Abstract
This study evaluated the effect of axillary administration of a 2% testosterone solution (Axiron®) in hypogonadal (HGN) men who had had a suboptimal response to treatment with a commercially available topical testosterone gel. HGN men averaging 57 years old, with a mean body mass index of 31.9 kg/m2 and median baseline testosterone level (T-level) of 185.2 ng/dL, who had failed to reach normal T-levels with a topical testosterone gel (Androgel 1.62%, Androgel, Testim, or Fortesta) were treated with a 2% testosterone solution until T-levels reached a normal range (from ≥300 to ≤1,050 ng/dL) or for up to 9 weeks. Outcomes included the cumulative percentage of men with a serum T-level in the normal range during treatment with Axiron and improvement in symptoms of low energy level and low sexual drive. During the study, 95% of HGN men (72/78) attained a T-level in the normal range. The median T-level at endpoint was 495.7 ng/dL, a threefold increase over baseline, p < .001, 70% achieving normal T-levels within the first 2 weeks of treatment. In a post hoc analysis, all subjects with baseline body mass indexes >35 kg/m2 (n = 19) achieved T-levels in the normal range. Prior to treatment, over 61% of subjects (48/78) reported impairment in either energy level or sexual drive. After treatment (or testosterone normalization), energy level improved in 75% of subjects and sexual drive improved in 70%. Topical 2% testosterone solution is a safe and effective treatment for HGN men who have had a suboptimal response to previous treatment with topical testosterone gels.
Introduction
Testosterone replacement therapy (TRT) is recommended for symptomatic men with consistently low testosterone levels to relieve the symptoms associated with hypogonadism and to improve quality of life and overall health (Bhasin et al., 2006, 2010). Hypogonadism affects an estimated four to five million men in the United States, and the incidence varies by age group, comorbidities, testosterone levels (which gradually decrease with increasing age [Araujo et al., 2007; Feldman et al., 2002; Harman, Metter, Tobin, Pearson, & Blackman, 2001; Travison, Araujo, Hall, & McKinlay, 2009; Wang et al., 2008; Wu et al., 2008] and in the presence of chronic diseases [Feldman et al., 2002; Harman et al., 2001; McNicholas, Dean, Mulder, Carnegie, & Jones, 2003; Travison et al., 2009; Wu et al., 2008]), and modifiable risk factors such as obesity (Feldman et al., 2002; Harman et al., 2001; Travison et al., 2009) and smoking (Harman et al., 2001). Restoring serum testosterone to normal levels can result in improvements in body composition (McNicholas et al., 2003), bone density (Wang et al., 2004), mood (Wang et al., 2004), libido, and sexual function (Bouloux, 2005; McNicholas et al., 2003).
Two topical testosterone gels, Androgel® and Testim®, were the most commonly prescribed forms of TRT in the United States for adult males with hypogonadism before the introduction of other topical testosterone products in 2010. When these two treatments were applied as directed to the appropriate application sites (upper arms/shoulders or abdomen), testosterone levels failed to return to the normal range (from ≥300 to ≤1,050 ng/dL) in approximately 20% of patients (AbbVie Inc., 2014; Endo Pharmaceuticals Inc., 2014). Since 2010, three new topical testosterone therapies with concentrations ranging from 1.62% to 2% have been approved for use in the United States. When applied as directed to the appropriate application sites (thigh, upper arms, and shoulders, or axilla), these medications also restored total testosterone levels to the normal range in about 80% of men (AbbVie Inc., 2014; Eli Lilly and Company, 2014; Endo Pharmaceuticals Inc., 2014).
In 2008, Grober, Khera, Soni, Espinoza, and Lipshultz reported the outcome of a study evaluating changing topical therapy in a group of patients that failed to respond to previous treatment with the two approved topical TRTs marketed at that time. The authors identified a cohort of men who had undergone a change in testosterone gel treatment and determined that changing to the other topical gel did allow some men to achieve normal testosterone levels with resultant improvement in related symptoms. However, the authors reported that up to 27% of the subjects had testosterone levels that remained below 300 ng/dL (Grober et al., 2008). Since the approval of the newer topical TRTs, no other studies have been identified evaluating the outcome of changing topical therapy in men who failed to achieve therapeutic testosterone levels with other topical therapies.
The anatomical and physiologic differences between the approved application sites for 2% testosterone solution (axilla) and those of other topical formulations (abdomen, shoulder, upper arm, and thigh) led to the hypothesis that treatment with 2% topical solution would increase serum testosterone levels in individuals who had had suboptimal responses to a previous trial of TRT (topical gel only).
This Phase IV, open-label, single-arm study, designed to reflect clinical practice, addressed the clinical question “Would 2% topical solution (Axiron) work for men for whom other topical TRT failed?” This study evaluated the effect of axillary administration of a 2% testosterone topical solution in hypogonadal (HGN) men who had had a suboptimal response (defined as a documented history of subtherapeutic levels [total T-level < 300 ng/dL]) to treatment with a topical testosterone gel.
Patients and Method
Study Design
This was a Phase IV, open-label, single-arm, multicenter, outpatient, interventional study in which the primary endpoint was the cumulative percentage of HGN men with a serum total testosterone concentration within the normal range (from ≥300 to ≤1,050 ng/dL) during treatment with 2% topical solution for up to 9 weeks. The duration of the 9-week open-label treatment period allowed for the assessment of testosterone levels approximately every 2 weeks after treatment initiation and dose adjustment, if needed, consistent with package labeling (Figure 1). Improvement in the symptoms of low sexual drive and low energy level was also assessed using the Patient Global Impression (PGI) questionnaire.
Study design.
Subject Selection
Subjects were male patients ≥18 years of age with diagnoses of hypogonadism, documented total testosterone levels <300 ng/dL when they were treated with the highest dose of a topical testosterone gel tolerated by the patient, and prostate-specific antigen levels <4 ng/mL at Visit 1. Subjects were excluded if they had received previous treatment with 2% testosterone topical solution; had any known or suspected or history of breast or prostate cancer or had suspicious nodules on digital rectal exam at Visit 1; had used long-acting intramuscular testosterone undecanoate in the 6-month period before screening; had history of using implanted testosterone pellets; had International Prostate Symptom Score total scores >19 at Visit 1; had hematocrit ≥50% at Visit 1; had significant history of allergy and/or sensitivity to the drug products or excipients, including testosterone and/or sunscreens; had dermatologic conditions in the underarm area that might interfere with testosterone absorption or be exacerbated by topical TRT; had history of luteinizing hormone–releasing hormone antagonist or agonist treatment in the 6 months before Visit 1; had exhibited any evidence of congestive heart failure within 6 months before Visit 1; exhibited evidence of severe renal impairment at Visit 2; had history of severe liver disease or clinical evidence of hepatic impairment at Visit 1 and/or Visit 2.
Dosing and Administration
Participants were screened 1 to 30 days before the treatment visit. At the screening visit (Visit 1), each subject provided written informed consent and underwent a complete physical examination that included a medical history. Blood samples were taken for hematology and chemistry laboratory panels and prostate-specific antigen measurement, and blood pressure, pulse rate, weight, height, and body mass index (BMI) were recorded. Previous treatment for hypogonadism was recorded, as was concomitant treatment with drug or nondrug therapies. Questionnaires (International Prostate Symptom Score and PGI–Improvement (PGI-I) and PGI–Severity (PGI-S) modified scales for assessment of sexual drive and energy level) were completed. During the screening visits, subjects had their morning testosterone levels measured. Men with testosterone levels <300 ng/dL who met all other study entry criteria began therapy at Visit 2 with 2% topical solution 60 mg once daily (30 mg/1.5 mL applied to each underarm). Dosage adjustment, if needed, occurred at Visits 4 and 6 and was based on serum testosterone levels measured at Visits 3 and 5. Blood samples for serum testosterone were taken at Visit 1 (before study drug administration) and then at Visits 3, 5, and 7 (Study Days 15, 36, and 57). Patients were instructed to apply the topical solution at least 2 hours before each study visit and to administer their required dose at approximately the same time each day. Patients were deemed to have completed the study once serum testosterone levels were in the normal testosterone range of ≥300 to ≤1,050 ng/dL, or the Day-64 visit (Visit 8), whichever occurred first. Patients could successfully complete the study any time after Visit 4 (Figure 1).
Main Outcome Measures
The primary efficacy measure was serum testosterone level measured by liquid chromatography and tandem mass spectrometry assayed at a central laboratory accredited by the Centers for Disease Control (Covance, Indianapolis, IN). Serum testosterone levels were used to determine the percentage of men who reached a testosterone level in the normal range (from ≥300 to ≤1,050 ng/dL). Secondary efficacy measures were scores on the PGI-I scales and PGI-S modified scales for assessment of sexual drive and energy level after beginning the study drug. The PGI-I scales for sexual drive and energy level are patient-rated questionnaires that measure change in the symptoms of low sexual drive and energy level after patients begin the study drug. PGI-I was assessed at Visits 3 through 8 using a 7-point scale. The PGI-S modified scales of sexual drive and energy level are patient-rated questionnaires used to determine the severity of symptoms of low sexual drive and low energy level at baseline. PGI-S was assessed at Study Day 1 (Visit 2).
Safety Assessments
Adverse events and vital signs were assessed at every study visit. Blood for clinical laboratory tests was obtained at Visits 1, 5, and 8 (or in the event of discontinuation earlier than Visit 8).
Statistical Evaluation
Statistical analysis was performed on the modified intent-to-treat population. Clopper–Pearson 95% confidence interval (CI) was calculated for the cumulative percentage of patients with serum testosterone levels in the normal range after initiating therapy. With 78 patients enrolled, the associated margin of error for the estimated percentage of patients achieving normal testosterone levels (based on a 95% CI) ≤0.114. Total testosterone levels at study endpoint were compared with those at baseline using the Wilcoxon signed-rank test. Additionally, levels of improvement as measured by the different PGI-I scales were summarized. Adverse events were summarized using Medical Dictionary for Regulatory Activities preferred terms.
Results
A total of 78 men were enrolled in the study; their mean (standard deviation) age was 57 (10.9) years, mean (standard deviation) BMI was 31.9 (5.73) kg/m2, and mean baseline testosterone level was 180.9 ng/dL. All the subjects had failed to reach normal testosterone levels with any of the commercially available topical testosterone gels, Androgel 1.62% (48%), Androgel (32%), Testim (34%), or Fortesta (8%), and were treated with 2% topical solution until testosterone levels reached a normal range (from ≥300 to ≤1,050 ng/dL) or for up to 9 weeks. Fifty percent of the subjects were between the ages of 50 and 65 years; 94% (73/78) were White, 5% (4/78) were Black, and 1% (1/78) was Asian. Ten percent (8/78) of patients identified themselves as Hispanic or Latino.
During the 2% topical solution treatment period, 95% (72/78) of patients achieved serum testosterone levels from ≥300 to ≤1,050 ng/dL, 95% CI [0.87, 0.99]. Two weeks after beginning treatment (Visit 3) and before any adjustment of testosterone dose, 70% of patients (53/78) achieved testosterone levels within the normal range. A post hoc analysis of subjects with baseline BMIs ≥ 35 kg/m2, about 25% (19/78) of the total cohort, revealed that all (19/19) of those patients achieved serum testosterone levels in the normal range over the course of the study, 95% CI [0.82, 1.00]. Approximately 74% (14/19) of the subjects with high BMIs achieved normal testosterone levels within 2 weeks after beginning treatment and before any adjustment of testosterone dose (Table 1).
Subjects Who Achieved a Serum Testosterone Level in the Normal Range (From ≥300 to ≤1,050 ng/dL) During the 2% Topical Testosterone Solution Treatment Period.
Note. BMI = body mass index; CI = confidence interval; n = number of subjects; T = testosterone; NA = not applicable. CIs are based on the Clopper–Pearson 95% CI calculation.
Subjects with BMI > 35 kg/m2. b95% CI [0.87, 0.99]. c95% CI [0.82, 1.00].
Of the 78 patients who entered in the study, 75 successfully completed it. At study completion, 2 patients had a final dose of 30 mg/day, 53 had a final dose of 60 mg/day (the starting dose), 14 had a final dose of 90 mg/day, and 6 had a final dose of 120 mg/day.
The median (range [minimum-maximum]) serum testosterone level at baseline was 185.2 (7.2-293.9) ng/dL; the median level increased to 495.7 (141.2-1319.9) ng/dL at the study endpoint (Table 2). The observed median change from baseline to endpoint was 319.9 (−70.6-1270.9) ng/dL (p < .001).
Serum Testosterone (ng/dL) Change From Baseline to Endpoint.
p <. 001 based on Wilcoxon signed-rank test.
Each patient rated his illness at baseline using the four categories (normal, not ill at all; mildly ill; moderately ill; and severely ill) of the PGI-S modified scales for energy level and sexual drive (Table 3). At baseline, 36% of patients (28/78) rated themselves moderately ill or severely ill on the energy level scale, and 50% (39/78) rated themselves moderately ill or severely ill on the sexual drive scale.
Symptom Improvement as Measured by Patient-Rated PGI Scales.
Note. PGI = Patient Global Impression, n = number of subjects.
The PGI–Severity modified scale assessed the severity of symptoms of low energy level and sexual drive at baseline. bThe PGI–Improvement scale measured changes in the symptoms of low sexual drive and energy level after patients began the study drug and was assessed at Visits 3 through 8; results from endpoint (defined as last nonmissing value after Visit 2) are reported here.
At each visit starting with Visit 3, patients assessed their improvement from baseline on the dimensions of energy level and sexual drive using the 7-point PGI-I scale (Table 2). The available categories were very much better (1), much better (2), a little better (3), no change (4), a little worse (5), much worse (6), and very much worse (7). At endpoint, 75% (58/78) of patients said their energy levels were better (35% [27/78] a little better and 40% [31/78] either much better or very much better), 22% (17/78) reported no change, and 3% (2/78) reported that their energy levels were a little worse. For sexual drive at endpoint for each patient, 70% (54/78) reported improvement (35% [27/78] a little better and 35% [27/78] either much better or very much better), 29% (22/78) reported no change, and 1% (1/78) were a little worse (Table 3).
There were no deaths or serious adverse events reported in this study. There were 22 subjects who experienced a total of 32 treatment-emergent adverse events (TEAEs), and 7 subjects experienced a total of 9 TEAEs that were judged related to study treatment. With the exception of one severe headache (related to study drug, resolved) and one TEAE of severe fatigue (not related to study drug, resolved), all TEAEs were either mild or moderate in severity. One case of contact dermatitis, judged related to study treatment resulted in discontinuation (1/78 patients, 1.3%). Of the 78 patients in the modified intent-to-treat population, the three patients who discontinued the study prematurely all had a final dose of 60 mg/dL. There were no remarkable changes observed in vital signs or clinical laboratory measurements. Of particular note was that hematocrit and hemoglobin values did not appear to shift from baseline to study completion.
Discussion
The current study was designed to replicate clinical practice with topical TRT by evaluating the effect of axillary administration of 2% testosterone solution in HGN men who had had a suboptimal response after previous treatment with a topical testosterone gel. This study demonstrated that treatment of these men with 2% testosterone solution resulted in their achieving testosterone levels in the normal range and in improvements in their energy levels and sexual drives.
The major findings are that, 95% (72/78) of the men enrolled who had a less than optimal response to therapy with a topical testosterone gel, achieved testosterone levels within the normal range of ≥300 to ≤1,050 ng/dL during the course of the study. The majority of those men (70%, [53/78]) achieved that therapeutic goal within 2 weeks after beginning 2% testosterone solution treatment. The patients’ mean serum testosterone level had increased by 355 ng/dL at study completion, reaching the normal range reported in healthy men according to recommendations in the 2010 Endocrine Society guidelines (Bhasin et al., 2010).
Potential explanations for this high percentage of men attaining normative testosterone levels include axillary characteristics that could enhance absorption: for example, the thickness of the axillary stratum corneum compared with those of application areas for the other therapies or the concentration of hair follicles and sweat glands in the axilla, which may allow for increased permeability by providing a “shunt” pathway across through the stratum corneum (Ramteke, Dhole, & Patil, 2012). Lymphatic flow, blood flow to the axilla, and higher temperature of the axilla than of other skin surfaces may also cause permeability of stratum corneum to be higher than that of the application sites of the other therapies (Ramteke et al., 2012).
The majority of previously conducted studies of topical testosterone administration excluded men with BMIs > 35 kg/m2, presumably because of the concern that central adipose tissue contains higher levels of aromatase, which could convert testosterone to estradiol. Although specific pathogenetic mechanisms involved in this phenomenon are complex and not completely understood, evidence indicates that testosterone deficiency induces increased adiposity, while increased adiposity induces hypogonadism (McNicholas et al., 2003; Tan & Pu, 2002; Wang et al., 2004). Because this study was designed to mirror clinical practice, men with high BMIs were not excluded. At study conclusion, approximately 25% (19/78) of men in the study had baseline BMIs ≥ 35 kg/m2. A post hoc analysis of testosterone levels of those with high BMIs revealed that 100% (19/19) of those men had a normal testosterone level at study completion and that 74% (14/19) achieved that target within 2 weeks of treatment initiation. This suggests that axillary administration of testosterone is not subject to the high aromatase levels observed in central adiposity and is a viable treatment option for men with high BMIs and hypogonadism.
TRT is used to alleviate symptoms in HGN men; the majority of patients receiving 2% topical solution in the current study experienced symptoms at treatment initiation. Most patients reported improvement in their symptoms of reduced sexual desire and energy level over the course of the study. Before starting treatment, over 61% (48/78) of the study participants reported impairment in either energy level or sexual drive. After treatment, energy level improved in 75% of subjects (58/78) and sexual drive improved in 70% (54/78), and fewer than 3% (2/78) reported a worsening of their symptoms.
Adverse events observed were consistent with those previously reported and with the 2% topical solution labeling. The study treatment appeared to be well tolerated, with only 2 of 25 TEAEs assessed as severe.
This was an open-label study designed to mimic real-world clinical experience and therefore did not include a placebo comparator, rechallenge, or crossover from other TRTs. Patients were not required to have been on the maximum dose of the previous TRT before treatment failure but were required to have documented evidence of a testosterone level below 300 ng/dL, but those testosterone levels were not collected for the study. Testosterone levels during treatment were determined via a single blood draw. Each subject completed the study as soon as he achieved a testosterone level in the normal range. Given the variability in testosterone levels over time, it is possible that subjects may not have remained in the normal range over a longer treatment period.
Conclusion
Axillary administration of a 2% topical testosterone solution was an effective and safe TRT in HGN men who have had a suboptimal response when treated with topical testosterone gel formulation. In addition, the axillary administration of a testosterone solution appears to be an effective therapy for obese men with hypogonadism.
Footnotes
Acknowledgements
The authors thank Robert Panek of INC Research (Raleigh, NC) for writing assistance with this article.
Authors’ Note
Patrick Burns and Dustin Ruff are employees and shareholders of Eli Lilly and Company. Allen Seftel is on the Journal of Urology editorial board and Edward Kim is a speaker and author for Eli Lilly and Company.
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: This work was sponsored by Eli Lilly and Company.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.