Safety and efficacy of topically applied gel H-100 composed of Nicardipine, superoxide dismutase and emu oil for treatment of acute phase Peyronie’s disease (PD) was evaluated. Twenty-two patients (PD <12 months duration) were studied in a prospective, randomized, double-blind, placebo-controlled study. Eleven patients received H-100 and 11 patients received placebo for 3 months. All 22 patients then received H-100 for the final 3 months. Flaccid-stretched penile length, degree of penile curvature, pain level and side effects were assessed monthly. H-100 showed significant improvement in all PD parameters at 6 months: mean stretched penile length increase (22.6%, P=0.0002), mean curvature reduction (40.8%, P=0.0014), and mean pain level reduction (85.7%, P=0.004). Placebo group showed no significant improvement except for mean stretched penile length increase (6.8%, P=0.009). Crossover patients from placebo to H-100 showed significant improvement in all parameters: mean stretched penile length increase (17.5%, P=0.000007), mean curvature reduction (37.1%, P=0.006), and mean pain level reduction (40%, P=0.17). Treatment was well tolerated. A self-limited rash was the only side effect in three patients. Statistically significant improvements in flaccid-stretched penile length, curvature and pain suggest that H-100 is a safe and possibly effective non-invasive, topically applied treatment for acute phase Peyronie’s Disease.
Peyronie’s disease (PD) is a condition in which scar tissue forms within the tunica albuginea of the corpus cavernosum. There is no known cure and a reliable, non-surgical option has not been identified. Oral products have been unsuccessful. Injectable verapamil and interferon have shown inconsistent results.1 Topically applied verapamil gel showed some benefit in early quasi-controlled studies, but subsequent independent prospective studies have been unable to confirm these results.2 The only Food and Drug Administration-approved product for the treatment of PD is collagenase Clostridium histolyticum (Xiaflex, Auxilium Pharmaceuticals, Chesterbrook, PA, USA). It is a proteolytic enzyme delivered via a series of intralesional injections and has significant local side effects, including ecchymosis, swelling and pain.3
This study was designed to evaluate the safety and efficacy of a newly developed, topically applied gel to treat acute phase PD, defined as disease <12 months duration. The acute phase is when most active inflammation and scar tissue formation occurs. If this process can be blocked or mitigated, the development and progression of the Peyronie’s plaque may be limited or reversed. The treatment tested in this study, H-100, combines a natural carrier agent, emu oil, with two traditional pharmaceuticals, nicardipine and superoxide dismutase. Emu oil is rich in fatty acids making it an effective transdermal carrier agent.4 It has also been described as encouraging scar remodeling by an unknown mechanism of action.5 Nicardipine is a dihydropyridine-type calcium channel blocker and may be more efficacious in reducing glycosaminoglycan synthesis and blocking collagen production than non-dihydropyridine-type calcium channel blockers, such as verapamil.6 Superoxide dismutase is a scavenger of free oxygen radicals, which are important in the inflammatory process.7
Material and methods
The Declaration of Helsinki protocols were followed and all patients gave their written, informed consent and the study was registered with clinicaltrials.gov (study ID PDTP1). After Institutional Review Board approval, a prospective, randomized, double-blind study was initiated at a single center. The primary end point of this study was to evaluate the safety of H-100 gel, and therefore the study sample size was intentionally kept small. The secondary end point was to study the efficacy of H-100 gel in the treatment of acute phase Peyronie's disease. Twenty-two patients were sequentially selected for participation in this pilot study. All patients were screened via telephone and during an initial office visit. All patients signed an Institutional Review Board-approved study consent. Study participants were required to have documented PD of <12 months duration, and patients could not have used a treatment for PD in the 6 months prior to enrollment. All patients for inclusion in the study had disease <12 months duration at the time of initial screening. Because of a short delay between screening and randomization/initiation of therapy, three patients did not begin therapy until months 12 and 13. All men had to have an adequate erection with or without phosphodiesterase inhibitors to achieve penile rigidity adequate for penetration. They were allowed into the study if penile curvature, not lack of penile rigidity, prevented penetration. Penile ultrasound was performed at the initial visit to evaluate plaque calcification. Plaque calcification was graded as 0=no calcification, 1=<3 mm calcification, 2=3–15 mm calcification, 3=>15 mm or 2 plaques each with >10 mm calcification.8 Participants were included if their calcium grade was 0 or 1.
Patients were sequentially randomized by a computerized random number generator to either placebo (11 patients) or active treatment (11 patients) for 3 months. After 3 months, all study patients received 3 months of H-100 treatment. The investigator and the patients were blinded as both treatments were packaged in identical metered dispensers and both treatments had an identical physical appearance. An independent observer maintained the study key.
Patients were instructed in proper application of the treatment to the entire penile shaft twice daily. Each metered dose delivered 0.5 ml of the product. Patients were directed to focus application on the area of the palpable plaque and spread remaining gel onto the entire shaft. In all, 0.5 ml of H-100 provided sufficient coverage. Patients maintained a study diary, which confirmed application times and dates, and they returned dispensers monthly, which were weighed to verify appropriate use during the preceding month. Patients could not use any other treatment for PD during the study, including manual modeling of the penis.
The same investigator conducted all visits and examinations. Stretched flaccid penile length was measured in centimeters from base of dorsal shaft to tip of glans. Penile curvature was measured in degrees by marking maximum angle in the photograph using a protractor. Penile pain related to the plaque was graded by the patient on a visual analogue pain scale (0–10).
The initial study visit and all monthly study visits included the measurement of: stretched penile length, penile curvature, and penile pain related to the plaque. Each visit also included assessment of any side effects. At visits 1, 4 and 7 (0, 3 and 6 months), patients had photos taken of the erect penis for measurement of penile curvature. Photos were taken in a standardized manner by inducing an erection with intracavernosal alprostadil (5–10 mcg) to produce an erection similar to or better than that normally attained with sexual stimulation. Photos were taken to demonstrate the maximum degree of curvature.
Twenty-two patients who met eligibility criteria were sequentially enrolled and completed the study by attending each monthly visit. The demographics of the two groups were well matched. The duration of PD for the placebo group was 5.7 months (range 2.7–8.8); for the H-100 group: 8.7 months (range 2.8–13.9); and for all enrollees: 7.2 months (range 2.7–13.9). The placebo and active treatment arm (H-100) had similar average age, penile length and degree of curvature. The only difference noted was in pain level, with the H-100 group having an average pain level of 2.2 (0–10 scale) more than the placebo arm.
The only side effect reported during the study was a rash at the site of application, which occurred in 3/22 patients (13.6%). Two patients had a mild rash and continued to complete the study. One patient in the active treatment arm stopped use of the therapy at 3 months owing to a more bothersome rash that resolved with discontinuation of the therapy.
Data were compared in a pairwise manner. Parameters at initial enrollment (visit 1, day 1), at the end of 3 months (visit 4) and at the end of 6 months (visit 7) were included in the comparison. The Student's t-test was used to obtain P-values and listwise deletion was used when comparing data that included the one patient who did not have treatment data for visit 7. Of the 66 possible study data points for this analysis, 65 (98.5%) were obtained.
Mean stretched flaccid penile length increased while on placebo (6.8%, mean=0.8 cm, range=−0.8–1.9 cm, P=0.009) and continued to increase when switched to H-100 (17.5%, mean=2.2 cm, range=0.9–3.2 cm, P=0.000007). Mean stretched flaccid penile length increased for the H-100 group at 3 months (17.1%, mean=1.8 cm, range=0–4.1 cm, P=0.0007), and there was a further overall increase at 6 months (22.6%, mean=2.4 cm, range=0.7–4.3 cm, P=0.0002) (Figure 1).
There was an average curvature reduction while on placebo (2.5%, mean=1.2 degrees, range=−34–14, P=0.76) and a continued reduction when switched to H-100 (37.1%, mean=17.4 degrees, range=0–59, P=0.006). There was an average curvature reduction for the H-100 group at 3 months (27.1%, mean=13.9 degrees, range=0–35, P=0.001) and an overall reduction at 6 months (40.8%, mean=20.2 degrees, range=3–55, P=0.001) (Figure 2).
Overall pain was measured on a scale from 0 (least) to 10 (most). There was an average reduction of pain while on placebo (54.6%, mean=0.55, range=−3 to 5, P=0.38) and further reduction when switched to H-100 (40%, mean=0.18, range=0–1, P=0.17). There was an average pain reduction for the H-100 group at 3 months (65.7%, mean=2.1, range=−2 to 8, P=0.03) and an overall reduction at 6 months (85.7%, mean=3.0, range=0–8, P=0.004) (Figure 3).
During the blinded portion of the study, there were significant differences in treatment response when comparing placebo and H-100 treatment between visits 1 and 4. There was similar improvement in most parameters when comparing the blinded H-100 treatment arm visits 1 and 4 with the placebo crossover to H-100 treatment arm visits 4–7.
PD has been a frustrating medical condition for physicians and patients alike. The physical and psychosocial implications can be devastating.9 Studies have documented the correlation of PD to relationship issues, self-esteem and overall life satisfaction. The patient's partner can also feel guilt for their real or perceived involvement of the development of the problem.
Many treatment options have been tried in the past. To date, controlled trials have failed to show any reliable efficacy with oral therapies. Intralesional injection of verapamil and interferon require local anesthesia with administration, and treatment results have been inconsistent. Topical verapamil lacks any independent, placebo controlled trials showing efficacy, and tunical tissue sampling has failed to show any infiltration into the tunica albuginea with transdermal application.1, 10 Intralesional injection of collagenase clostridium hystoliticum (Xiaflex) was recently Food and Drug Administration approved for treatment of patients with a palpable plaque and penile curvature of ⩾30 degrees. It requires up to 8 injections and is combined with physician and patient penile modeling. Drug cost and local side effects are potential issues. Surgical repair with either plication or grafting procedures remains the gold standard for men with significant, stable disease.
There are no minimally invasive options that have proven consistently successful, and many patients are reluctant to use invasive procedures, such as injections or surgery. One ideal treatment for PD would be topically applied to the affected area and allow penetration directly into the plaque with little or no systemic effect. This would require both an effective carrier agent for delivery of medication to the plaque as well as an effective medication(s) that would alter plaque metabolism. We theorize that emu oil could act as an ideal carrier agent and that the calcium channel blocker nicardipine combined with superoxide dismutase could act effectively to modify plaque development and remodeling.
H-100 was developed to create a noninvasive, effective treatment option to minimize or possibly mitigate the signs and symptoms associated with acute phase PD. An effective carrier agent must have a high concentration of fatty acid to allow absorption and penetration of the skin. Emu oil is high in these necessary fatty acids. Gas chromatography revealed that emu oil contains approximately 70% unsaturated fatty acids, predominately oleic acid (40%), with lesser amounts of essential fatty acids linoleic (20%) and alpha-linolenic (1–2%).4, 11 These short chain monounsaturated fatty acids have been shown to penetrate the stratum corneum of the skin.4 Thin layer chromatography of emu oil has also found essentially no phospholipid content, another characteristic that enhances skin penetration.4 Emu oil also has an anti-inflammatory effect as demonstrated in animal studies.12 Topically applied emu oil decreases the levels of local proinflammatory cytokines in tissue and promotes wound healing by inhibiting local secondary inflammation.5 Emu oil is derived from the fat of the Emu, a flightless bird native to Australia.
Although verapamil has been utilized in the past for transdermal13 and intralesional use,14 one prospective, randomized single-blind trial indicates that nicardipine may be a better agent.15 Although verapamil and nicardipine are both calcium channel blockers, nicardipine is a dihydropyridine (DHP) type of calcium blocker, whereas verapamil is a non-DHP-type calcium blocker. Both DHP and non-DHP types may inhibit fibroblast proliferation, increase proteolytic activity of collagenase and inhibit the secretion of collagen. The DHP-type calcium channel blockers such as nicardipine may have advantages over their non-DHP counterparts.16 DHP types decrease nitric oxide levels and limit associated tissue damage. DHP types also work extracellular rather than intracellular and therefore are thought to be more potent anti-inflammatory agents than non-DHP types.
Superoxide dismutase blocks the accumulation of free oxygen radicals that form in affected tissue during the acute phase of PD. Superoxide dismutase inactivates the superoxide ion, which is the key substrate in the free oxygen radical cascade.17 Superoxide dismutase blocks production of these destructive free oxygen radicals, which, if left untreated, lead to progressive inflammation, increased collagen synthesis and pain.18 Studies show a higher concentration of reactive oxygen species in Peyronie’s plaque than in normal tunical tissue. Riedl et al.18 showed benefit in pain reduction with topically applied liposomal recombinant human superoxide dismutase in a prospective, randomized, double-blind trial. We utilized superoxide dismutase derived from the yeast Saccharomyces cerevisiae. This form of superoxide dismutase has better solubility and stability than other sources and requires no refrigeration.
In this study, patient selection was limited to those patients with acute phase disease with little or no plaque calcification. Most experts agree that acute phase describes the first 12 months after onset of symptoms.1 It is felt that most active inflammation, scar development and pain occur during this phase, and therefore treatments directed at inhibiting scar formation and encouraging scar remodeling would be most effective in this acute phase.19 H-100's mechanism of action make it well suited to treat this pathophysiology.
Side effects in the study were minimal. Three of the 22 patients noted a rash at the application site. Of these three patients, two had a mild rash that required no treatment and they completed the study. One patient stopped using the medication after 3 months owing to a bothersome rash. The rash resolved with discontinuation of therapy. The patient who stopped the medicine was in the active treatment arm and had both subjective and objective improvement after his 3 months of treatment. No other side effects were reported.
Although the study size was small and was performed at a single center, improvement in all of the studied parameters reached statistical significance. These statistically significant changes were seen in both the H-100 treatment arm and in the crossover arm from placebo to H-100. The degree of improvement was similar in the H-100 treatment arm from 0 to 3 months and in the crossover arm from placebo to H-100 at 4–7 months. This provided an internal validation of the statistical results.
Enhanced stretched flaccid penile length was noted in both groups exposed to H-100. The mechanism of action to explain this improvement is unknown at this time.
No penile modeling or traction was utilized in this study. These modalities may enhance correction of deformities associated with PD. The addition of these modalities combined with the use of H-100 may result in even further improvement and will be considered in further trials.
The study size was intentionally small given the primary end point was to assess safety. The small study size limits the statistical power of efficacy data. Larger trials are now warranted to confirm these initial encouraging results. Tissue sampling may be considered in follow-up studies to confirm levels of H-100 in the tunica albuginea.
This small but randomized placebo controlled trial showed safety and efficacy with the use of a topically applied gel combining emu oil, nicardipine and superoxide dismutase (H-100) for treatment of acute phase PD. The medication was well tolerated and showed significant improvement in stretched penile length, curvature and pain. A larger study is warranted to confirm these initial encouraging results.
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We thank Harold Hoium, MBA, for contributions to study design, IRB compliance, ClinicalTrials.gov registration, coordination of drug development, database development, statistical analysis and statistics write-up. Statistical analysis was completed using standard features in Microsoft Excel.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on International Journal of Impotence Research website
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Twidwell, J., Levine, L. Topical treatment for acute phase Peyronie’s disease utilizing a new gel, H-100: a randomized, prospective, placebo-controlled pilot study. Int J Impot Res 28, 41–45 (2016). https://doi.org/10.1038/ijir.2015.22
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