Patient Satisfaction with Oral Testosterone Undecanoate in Men Who Received Prior Testosterone Therapy: An Open-Label, Single-Center Clinical Trial

1. Patient population

In this study, we enrolled men aged 18 to 75 years previously diagnosed with hypogonadism and treated with various forms of TTh. Hypogonadism was identified if the T level was less than 350 ng/dL, accompanied by at least one symptom such as fatigue, low libido, depressed mood, and/or erectile dysfunction, in line with the guidelines from multiple international associations, including the International Society for Sexual Medicine [10]. To ensure the reliability of our study, we insisted that patients completed an adequate washout period after stopping their prior TTh (4 weeks for gels and injection-based therapies and 16 weeks for subcutaneous pellets). We deemed a single T measurement during the washout period sufficient for inclusion in the trial. Exclusion criteria included body mass index >40 kg/m²; SBP >150 mmHg or diastolic blood pressure (DBP) >90 mmHg; abnormal results for prostate exam or prostate-specific antigen (PSA); hemoglobin >16 g/dL; hematocrit (HCT) <35% or >50%; history of stroke or myocardial infarction in the past 5 years; untreated, severe obstructive sleep apnea; history of seizures; or history of breast or prostate cancer.

2. Intervention and data collection

Patients initially completed the 9-item Treatment Satisfaction Questionnaire for Medication (TSQM-9) and the quantitative androgen deficiency in aging males (qADAM) questionnaire to record their experiences with previous TTh. After completion of the washout period, patients were started on oral TU (Jatenzo^®) 237 mg twice daily (BID, morning and evening) with food. Serum total T, estradiol (E2), HCT, and PSA were measured after completion of the washout period and at each subsequent follow-up visit. At the 1-month follow-up visit, the oral TU dosage was titrated based on total serum T in accordance with FDA prescribing guidelines [11]. The 3-month and 6-month follow-up visits included a physical examination, repeat laboratory studies, and completion of the TSQM-9 and qADAM questionnaire with regards to their experience with oral TU. Throughout the study, patients were required to remain off all forms of TTh except for the study medication. Therapeutic T range was defined as ≥350 ng/dL. Patients with polycythemia (HCT >52%) at 3- or 6-month follow-up were referred for therapeutic phlebotomy.

3. Outcomes

The primary outcomes were 3- and 6-month changes in patient satisfaction, as measured by the TSQM-9 (score range 0–100); and in hypogonadal symptom control, as measured by the qADAM questionnaire (score range 10–50) [12, 13]. The secondary outcomes were 3- and 6-month changes in serum total T, E2, HCT, and PSA. As oral TU carries a black box warning for blood pressure increases, we also monitored SBP and DBP at each visit.

4. Statistical analysis

We used descriptive statistics to succinctly summarize demographic and baseline characteristics of the sample. Outcome measures at the 3- and 6-month evaluations were presented as means with a 95% confidence interval (CI). To decipher mean changes over time, we executed longitudinal data analyses using a linear mixed model. We assumed that any missing data are missing at random. When the overall changes were significant, we performed pairwise comparisons using Bonferroni correction. Statistical significance was considered at a p-value of less than 0.05. All our analyses were performed in SAS 9.4.

1. Primary outcomes

Patient satisfaction with oral TU as measured by the TSQM-9 was significantly higher at 3 and 6 months relative to baseline. From longitudinal analyses, overall time effect was significant in all three domains of the TSQM-9 (p<0.05). Effectiveness scores increased from an estimated mean of 63.0 (95% CI: 51.2–74.7) at baseline to 78.2 (95% CI: 71.1–85.3, p=0.025) at 3 months and 78.1 (95% CI: 70.8–85.5, p=0.028) at 6 months. Convenience scores increased from an estimated mean of 62.4 (95% CI: 50.4–74.4) at baseline to 84.5 (95% CI: 77.5–91.5, p=0.002) at 3 months and 86.6 (95% CI: 79.9–93.2, p=0.001) at 6 months. Global Satisfaction scores increased from an estimated mean of 66.7 (95% CI: 55.0–78.3) at baseline to 83.3 (95% CI: 77.1–89.4, p=0.015) at 3 months and 83.0 (95% CI: 74.9–91.1, p=0.026) at 6 months. Finally, there was no significant change in hypogonadal symptom control as measured by the qADAM questionnaire (p=0.060) (Table 2, Fig. 2).

Fig. 2
Mean TSQM-9 scores for (A) Effectiveness, (B) Convenience, (C) Global Satisfaction, and (D) qADAM with 95% confidence intervals. TSQM-9: the 9-item Treatment Satisfaction Questionnaire for Medication, qADAM: quantitative androgen deficiency in aging males. ^*Significant difference from baseline (Bonferroni adjusted p<0.05, NS indicate p≥0.05).

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Table 2
Patient satisfaction measured by TSQM-9 and qADAM

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2. Secondary outcomes

With oral TU treatment, overall time effect supporting improvement of outcome was significant for serum total T (p<0.0001) and E2 (p=0.004). Serum total T increased from an estimated mean of 200.3 (95% CI: 177.5–223.1) at baseline to 485.2 (95% CI: 399.5–571.0, p<0.0001) at 3 months and 649.2 (95% CI: 507.1–791.2, p<0.0001) at 6 months. Therapeutic T levels were attained in 66.7% (18/27) of patients at 3 months and 76.0% (19/25) of patients at 6 months. Serum E2 increased from an estimated mean of 14.4 (95% CI: 10.9–17.9) at baseline to 21.8 (95% CI: 17.3–26.2, p=0.008) at 3 months and 21.2 (95% CI: 15.8–26.6, p=0.040) at 6 months (Fig. 3). During the trial, two patients were started on anastrozole, dosed at 0.25 to 1 mg twice per week. For both HCT and PSA, there were no significant changes over time (overall time effect p=0.340 for HCT and p=0.816 for PSA, Fig. 3). One patient had polycythemia at 3 months and was thus referred for therapeutic phlebotomy. There were no significant changes over time in mean SBP or DBP (Table 3).

Fig. 3
Mean values for (A) serum total testosterone, (B) hematocrit, (C) estradiol, and (D) PSA with 95% confidence intervals. PSA: prostate-specific antigen. ^*Significant difference from baseline (Bonferroni adjusted p<0.05, NS indicate p≥0.05).

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Table 3
Testosterone, HCT, Estradiol, PSA, and blood pressure outcomes

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3. Losses and adverse events

As illustrated in Fig. 1, among 41 enrolled patients, there were 11 patient dropouts before 3-month visit, including 6 lost to follow-up, 4 dissatisfied with treatment, and 1 adverse event. Among 30 patients with baseline evaluation, 27 and 25 completed evaluations at 3 and 6 months, respectively. The one adverse event-related dropout was due to worsening chronic kidney disease requiring transplant, which preceded the trial in onset. Other adverse events include 3 patients with hypertension, 2 with polycythemia, and 1 with new-onset nocturia (Table 4).

Table 4
Adverse events during treatment period

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1. Primary outcomes

Patients treated with oral TU demonstrated significantly increased scores in the Effectiveness, Convenience, and Global Satisfaction domains of the TSQM-9, indicating a positive perception of the treatment's effectiveness in alleviating symptoms and improving overall satisfaction. The observed improvements in these domains suggest that oral TU is effective in addressing the concerns and needs of the study population. However, no significant change was observed in hypogonadal symptom control as measured by the qADAM questionnaire. This finding suggests that while patients reported increased satisfaction with oral TU, it may not have led to significant improvements in specific hypogonadal symptoms relative to previous TTh. These results highlight the multifaceted nature of patient satisfaction, wherein subjective perceptions of effectiveness and convenience play a crucial role but may not correlate with control of symptoms. The increased patient satisfaction observed in the present study is likely, in part, associated with the route of administration [14]. Oral medications are easy to administer and often more convenient for patients to incorporate into their daily routines compared to parenteral routes of administration [15, 16].

2. Secondary outcomes

The trial demonstrated a significant increase in serum total T levels at both the 3- and 6-month time points, indicating the effectiveness of oral TU in raising T levels in patients with hypogonadism. Additionally, there were significant increases in serum E2 levels, consistent with aromatization of circulating T [17]. No significant changes were observed in HCT levels or PSA levels during the treatment period, suggesting that oral TU did not significantly affect red blood cell count or prostate health. Mean HCT increased 0.8% over 6 months, but this change was not statistically significant. It should be noted that patients in the present study may have had residually increased HCT at baseline secondary to previous TTh, thereby “masking” the full impact of oral TU on HCT levels. Nevertheless, these results contribute to a better understanding of the hormonal effects of oral TU treatment and provide reassurance regarding its safety profile. With attention to oral TU’s black box warning, enrolled patients developed new-onset hypertension at a rate comparable to that of a previous trial [9]. However, the overall mean SBP and DBP experienced no significant changes.

3. Losses

The patient dropouts may have potential implications for practical use of oral TU. The high rate of loss to follow-up, amounting to 26.8% (11/41) of patients, is likely specific to this single center study population, as higher follow-up rates were achieved in a 2-year multicenter study [9]. A total of 4 patients (9.8%) dropped out due to dissatisfaction—lack of symptom relief—with oral TU. Of these patients, 1 was previously on short-acting intramuscular injections, 1 on intranasal gel, and 2 on subcutaneous pellets. These findings suggest that alternative forms of TTh may offer advantages in terms of patient adherence and satisfaction [4]. Oral TU is dosed frequently (BID), which may lead to decreased compliance with missed scheduled doses. Yet other patients may be adherent with BID dosing, but have inadequate co-intake with food, resulting in poor absorption, another possible reason for lack of symptom relief with oral TU [7, 18]. It is crucial for healthcare providers to consider these factors when making treatment decisions and discussing the practical use of TTh options with patients, accounting for individual preferences, lifestyle, and the potential impact on treatment outcomes [19]. Regarding adverse events, only one led to dropout, namely chronic kidney disease requiring kidney transplantation, which preceded the trial in onset and is thus not attributable to the study treatment.

4. Strengths and limitations

The study demonstrates several strengths, including high medication adherence, adequate follow-up rates, diverse patient backgrounds, positive primary outcomes, significant improvement in hormone levels, and minimal adverse events. Despite some dropouts before the 3-month visit, a substantial number of patients (65.8%) returned for the 3-month visit, and a majority (61.0%) completed the 6-month visit. These follow-up rates suggest good retention and cooperation from the patients. The results demonstrate that patient satisfaction with oral TU, as measured by the TSQM-9, significantly increased at both the 3-month and 6-month marks compared to baseline. The improvements were observed across all three domains of the TSQM-9 (Effectiveness, Convenience, and Global Satisfaction). These findings highlight the favorable impact of oral TU on patient-reported outcomes. The study revealed a substantial increase in serum total T levels after treatment with oral TU. The improvements were observed at both the 3-month and 6-month assessments, with most patients (66.7% at 3 months and 76.0% at 6 months) achieving therapeutic T levels. These results emphasize the efficacy of oral TU in restoring T levels in hypogonadal men.

This study is not without its limitations. Firstly, this is an open-label trial with no comparison group. Without a control group receiving an alternative treatment or a placebo, it is likely that the observed patient satisfaction scores are influenced by other factors, such as the consumption of TTh at no cost [19]. Future studies may seek to investigate the effect of the cost of TTh on patient satisfaction. In addition, men in this trial may have been inherently dissatisfied with their prior form of TTh therapy, leading to their willingness to enroll and higher satisfaction with a new formulation. The trial suffers from a small sample size at a single center, which can compromise the generalizability and statistical power of the findings. The TSQM-9 is a Likert scale-based questionnaire that is subject to response bias and lacking validation in this specific study population, which may diminish the reliability and validity of the collected data. As men completed blood draw appointments independently at external laboratories, we were unable to control for the timing of T measurements. Men were instructed to complete blood draws at set intervals from their last dose (4–6 hours post dose). But adherence to this timing was not enforced, nor was medication adherence enforced via collection of medication bottle or other methods. Finally, there is a possibility of overestimating patient satisfaction scores due to patient dropouts. At least 4 (9.8%) patients discontinued the trial due to dissatisfaction with the treatment, and their exclusion from the analysis may lead to an inflated perception of patient satisfaction.