We expect to report efficacy data as soon as it becomes available. Our study is the first study in the USA accruing men with PRP for PD in a clinical trial and believe that safety and efficacy data accumulated from our study will be important for patient counseling. Disclosure No

(080) Exploring the Effects of Actinidin as a Novel Collagenase on Human Peyronie’s Disease Cells

Abstract Introduction Peyronie’s Disease (PD) is a connective tissue disorder of the penile tunica albuginea that affects approximately 10% of men. The plaques that hallmark PD contain excessive amounts of collagen and can result in penile curvature, painful erections, and/or erectile dysfunction. Intralesional Collagenase Clostridium histolyticum injection for PD are no longer available in Canada, making treatment options limited. Hayward kiwi fruit are rich in natural actinidin, a soluble enzyme that has the unique ability to hydrolyze various types of collagen and fibrinogen. Actinidin is considered a collagenase alternative; however, there have been no studies evaluating the application of actinidin on in vitro cellular PD models. Objective To determine the effectiveness of actinidin at reducing the collagen component of a 2D human PD cell model. Secondly, to determine the cytotoxicity of kiwifruit extract on human PD cells. Methods Human PD tissues obtained during penile prosthesis implantation were isolated for fibroblast cells and cultured using complete media. The cells were plated on a 96-well plate and treated with one of 4 treatment groups: media, saline, and low and high concentration actinidin treatment (0.5 mg/ml to 37.5 mg/ml). The actinidin treatments were prepared by dissolving freeze-dried kiwi powder in saline and then filtered; the low concentration was further diluted with saline. Cells were incubated at 37°C for 24 hours and then collagen was extracted and measured using a soluble collagen quantification assay kit and a fluorescent microplate reader. To measure cytotoxicity, cells were stained for the nucleus and actin filaments using DAPI and Phalloidin-conjugated FITC, respectively. A twelve-hour timelapse capturing images of FITC and DAPI fluorescein were carried through using a fluorescent confocal microscope. The total fluorescent area of each well was measured using ImageJ. Actin signals were normalized by DAPI signals, and all values were analyzed using Python and Prism10. Results The higher concentration of actinidin treatment significantly reduced cellular collagen of human PD fibroblasts compared to the media treatment (P < 0.05). The high concentration actinidin treatment had a significantly higher normalized actin signal than other treatment groups (P < 0.0001). This ratio allows us to observe the treated cells with compromised plasma membranes. The low concentration of actinidin did not have any significant difference from media and saline treatment groups. A significant increased level of normalized actin indicated that actinidin may have mechanisms to disturb the plasma membrane. Conclusions Our preliminary study suggests that the natural collagenase actinidin can break down PD cells by reducing the extracellular collagen content and compromising the cellular membrane. Further studies are underway to investigate treatment in 3D models and to determine the optimal actinidin concentration that can further reduce the collagen composition in human PD cell models. Actinidin has the potential to be a novel treatment option for patients suffering from PD. Disclosure Yes, this is sponsored by industry/sponsor: KiwiEnzyme.com Ltd Clarification No industry support in study design or execution

The efficacy and safety of intralesional injection of collagenase Clostridium histolyticum for Peyronie's disease: A meta-analysis of published prospective studies.

Background: Peyronie’s disease (PD) is a progressive fibrotic disorder of the penis that is adverse to men’s health. Currently, effective and reliable non-surgical options for PD are limited. Since the Food and Drug Administration (FDA) approved it in 2013, intralesional injection of collagenase Clostridium histolyticum (CCH) became the only licensed treatment for PD. This meta-analysis aims to evaluate the clinical efficacy and safety of CCH in treating PD, predominantly based on post-FDA studies. Methods: The primary outcome was clinical efficacy evaluated by the percentages of improvement in penile curvature (PC) and Peyronie’s disease symptom bother score (PD bother score). The secondary outcome was the safety assessed by treatment-related adverse events (TRAEs). Heterogeneity was assessed by Cochran’s Q and I 2 tests. Sensitivity and subgroup analyses were performed to explore the source of heterogeneity. Funnel plots and Egger’s test were used to evaluate the publication bias. Results: A total of 11 studies with 1,480 intentions to treat (ITT) population were included. The pooled effect of the improvement of PC was 35% (95% CI: 0.33–0.38), and the pooled improvement of the PD bother score was 41% (95% CI: 0.37–0.45). No heterogeneity was found at the pooled improvement of PC (p = 0.845, I 2 = 0.00%). Meanwhile, some heterogeneity existed in the pooled improvement of the PD bother score (p = 0.069, I 2 = 43.4%). The pooled effect of TRAEs was 93% (95% CI 0.88–0.97) with significant heterogeneity (p < 0.000, I 2 = 92.3%). Conclusion: The intralesional injection of CCH could significantly improve the penile deformity of PD patients. Meanwhile, CCH appears to ameliorate the PD bother score to some extent and has acceptable clinical safety. Future studies are required to clarify the long-term outcomes of CCH injection in the treatment of PD.

Safety and Feasibility of Platelet-Rich Plasma Injections for Peyronie's Disease: Update From a Single-center Double-blind Placebo-controlled Randomized Trial

ABSTRACT Introduction Peyronie's Disease (PD) is prevalent in approximately 7.1% of the general population. Current treatment approaches include medical therapy and surgical intervention, and intervention only occurs once the disease process has entered the chronic, stable phase. The only FDA-approved medical therapy involves use of intralesional collagenase clostridium histolyticum injection and surgical interventions include tunica albuginea plication, plaque excision without grafting, or placement of penile prothesis. Additional PD therapies are needed as current treatment modalities have limited efficacy and considerable side effects. Platelet-derived therapies have seen increased use across various specialties in medicine, especially in orthopedics, due to their potential ability in wound healing and tissue regeneration. As calcified scar plaques are frequently identified in PD patients, autologous platelet rich plasma (PRP) may prove to be a viable treatment for this patient population. Objective We reviewed an initial series of patients receiving PRP vs placebo for PD to assess safety and feasibility among men recruited in a double-blind placebo controlled single-center clinical trial. Methods We reviewed data for men recruited into the clinical trial treated with PRP vs placebo at our center from April 2021 to July 2021. Patients were observed immediately post-injection and at follow-up for complications and tolerability. Where applicable, International Index of Erectile Function (IIEF-5) scores were reviewed before and after injections for PD. Results We report data from the men who have completed 2 completed injections (PRP or placebo). No post-procedural minor adverse events were seen in any of the men. None of them reported adverse effects such as penile bruising, swelling, edema, allergy, penile fracture, or mild pain at injection site. No patients experienced complications at follow-up. No worsening curvature was observed in men completing pre/post evaluations. Conclusions PRP appears to be a safe and feasible treatment modality in patients with PD from our limited data accumulated thus far in our ongoing randomized placebo-controlled trial with PRP for PD. Our study is the first study in the USA accruing men with PRP for PD and believe that safety and efficacy data accumulated from our study will be important for patient counseling. Disclosure No

A state-of-art review on collagenase Clostridium Histolyticum and Peyronie’s disease: drug profile, clinical evidence and safety outcomes

ABSTRACTIntroduction: Collagenase clostridium histolyticum (CCH) is the first and only licensed medical treatment for men with Peyronie’s disease (PD). Published literature shows intralesional CCH injection as an effective and safe minimally invasive treatment in a specific subgroup of PD patients.Areas covered: The authors discuss pharmacodynamics and pharmacokinetics as well as clinical outcomes and safety profile from major CCH studies in PD. All relevant CCH studies published in PubMed and EMBASE databases up to June 2019 were included.Expert opinion: Given the variability in treatment schedule and drug access coupled with the potential need for further treatment, strict patient selection and the use of adjunctive strategies are key determinants to maximize clinical efficacy of intralesional CCH. Furthermore, longer-term follow-up data on the clinical outcomes, safety and durability of CCH in larger multi-center studies and post-marketing surveillance data are necessary to provide a comparison to other standard PD treatment options.

Les thérapeutiques non chirurgicales de la maladie de Lapeyronie : état des lieux des connaissances actuelles

BackgroundPeyronie's disease is an inflammatory disorder of the penis, where scar tissue creates a plaque at the level of the albuginea, limits its extension, and leads to a bent and shorter penis during erections. There are no international standards for the evaluation and the treatment of the disease. The aim of this article is to review the current knowledge about the management of Peyronie's disease and to suggest an algorithm to help physicians evaluate and manage this condition. Material and methodsA literature review was conducted through PubMed database following PRISMA guidelines using the Mesh terms: Peyronie, disease, treatment and diagnosis. Results are presented in a descriptive manner. ResultsMultiple treatment strategies have been proposed, but no conclusive randomized clinical trial is done to assess their efficacies. The oral treatment was shown to be more beneficial in the setting of a multi-modal approach to treat the acute phase. The non-steroidal anti-inflammatories and the potassium para-aminobenzoate are superior to the other molecules of oral therapy for pain management. Local treatment with topical verapamil, iontophoresis and intra-lesional injection of verapamil, interferon alfa-2b and collagenase clostridium histolyticum (CCH) revolutionized the management of the disease by the modification of the plaque size and angulation. Alternative treatments using extra-corporeal shock wave or traction devices are promising. Intra-lesional injection of CCH is the only therapy approved by the Food and Drug Administration for this condition after the stabilization of the disease. The channeling of the plaque before CCH injections is making better results than the initial protocol, concerning angulation improvement. ConclusionMultiple therapeutic strategies exist for the management of the Peyronie's disease, but they lack evidence based data. Further randomized clinical trials are needed to evaluate the current practices and to study more efficient treatments.

Review of Intralesional Collagenase Clostridium Histolyticum Injection Therapy and Related Combination Therapies in the Treatment of Peyronie's Disease (an Update).

Collagenase Clostridium histolyticum (CCH) is an injectable agent used to treat Peyronie's disease (PD) by enzymatically degrading the interstitial collagen in plaques. CCH has been administered via multiple treatment protocols, in combination therapies, to patients with varying curvatures and in both the acute and stable phases of this condition. To review the current literature and provide an update on CCH as an injectable therapy for PD, as a singular therapy or in conjunction with combination therapies, and its associated complications. We provide a brief background of PD treatments, evaluate CCH efficacy in penile curvature reduction and subjective improvement in a variety of protocols, and compare combination therapies (penile traction, sildenafil), plaque location, and efficacy in both acute and stable diseases. We performed a systematic review of the existing PubMed literature pertaining to CCH injection therapy in the treatment of PD and compared the effectiveness to different treatment modalities. CCH is a safe and effective injectable agent for all curvature directions in both acute and stable PD. It can be used in conjunction with multiple penile modeling techniques, in combination with sildenafil, and following a shortened administration protocol. Moderate to severe treatment-related adverse events occur at a rate of 9% and are typically managed conservatively. Intralesional injections of CCH are FDA approved as a nonsurgical treatment for men with PD. The IMPRESS trials were instrumental in demonstrating the efficacy and safety of CCH and provided a standard protocol for administration. Additional studies are required to optimize treatment protocols and use in combination therapies. Further investigation of patients with ventral curvatures, hourglass deformities, and those in acute phase is needed. Natale C, McLellan D, Yousif A, etal. Review of Intralesional Collagenase Clostridium Histolyticum Injection Therapy and Related Combination Therapies in the Treatment of Peyronie's Disease (an Update). Sex Med 2021;9:340-349.

156 Intralesional Collagenase Clostridium Histolyticum Therapy for Peyronie's Disease is Safe in Patients Continuing Antiplatelet and Anticoagulant Therapy: A Single Center Experience

The initial clinical trials for intralesional collagenase Clostridium histolyticum (CCh) injection therapy for Peyronie’s disease (PD) excluded men on anticoagulant or antiplatelet medications except those on low-dose aspirin. Men with PD who take blood thinners present a challenging clinical scenario due to a lack of evidence regarding the safety of CCh while on anticoagulant or antiplatelet therapy. Blood thinning medications critically prevent cardiovascular mortality, and therefore their suspension for a non-life-threatening condition is problematic. Physicians may want to offer CCh to these patients without discontinuing these drugs, however they face the dilemma of having insufficient evidence of the drug’s safety while on such medication. This study aimed to evaluate safety outcomes among patients continuing anticoagulant and antiplatelet therapy during ongoing intralesional CCh injection treatment for PD. An institutional review board approved database of 187 patients treated with CCh at an academic men’s health practice from January 2016 through April 2019 was reviewed. Data on patient demographics, comorbidities, CCh injection details, use or non-use of blood thinner medications, and adverse events were extracted from the electronic medical record. Rates of hematoma formation, bruising, swelling, and corporal rupture were determined. Univariate statistical analysis compared clinical data and adverse events between men on or off blood thinner medications.

355 Safety and Efficacy of Intralesional Collagenase Clostridium Histolyticum Injection Therapy in the Acute Phase of Peyronie's Disease: A single-center, Retrospective Cohort Study

Peyronie’s disease (PD) is classically divided into two categories: the acute phase, followed by the chronic (stable) phase. The initial clinical trials for intralesional collagenase Clostridium histolyticum (CCH) excluded men in the acute phase. Though the acute phase has varying definitions in the literature, it is generally understood that it can last 12-18 months and is accompanied by pain or progression of deformity. For men in the chronic phase, intralesional CCH has been shown to be effective in improving penile curvature, with an acceptable risk for adverse events, including swelling, bruising, hematoma, and corporal rupture. Few studies have evaluated the role of intralesional CCH in the acute phase of Peyronie’s disease. To evaluate the safety and efficacy of intralesional CCH during the acute phase of PD compared to the chronic phase. All men receiving CCH injections from January 2016 through June 2019 at a single academic institution were included in an institutional review board (IRB) approved database. Curvature outcomes and adverse events were retrospectively assessed. To account for varying definitions in literature, patients were stratified into the acute and chronic phase using two definitions: 1) acute phase – symptoms of PD ≤ 12 months (Group 1), chronic phase – symptoms of PD > 12 months (Group 2); and 2) acute phase – symptoms of PD ≤ 12 months and reported pain at time of first CCH injection (Group 3), chronic phase – symptoms of PD > 12 months without pain (Group 4). Adverse events were defined as swelling, bruising, hematoma, or corporal rupture. A Wilcoxon rank sum test was used to analyze percent change in penile deformity between groups, and a one-way ANOVA was used to analyze adverse event development between groups.

Management of Peyronie's disease with collagenase Clostridium histolyticum in the acute phase.

Peyronie's disease (PD) can affect men of all ages and is associated with penile pain as well as curvature and erectile dysfunction. Treatment modalities for PD include conservative, less invasive and surgical treatments. Choice of treatment depends on the disease's phase. Injection of collagenase Clostridium histolyticum (CCH) is only the Food and Drug Administration approved treatment for the management of the chronic phase of the disease. Only a few limited studies have evaluated its potential benefits during the acute phase. To evaluate the current evidence on the use of injectable CCH during the acute or active phase of PD. We performed a PubMed database search for articles published between 2015 and 2018 that investigated the use of CCH for the management of the acute phase of PD. Search keywords included "Peyronie's disease", "collagenase Clostridium histolyticum", and "acute phase". Changes in penile curvature after treatment with injectable CCH. Mean curvature decrease ranged between 15.8° and 22.6° corresponding to 27.4-37.4% decrease from baseline after 2.5-4 cycles, corresponding to 5-8 injections, of CCH treatment in patients during the acute phase of PD. Intralesional CCH injection therapy during the acute phase of PD can be both safe and effective and clinically significant improvements in penile curvature may be achieved. Larger multi-institutional studies are, however, still needed to confirm these results and validate this additional indication for CCH.

Multi-institutional Prospective Analysis of Intralesional Injection of Collagenase Clostridium Histolyticum, Tunical Plication, and Partial Plaque Excision and Grafting for the Management of Peyronie's Disease

ObjectiveTo compare in a prospective nonrandomized fashion, the outcomes of collagenase clostridium histolyticum (CCH) and surgical interventions (tunical plication [TP] and partial plaque excision and grafting [PEG]) in patients with Peyronie's disease (PD). Intralesional injection of CCH is the only Food and Drug Administration-approved nonsurgical intervention for PD. Materials and MethodsBetween June 2015 and January 2017, 57 patients with PD and dorsal, dorsolateral, and/or lateral penile curvatures 30°-90° were included in this study. Patients with ventral curvature, hourglass deformity, and previous surgery for PD were excluded. All patients completed questionnaires and underwent penile measurements and penile vascular studies prior to and after completion of treatment, and were followed for at least 6 months. ResultsCCH was administered to 18 patients, TP performed in 14, and PEG in 25. The median follow-up for the whole cohort was 12 months (6-28). Mean changes in curvature after treatment were 23.3° (34.4%) for CCH, 72.0° (92.2%) for TP, and 71.8 ° (94.9%) for PEG, P<.001. Mean changes in International Index of Erectile Function-5 scores were +5.7 for CCH, +4.9 for TP, and +2.2 for PEG, P = .395. Mean penile length changes were −0.2 cm for CCH, −1.0 cm for TP, and +0.9 cm for PEG, P<.001. Three patients in the CCH group had bothersome residual curvature and underwent uneventful TP. ConclusionSurgical options are associated with superior curvature correction. CCH is an effective and safe option for motivated patients who prefer to avoid surgery. PEG is associated with a small stretched penile length gain.

Collagenase Clostridium histolyticum in the management of Peyronie's disease: a review of the evidence.

Peyronie's disease (PD) is a connective tissue disorder resulting in the abnormal accumulation of scar or plaques in the tunica albuginea of the penis. The condition is characterized by two phases: an active, inflammatory phase, and a stable, chronic phase. Collagenase Clostridium histolyticum (CCH) was isolated in the mid-1900s and postulated as a potential pharmacologic strategy for breaking down the abnormal connective tissue plaques of PD. Prior to the introduction of CCH, a wide variety of treatment modalities for PD were used in clinical practice, including oral and topical medications, intralesional injections, electromotive drug administration, extracorporeal shockwave therapy, traction, and invasive surgery, all with variable results. This review aims to examine the known data surrounding the use of intralesional CCH injections in the treatment of PD. CCH is a recently US Food and Drug Administration approved pharmacologic treatment for PD. Clinical trials using intralesional CCH injection therapy for the treatment of PD were reviewed for clinical safety and efficacy of treatment. Studies demonstrated that CCH treatment administered in multiple cycles led to significant benefit in both the psychological and physical aspects of PD. The strongest evidence for CCH's effectiveness was revealed in large, multicenter randomized controlled trials (Investigation for Maximal Peyronie's Reduction Efficacy and Safety Studies I and II) in which intralesional CCH was combined with manual modeling of the penis. Although adverse events from treatment are relatively common, the majority are mild to moderate in degree, including penile pain, swelling, and bruising, which all resolve spontaneously. Overall, evidence indicates that CCH is a valuable, effective, and safe minimally invasive treatment option for men with PD.

Peyronie's disease: What's around the bend?

Introduction:Peyronie's disease (PD) is a fibrotic diathesis of the tunica albuginea that results in penile plaque formation and penile deformity, negatively affecting sexual and psychosocial function of both patients and their partners. In this review, we discuss the PD literature and PD treatment options, with special emphasis on potential future therapies.Methods:The PD literature was reviewed, and articles of interest were identified using keyword search in PubMed. Articles evaluating investigational and novel PD treatments were emphasized.Results:Existing PD treatment modalities are diverse and include oral, topical, intralesional, mechanical, and surgical therapies. Surgical treatment has high success rates and is indicated in men with significant, stable deformity. The United States Food and Drug Administration-approved intralesional collagenase Clostridium histolyticum injection therapy is a minimally invasive option with demonstrated efficacy in PD. Other nonsurgical therapies have been reported, including Botox and stem cell therapy, but these currently have little or equivocal evidence to support their efficacy.Conclusions:Further research is essential to develop novel, safe, and effective minimally invasive PD treatment options. This work is ongoing, with the promise of specific, targeted, and highly effective therapies on the horizon.

Collagenase clostridium histolyticum: a novel nonsurgical option for the treatment of Peyronie’s disease

Commercially available collagenase clostridium histolyticum (CCH) comprises a mixture of clostridial type-I/II collagenase enzymes, which enzymatically destroy collagen deposits. CCH is currently approved in the USA, EU and Canada for the treatment of Dupuytren’s contracture with a palpable cord in the hands of adult patients. Intralesional injection of CCH has demonstrated safety and efficacy in the treatment of Peyronie’s disease (PD) in Phase I–III clinical trials. Improvement of penile curvature deformity and psychological symptoms (degree of patient bother associated with PD) has been achieved among patients with PD. CCH is safe and well tolerated, with adverse events localized to the injection site. This article reviews the potential mechanism of action and summarizes the clinical experience with CCH in patients with PD.