madman
Super Moderator
A new oral testosterone (TLANDO) treatment regimen without dose titration requirement for male hypogonadism (2022)
Anthony DelConte, Kongnara Papangkorn Kilyoung Kim Benjamin J. Bruno Nachiappan Chidambaram Mohit Khera Irwin Goldstein Tobias S. Kohler Martin Miner Adrian S. Dobs Mahesh V. Patel
Abstract
Background: Male hypogonadism (testosterone level < 300 ng/dl) is a clinical syndrome that results from failure of the testis to produce physiological levels of testosterone. Most marketed testosterone replacement therapy products often require multiple dose adjustment clinic visits to achieve the desired, eugonadal testosterone levels.
Objective: To evaluate the efficacy and safety of a novel oral testosterone undecanoate therapy for the treatment of hypogonadism.
Material and methods: Ninety-five (N = 95) hypogonadal men were enrolled in this open-label, single-arm, multicenter study in the United States (NCT03242590). Subjects received 225 mg of oral testosterone undecanoate (TLANDO) twice a day for 24 days without dose adjustment. Primary efficacy was percentages of subjects who achieved mean 24-h testosterone levels within the eugonadal range and secondary efficacies were evaluated based on the upper limit of lab normal range of testosterone concentration.
Results: Subjects enrolled were on average age of 56 years, with about 17% of subjects older than 65 years. The mean body mass index was 32.8 kg/m2. The baseline mean total testosterone values were below the normal range (202 ± 74 ng/dl). Posttreatment with 450 mg testosterone undecanoate daily dose without dose adjustment, 80% of subjects (95% confidence interval of 72%–88%) achieved a testosterone Cavg in the normal range and restored testosterone levels to mean testosterone Cavg of 476 ± 184 ng/dl at steady state. Testosterone restoration was comparable to other approved testosterone replacement therapy products. TLANDO was well tolerated with no deaths, no drug-related serious adverse events, and no hepatic adverse events.
Discussion and conclusions: TLANDO restored testosterone levels to the normal range in the majority of hypogonadal males. This new oral testosterone replacement therapy can provide an option for no-titration oral testosterone replacement therapy. This therapy has the potential to improve patient compliance in testosterone replacement therapy.
INTRODUCTION
Male hypogonadism (testosterone [T] level < 300 ng/dl) is a clinical syndrome that results from failure of the testis to produce physiological levels of T due to disruption of one or more levels of the hypothalamic-pituitary-testicular axis.1 Primary hypogonadism results from testicular defects, whereas secondary hypogonadism is the failure of the hypothalamus or pituitary gland to produce sufficient gonadotropins. The prevalence of male hypogonadism increases from about 12% for men in their 50s to 50% for men in their 80s.2 Furthermore, an estimated 481,000 new cases of T deficiency can be expected per year, in US men, in 40 to 69 years of age.3
The Endocrine Society guidelines recommend replacement therapy for symptomatic men with androgen deficiency.1 Previously, numerous reports suggested testosterone replacement therapy (TRT) has shown health benefits for bone mineral density, anemia, glycometabolic and cardiometabolic functions, body composition, and improvement in signs and symptoms of mental and sexual functions as well in men with low T levels.4–7 Various TRTs are available in the market including intramuscular injection of T-esters, subcutaneous implants, transdermal patches, oral tablets and capsules, buccal, sublingual, nasal, and topical gel formulations of T.
Oral administration of non-esterified T generally results in low bioavailability as it is extensively metabolized through first-pass metabolism.8 Testosterone undecanoate (TU) is a fatty acid ester of T, with a straight carbon chain (alkylated chain with 11 of carbons) ester at the C17 position of the D-ring. Oral administration of TU provides a sufficient TU level by lymphatic route absorption through the gastrointestinal tract avoiding the first-pass metabolism, then TU is converted to T by non-specific esterases abundant in the body, overcoming the low oral bioavailability of native T.9 Oral administration of TU appears to avoid the serious hepatic adverse effects and fatal complications observed after oral administration of 17-α-methylated T products.10,11 Most marketed TRT products require dose titrations to achieve the eugonadal T levels. One of the top reasons for discontinuation in TRT is lack of perceived efficacy, possibly related to insufficient T levels within the first 3–6 months of therapy, which may be within dose titration duration.12
TLANDO is an oral capsule product having 112.5 mg of TU in a unique lipid formulation containing predominantly predigested triglycerides (mono- or di-glycerides). It was designed to enable absorption of TU via the intestinal lymphatic pathway. In a previous 52-week, multicenter, open-labeled, active-controlled study with TLANDO using a dose titration regimen in hypogonadal men (N = 315, NCT02081300), it was found that there is little impact of titration for TLANDO on achieving eugonadal total T levels (300–1140 ng/dl).13 Titrations in the study were performed two times at weeks 4 and 8 after measuring 24-h pharmacokinetics (PK) at weeks 3 and 7 to identify who should be titrated, then the final PK measuring at week 13 was performed. As a result, the mean dose for post-titration was 213 mg TU twice daily (426 mg daily) compared to 225 mg TU twice daily (450 mg daily) for pre-titration. PK results at week 3 (no titration) showed 86% of subjects within the normal range and the results at week 13 (post two titrations) showed 87% of subjects within the normal range. The distributions of Cavg and Cmax were also shown little impact of titration (p = 0.24 for Cavg and p = 0.31 for Cmax). With the unique formulation and the previous study PK results on the titration regimen of TLANDO, it was hypothesized that the TLANDO treatment regimen (225 mg BID (twice daily)) may not require dose titration to find an appropriate dose for therapeutic T levels. The goal of this study is to validate the TLANDO dosing regimen without titration and evaluate safety and efficacy.
Here we report the clinical outcomes from this phase III study of oral TU (TLANDO) administered as 225 mg twice daily (450 mg daily) without dose titration.
2 MATERIALS AND METHODS
2.1 Study design
This was a multicenter, open-label study evaluating the efficacy of TLANDO with no titration in adult hypogonadal male subjects. The study design and the dose of TLANDO were selected based on results from previous Phase 2 and 3 studies conducted with TLANDO.13–15 Twelve US-based study centers participated in this study from January 2017 to April 2017. This study was conducted in accordance with the tenets of the Declaration of Helsinki and complied with International Council for Harmonization and Good Clinical Practice guidelines. The study protocol and informed consent form were reviewed and approved by the single central Institutional Review Board. Written informed consent was obtained from all patients before any study-related procedures were performed. The study was registered at clinicaltrials.gov under identifier: NCT03242590.
Subjects underwent a screening period to complete the pre-study examinations and to confirm their hypogonadal status (total T below 300 ng/dl on two consecutive blood samples obtained on separate days at approximately the same time (from 6 to 10 AM each day). Subjects on any T therapy were evaluated for screening following an appropriate washout process. Subjects who met study criteria were enrolled and assigned to receive 225 mg TU twice daily. Each dose was given 12 h apart and administered 30 min after morning and evening meals with no restriction of fat content. No dose adjustment was permitted for the duration of therapy. Following the administration of the morning dose on Day 24 with a meal, intensive PK sampling was carried out for up to 24 h post-AM dose. Blood samples were obtained at 0 (pre-dose), 2, 3, 4, 5, 6, 8, and 12 (before evening dose), 14, 15, 16, 17, 18, 20, and 24 h relative to morning dose. A total of 180 ml of whole blood was collected from 15 blood draws per subject. Within 60 min of collection, blood samples were centrifuged for 10 min at ∼1000 x g, and the serum was transferred into cryotubes. Plain red-top serum tubes (without esterase inhibitor) were used to collect blood samples and the blood was allowed to clot and the serum was removed prior to analysis in this study. Based on a previously performed in vivo phlebotomy study,16 there is minimal (∼5%) ex vivo conversion of TU to T during up to 60 min for blood sampling collection process. While this conversion may not be clinically significant, it may have relevance in the evaluation of the T Cmax outliers. Therefore, this was accounted into the Cmax outlier calculation. All serum aliquots were immediately frozen upright at –20◦C and maintained frozen until analysis.
2.3 Primary and secondary outcome measures
The definitions of data sets in this study are:
▪ Safety set (SS) includes all subjects who received at least one dose of the study drug (N = 95).
▪ Full analysis set (FAS) includes all subjects with at least 1 postbaseline efficacy variable response (N = 94).
▪ Pharmacokinetic set (PKS) includes all subjects in FAS who completed the study without major protocol deviations (N = 90).
The primary endpoint was the percentage of TLANDO-treated subjects who achieved a mean T concentration for 24 h (T Cavg) within the normal range of 300–1080 ng/dl upon completion of 24 days of treatment. The prespecified target responder rate was at least 75%. As prespecified, a 95%, two-sided, binomial confidence interval (CI) surrounding the point estimate must have a lower bound of 65% or more to conclude that TLANDO treatment is efficacious. The primary endpoint analysis was performed based on the SS population, which included all subjects who received at least one dose of the study drug, with the last observation carried forward including baseline (BLOCF) approach for missing PK data.
The secondary efficacy endpoints were based on the proportion of subjects with the maximum T concentration for 24 h (T Cmax) within target criteria in subjects treated with TLANDO for 24 days. The secondary efficacy endpoint analysis was performed based on the SS as a primary dataset with a model-based multiple imputation approach to impute missing T Cmax. The target criteria of the secondary efficacy endpoints were:
∙ T Cmax ≤ 1.5 × the upper limit of normal range (ULN): ≥ 85% of the subjects
∙ T Cmax between 1.8 × ULN and 2.5 × ULN: ≤ 5% of the subjects
∙ T Cmax > 2.5 × ULN: no subjects
The serum total T normal range established in this study was from 300 ng/dl to 1080 ng/dl, of which ULN is 1080 ng/dl. Therefore, 1.5 × ULN is 1620 ng/dl, 1.8× ULN is 1944 ng/dl, and 2.5× ULN is 2700 ng/dl.
The PKS was used for the PK analysis. Data from subjects with missing concentration values (missed blood draws, lost samples, samples unable to be quantified) were considered as missing and the subject’s data were used if the primary PK parameters can be estimated using available data points. Otherwise, those subjects were excluded from the PK analysis.
Serum hormone concentrations were measured during the study confinement period. PK samples were analyzed by a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Serum concentrations of T, dihydrotestosterone (DHT), TU, dihydrotestosterone undecanoate (DHTU), and estradiol (E2) were determined by using serum extracted from whole blood samples collected at the predetermined times. Each assay method was validated for linearity, precision, accuracy, recovery, and specificity. Analysis of the samples followed the principles of Good Laboratory Practice. In addition to the method validation, the LC-MS/MS methods were cross-validated with a Clinical Laboratory Improvement Amendments compliant laboratory (ARUP Labs, Salt Lake City, UT, US) to ensure the normal values can be adopted to the bioanalytical lab.
Safety analysis was carried out throughout the study on all subjects receiving TLANDO and was based on the SS population. Safety was assessed on the basis of AE reports, clinical laboratory data, electrocardiogram (ECG) parameters, physical examinations, and vital sign measurements. Key safety endpoints included incidence of AEs, physical examination results, clinical laboratory test results, and changes in HCT, lipids, serum transaminases, PSA, SHBG, FSH, and LH.
3 RESULTS
3.1 Characteristics of the patient population
3.2 Primary and secondary outcome measures
3.3 Pharmacokinetics
Figure 1 shows the plot of mean serum T concentration with standard errors at each time point versus time after the morning dose at Day 24 (end of study, EOS). As shown in Figure 1, mean serum T concentrations were restored to the normal range within 2 h after TLANDO dose administration. Serum T concentrations reached a peak concentration approximately 4–6 h after dosing. After that, T concentrations declined and approached pre-dose levels after approximately 12 h post-administration.
At baseline, the mean T concentration was 202 ng/dl. Mean (±SD) T Cavg obtained from 24-h PK measurement at EOS was 476 (±174) ng/dl in the PKS (N = 90). Mean (±SD) T Cmax measured at EOS in the PKS was 1178 (±484) ng/dl post the AM dose.
At EOS, pre-dose mean serum T, DHT, TU, DHTU, and E2 concentrations were 270 ng/dl, 88 ng/dl, 13 ng/dl, 12 ng/dl, and 28 pg/ml, respectively. The PK parameters (mean ± SD) for serum T, DHT, TU, DHTU, and E2 after TLANDO administration at EOS in the PK set are shown in Table 4.
3.4 Safety
3.5 Hematology, blood chemistry, and urine analysis
HCT values at EOS ranged from 33% to 57% with a mean increase from a baseline of 0.9 ± 3.00%. To minimize the impact of HCT increase, the study had a discontinuation criterion for subjects whose HCT exceeds 54%. None of the subjects met this criterion for discontinuation. One subject who exceeded 54% completed the study and had 57% of HCT at the exit. The subjects (n = 5) with T Cmax between 1.8 x ULN and 2.5 x ULN had HCT values within the normal range (40%–52%) at EOS. There were no clinically meaningful changes in hemoglobin values from baseline to EOS (mean change from baseline: 0.02 ± 0.82 g/dl). Hemoglobin values at EOS ranged from 10.7 to 17.1 g/dl
Mean decreases in lipids were observed (i.e., –1.5 ± 26.2 mg/dl for LDL, –6.9 ± 7.3 mg/dl for HDL, –8.9 ± 85.4 mg/dl for triglycerides, and –10.6 ± 33.1 mg/dl for total cholesterol).
A small increase from baseline for PSA was observed: 0.20 ± 0.44 μg/L (0.80 ± 0.44 μg/L at baseline and 1.00 ± 0.67 μg/L at EOS). There were mean decreases from baseline to EOS for SHBG, LH, and FSH, which were –10.81 ± 7.52 nmol/L, –4.74 ± 4.92 mIU/ml, and –4.91 ± 4.88 mIU/ml, respectively. For FSH and LH, 40% and 41%, respectively, of subjects were maintained within the normal range from baseline to EOS.
Discussion
Without dose adjustment, the results of this study demonstrated that the oral twice daily 225 mg TU dose (450 mg daily) of TLANDO is effective in restoring T levels to the normal range in the hypogonadal males. The primary efficacy endpoint was met with 80% of subjects (95% CI lower bound of 72%), achieving serum T Cavg within the normal range at EOS. One subject with missing data was counted as failed. Note that, 20% of subjects who did not achieve T Cavg within the normal range had a mean T Cavg of 245.9 ± 66.4 ng/dl. However, their T levels were increased by 70% from baseline.
It should be noted that the goal of this study was to validate the TLANDO dosing regimen without titration and evaluate safety and efficacy in comparison with the efficacy and safety obtained from the previous 1-year Phase 3 study of TLANDO with titration.13,14 The previous study with titration reported that 86% of subjects achieved T levels within the normal range before titration and 87% were with T levels within the normal range post two titrations.13 Therefore, the primary efficacy results in this study confirmed that TLANDO without dose adjustment restores hypogonadal men’s T levels to the eugonadal range.
There are pros and cons to using TRT without titration. For example, the absence of dose titrations may eliminate complex titration schemes based on serum T levels, potential titration decision errors, and additional potential clinic/pharmacy visits to seek the right dose for the eugonadal T levels. However, the poor- or super-responders for TRT may not have benefit from a no-titration regimen. Therefore, criteria for discontinuation for those patients were developed. The criteria require monitoring of serum T concentration (8–9 h after the morning dose) at 3–4 weeks after initiating TLANDO and periodically thereafter. Based on the serum T measurements, the continuation/discontinuation of TLANDO is determined as follows:
∙ If serum T concentration is within 300–1080 ng/dl: continue TLANDO
∙ If serum T concentration is <300 ng/dl: discontinue TLANDO
∙ If serum T concentration is >1080 ng/dl: discontinue TLANDO
Therefore, those patients who do not meet the criteria (<300 ng/dl or >1080 ng/dl) can visit one more time to confirm the levels of T. If T levels are confirmed out of the normal range, then the patients will be discontinued from TLANDO therapy and can pursue another TRT option.
*In the current study, a clinical cuff BP measure was performed at baseline and each visit during the study. The oral TU did not increase clinical cuff systolic BP (–0.5 ± 13.53 mmHg) and diastolic BP (–1.0 ± 7.95 mmHg) at 24 days in 94 hypogonadal subjects. There were no clinically meaningful BP changes.
5 CONCLUSIONS
A 225 mg BID oral dose of TLANDO (450 mg total daily dose) restored serum T levels to the normal range without the need for dose adjustment in hypogonadal men. TLANDO offers an alternative option for prescribers and patients with primary or secondary hypogonadism. TLANDO therapy without dose titration may improve patient compliance.
Anthony DelConte, Kongnara Papangkorn Kilyoung Kim Benjamin J. Bruno Nachiappan Chidambaram Mohit Khera Irwin Goldstein Tobias S. Kohler Martin Miner Adrian S. Dobs Mahesh V. Patel
Abstract
Background: Male hypogonadism (testosterone level < 300 ng/dl) is a clinical syndrome that results from failure of the testis to produce physiological levels of testosterone. Most marketed testosterone replacement therapy products often require multiple dose adjustment clinic visits to achieve the desired, eugonadal testosterone levels.
Objective: To evaluate the efficacy and safety of a novel oral testosterone undecanoate therapy for the treatment of hypogonadism.
Material and methods: Ninety-five (N = 95) hypogonadal men were enrolled in this open-label, single-arm, multicenter study in the United States (NCT03242590). Subjects received 225 mg of oral testosterone undecanoate (TLANDO) twice a day for 24 days without dose adjustment. Primary efficacy was percentages of subjects who achieved mean 24-h testosterone levels within the eugonadal range and secondary efficacies were evaluated based on the upper limit of lab normal range of testosterone concentration.
Results: Subjects enrolled were on average age of 56 years, with about 17% of subjects older than 65 years. The mean body mass index was 32.8 kg/m2. The baseline mean total testosterone values were below the normal range (202 ± 74 ng/dl). Posttreatment with 450 mg testosterone undecanoate daily dose without dose adjustment, 80% of subjects (95% confidence interval of 72%–88%) achieved a testosterone Cavg in the normal range and restored testosterone levels to mean testosterone Cavg of 476 ± 184 ng/dl at steady state. Testosterone restoration was comparable to other approved testosterone replacement therapy products. TLANDO was well tolerated with no deaths, no drug-related serious adverse events, and no hepatic adverse events.
Discussion and conclusions: TLANDO restored testosterone levels to the normal range in the majority of hypogonadal males. This new oral testosterone replacement therapy can provide an option for no-titration oral testosterone replacement therapy. This therapy has the potential to improve patient compliance in testosterone replacement therapy.
INTRODUCTION
Male hypogonadism (testosterone [T] level < 300 ng/dl) is a clinical syndrome that results from failure of the testis to produce physiological levels of T due to disruption of one or more levels of the hypothalamic-pituitary-testicular axis.1 Primary hypogonadism results from testicular defects, whereas secondary hypogonadism is the failure of the hypothalamus or pituitary gland to produce sufficient gonadotropins. The prevalence of male hypogonadism increases from about 12% for men in their 50s to 50% for men in their 80s.2 Furthermore, an estimated 481,000 new cases of T deficiency can be expected per year, in US men, in 40 to 69 years of age.3
The Endocrine Society guidelines recommend replacement therapy for symptomatic men with androgen deficiency.1 Previously, numerous reports suggested testosterone replacement therapy (TRT) has shown health benefits for bone mineral density, anemia, glycometabolic and cardiometabolic functions, body composition, and improvement in signs and symptoms of mental and sexual functions as well in men with low T levels.4–7 Various TRTs are available in the market including intramuscular injection of T-esters, subcutaneous implants, transdermal patches, oral tablets and capsules, buccal, sublingual, nasal, and topical gel formulations of T.
Oral administration of non-esterified T generally results in low bioavailability as it is extensively metabolized through first-pass metabolism.8 Testosterone undecanoate (TU) is a fatty acid ester of T, with a straight carbon chain (alkylated chain with 11 of carbons) ester at the C17 position of the D-ring. Oral administration of TU provides a sufficient TU level by lymphatic route absorption through the gastrointestinal tract avoiding the first-pass metabolism, then TU is converted to T by non-specific esterases abundant in the body, overcoming the low oral bioavailability of native T.9 Oral administration of TU appears to avoid the serious hepatic adverse effects and fatal complications observed after oral administration of 17-α-methylated T products.10,11 Most marketed TRT products require dose titrations to achieve the eugonadal T levels. One of the top reasons for discontinuation in TRT is lack of perceived efficacy, possibly related to insufficient T levels within the first 3–6 months of therapy, which may be within dose titration duration.12
TLANDO is an oral capsule product having 112.5 mg of TU in a unique lipid formulation containing predominantly predigested triglycerides (mono- or di-glycerides). It was designed to enable absorption of TU via the intestinal lymphatic pathway. In a previous 52-week, multicenter, open-labeled, active-controlled study with TLANDO using a dose titration regimen in hypogonadal men (N = 315, NCT02081300), it was found that there is little impact of titration for TLANDO on achieving eugonadal total T levels (300–1140 ng/dl).13 Titrations in the study were performed two times at weeks 4 and 8 after measuring 24-h pharmacokinetics (PK) at weeks 3 and 7 to identify who should be titrated, then the final PK measuring at week 13 was performed. As a result, the mean dose for post-titration was 213 mg TU twice daily (426 mg daily) compared to 225 mg TU twice daily (450 mg daily) for pre-titration. PK results at week 3 (no titration) showed 86% of subjects within the normal range and the results at week 13 (post two titrations) showed 87% of subjects within the normal range. The distributions of Cavg and Cmax were also shown little impact of titration (p = 0.24 for Cavg and p = 0.31 for Cmax). With the unique formulation and the previous study PK results on the titration regimen of TLANDO, it was hypothesized that the TLANDO treatment regimen (225 mg BID (twice daily)) may not require dose titration to find an appropriate dose for therapeutic T levels. The goal of this study is to validate the TLANDO dosing regimen without titration and evaluate safety and efficacy.
Here we report the clinical outcomes from this phase III study of oral TU (TLANDO) administered as 225 mg twice daily (450 mg daily) without dose titration.
2 MATERIALS AND METHODS
2.1 Study design
This was a multicenter, open-label study evaluating the efficacy of TLANDO with no titration in adult hypogonadal male subjects. The study design and the dose of TLANDO were selected based on results from previous Phase 2 and 3 studies conducted with TLANDO.13–15 Twelve US-based study centers participated in this study from January 2017 to April 2017. This study was conducted in accordance with the tenets of the Declaration of Helsinki and complied with International Council for Harmonization and Good Clinical Practice guidelines. The study protocol and informed consent form were reviewed and approved by the single central Institutional Review Board. Written informed consent was obtained from all patients before any study-related procedures were performed. The study was registered at clinicaltrials.gov under identifier: NCT03242590.
Subjects underwent a screening period to complete the pre-study examinations and to confirm their hypogonadal status (total T below 300 ng/dl on two consecutive blood samples obtained on separate days at approximately the same time (from 6 to 10 AM each day). Subjects on any T therapy were evaluated for screening following an appropriate washout process. Subjects who met study criteria were enrolled and assigned to receive 225 mg TU twice daily. Each dose was given 12 h apart and administered 30 min after morning and evening meals with no restriction of fat content. No dose adjustment was permitted for the duration of therapy. Following the administration of the morning dose on Day 24 with a meal, intensive PK sampling was carried out for up to 24 h post-AM dose. Blood samples were obtained at 0 (pre-dose), 2, 3, 4, 5, 6, 8, and 12 (before evening dose), 14, 15, 16, 17, 18, 20, and 24 h relative to morning dose. A total of 180 ml of whole blood was collected from 15 blood draws per subject. Within 60 min of collection, blood samples were centrifuged for 10 min at ∼1000 x g, and the serum was transferred into cryotubes. Plain red-top serum tubes (without esterase inhibitor) were used to collect blood samples and the blood was allowed to clot and the serum was removed prior to analysis in this study. Based on a previously performed in vivo phlebotomy study,16 there is minimal (∼5%) ex vivo conversion of TU to T during up to 60 min for blood sampling collection process. While this conversion may not be clinically significant, it may have relevance in the evaluation of the T Cmax outliers. Therefore, this was accounted into the Cmax outlier calculation. All serum aliquots were immediately frozen upright at –20◦C and maintained frozen until analysis.
2.3 Primary and secondary outcome measures
The definitions of data sets in this study are:
▪ Safety set (SS) includes all subjects who received at least one dose of the study drug (N = 95).
▪ Full analysis set (FAS) includes all subjects with at least 1 postbaseline efficacy variable response (N = 94).
▪ Pharmacokinetic set (PKS) includes all subjects in FAS who completed the study without major protocol deviations (N = 90).
The primary endpoint was the percentage of TLANDO-treated subjects who achieved a mean T concentration for 24 h (T Cavg) within the normal range of 300–1080 ng/dl upon completion of 24 days of treatment. The prespecified target responder rate was at least 75%. As prespecified, a 95%, two-sided, binomial confidence interval (CI) surrounding the point estimate must have a lower bound of 65% or more to conclude that TLANDO treatment is efficacious. The primary endpoint analysis was performed based on the SS population, which included all subjects who received at least one dose of the study drug, with the last observation carried forward including baseline (BLOCF) approach for missing PK data.
The secondary efficacy endpoints were based on the proportion of subjects with the maximum T concentration for 24 h (T Cmax) within target criteria in subjects treated with TLANDO for 24 days. The secondary efficacy endpoint analysis was performed based on the SS as a primary dataset with a model-based multiple imputation approach to impute missing T Cmax. The target criteria of the secondary efficacy endpoints were:
∙ T Cmax ≤ 1.5 × the upper limit of normal range (ULN): ≥ 85% of the subjects
∙ T Cmax between 1.8 × ULN and 2.5 × ULN: ≤ 5% of the subjects
∙ T Cmax > 2.5 × ULN: no subjects
The serum total T normal range established in this study was from 300 ng/dl to 1080 ng/dl, of which ULN is 1080 ng/dl. Therefore, 1.5 × ULN is 1620 ng/dl, 1.8× ULN is 1944 ng/dl, and 2.5× ULN is 2700 ng/dl.
The PKS was used for the PK analysis. Data from subjects with missing concentration values (missed blood draws, lost samples, samples unable to be quantified) were considered as missing and the subject’s data were used if the primary PK parameters can be estimated using available data points. Otherwise, those subjects were excluded from the PK analysis.
Serum hormone concentrations were measured during the study confinement period. PK samples were analyzed by a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Serum concentrations of T, dihydrotestosterone (DHT), TU, dihydrotestosterone undecanoate (DHTU), and estradiol (E2) were determined by using serum extracted from whole blood samples collected at the predetermined times. Each assay method was validated for linearity, precision, accuracy, recovery, and specificity. Analysis of the samples followed the principles of Good Laboratory Practice. In addition to the method validation, the LC-MS/MS methods were cross-validated with a Clinical Laboratory Improvement Amendments compliant laboratory (ARUP Labs, Salt Lake City, UT, US) to ensure the normal values can be adopted to the bioanalytical lab.
Safety analysis was carried out throughout the study on all subjects receiving TLANDO and was based on the SS population. Safety was assessed on the basis of AE reports, clinical laboratory data, electrocardiogram (ECG) parameters, physical examinations, and vital sign measurements. Key safety endpoints included incidence of AEs, physical examination results, clinical laboratory test results, and changes in HCT, lipids, serum transaminases, PSA, SHBG, FSH, and LH.
3 RESULTS
3.1 Characteristics of the patient population
3.2 Primary and secondary outcome measures
3.3 Pharmacokinetics
Figure 1 shows the plot of mean serum T concentration with standard errors at each time point versus time after the morning dose at Day 24 (end of study, EOS). As shown in Figure 1, mean serum T concentrations were restored to the normal range within 2 h after TLANDO dose administration. Serum T concentrations reached a peak concentration approximately 4–6 h after dosing. After that, T concentrations declined and approached pre-dose levels after approximately 12 h post-administration.
At baseline, the mean T concentration was 202 ng/dl. Mean (±SD) T Cavg obtained from 24-h PK measurement at EOS was 476 (±174) ng/dl in the PKS (N = 90). Mean (±SD) T Cmax measured at EOS in the PKS was 1178 (±484) ng/dl post the AM dose.
At EOS, pre-dose mean serum T, DHT, TU, DHTU, and E2 concentrations were 270 ng/dl, 88 ng/dl, 13 ng/dl, 12 ng/dl, and 28 pg/ml, respectively. The PK parameters (mean ± SD) for serum T, DHT, TU, DHTU, and E2 after TLANDO administration at EOS in the PK set are shown in Table 4.
3.4 Safety
3.5 Hematology, blood chemistry, and urine analysis
HCT values at EOS ranged from 33% to 57% with a mean increase from a baseline of 0.9 ± 3.00%. To minimize the impact of HCT increase, the study had a discontinuation criterion for subjects whose HCT exceeds 54%. None of the subjects met this criterion for discontinuation. One subject who exceeded 54% completed the study and had 57% of HCT at the exit. The subjects (n = 5) with T Cmax between 1.8 x ULN and 2.5 x ULN had HCT values within the normal range (40%–52%) at EOS. There were no clinically meaningful changes in hemoglobin values from baseline to EOS (mean change from baseline: 0.02 ± 0.82 g/dl). Hemoglobin values at EOS ranged from 10.7 to 17.1 g/dl
Mean decreases in lipids were observed (i.e., –1.5 ± 26.2 mg/dl for LDL, –6.9 ± 7.3 mg/dl for HDL, –8.9 ± 85.4 mg/dl for triglycerides, and –10.6 ± 33.1 mg/dl for total cholesterol).
A small increase from baseline for PSA was observed: 0.20 ± 0.44 μg/L (0.80 ± 0.44 μg/L at baseline and 1.00 ± 0.67 μg/L at EOS). There were mean decreases from baseline to EOS for SHBG, LH, and FSH, which were –10.81 ± 7.52 nmol/L, –4.74 ± 4.92 mIU/ml, and –4.91 ± 4.88 mIU/ml, respectively. For FSH and LH, 40% and 41%, respectively, of subjects were maintained within the normal range from baseline to EOS.
Discussion
Without dose adjustment, the results of this study demonstrated that the oral twice daily 225 mg TU dose (450 mg daily) of TLANDO is effective in restoring T levels to the normal range in the hypogonadal males. The primary efficacy endpoint was met with 80% of subjects (95% CI lower bound of 72%), achieving serum T Cavg within the normal range at EOS. One subject with missing data was counted as failed. Note that, 20% of subjects who did not achieve T Cavg within the normal range had a mean T Cavg of 245.9 ± 66.4 ng/dl. However, their T levels were increased by 70% from baseline.
It should be noted that the goal of this study was to validate the TLANDO dosing regimen without titration and evaluate safety and efficacy in comparison with the efficacy and safety obtained from the previous 1-year Phase 3 study of TLANDO with titration.13,14 The previous study with titration reported that 86% of subjects achieved T levels within the normal range before titration and 87% were with T levels within the normal range post two titrations.13 Therefore, the primary efficacy results in this study confirmed that TLANDO without dose adjustment restores hypogonadal men’s T levels to the eugonadal range.
There are pros and cons to using TRT without titration. For example, the absence of dose titrations may eliminate complex titration schemes based on serum T levels, potential titration decision errors, and additional potential clinic/pharmacy visits to seek the right dose for the eugonadal T levels. However, the poor- or super-responders for TRT may not have benefit from a no-titration regimen. Therefore, criteria for discontinuation for those patients were developed. The criteria require monitoring of serum T concentration (8–9 h after the morning dose) at 3–4 weeks after initiating TLANDO and periodically thereafter. Based on the serum T measurements, the continuation/discontinuation of TLANDO is determined as follows:
∙ If serum T concentration is within 300–1080 ng/dl: continue TLANDO
∙ If serum T concentration is <300 ng/dl: discontinue TLANDO
∙ If serum T concentration is >1080 ng/dl: discontinue TLANDO
Therefore, those patients who do not meet the criteria (<300 ng/dl or >1080 ng/dl) can visit one more time to confirm the levels of T. If T levels are confirmed out of the normal range, then the patients will be discontinued from TLANDO therapy and can pursue another TRT option.
*In the current study, a clinical cuff BP measure was performed at baseline and each visit during the study. The oral TU did not increase clinical cuff systolic BP (–0.5 ± 13.53 mmHg) and diastolic BP (–1.0 ± 7.95 mmHg) at 24 days in 94 hypogonadal subjects. There were no clinically meaningful BP changes.
5 CONCLUSIONS
A 225 mg BID oral dose of TLANDO (450 mg total daily dose) restored serum T levels to the normal range without the need for dose adjustment in hypogonadal men. TLANDO offers an alternative option for prescribers and patients with primary or secondary hypogonadism. TLANDO therapy without dose titration may improve patient compliance.
