A New Oral Testosterone Undecanoate Formulation Restores Testosterone to Normal Concentrations in Hypogonadal Men

Ronald S. Swerdloff; Christina Wang; William B. White; Jed Kaminetsky; Marc C. Gittelman; James A. Longstreth; Robert E. Dudley; Theodore M. Danoff

Disclosures

J Clin Endocrinol Metab. 2020;105(8) 

In This Article

Materials and Methods

The Phase 3 clinical trial detailed herein was approved by a central or site-specific Institutional Review Board before study initiation at each clinical site and was conducted in accordance with the Declaration of Helsinki and/or all relevant federal regulations, including Good Clinical Practice guidelines. Written informed consent was obtained from trial participants before any study-related procedures were conducted (CLAR-15012; ClinicalTrials.gov identifier: NCT02722278).

Study Design

This trial was an open-label, repeat-dose, dose-titration study in hypogonadal men to assess the safety and efficacy of oral TU administered for approximately 3–4 months with a minimum of 90–105 days treatment prior to final PK visit. The Screening Phase was followed by a Titration Phase when there were two opportunities for dose-titration based on T Cavg calculated from a 24-hour serial pharmacokinetics (PK) evaluation, a 35-day Maintenance Phase, and an end-of-study PK visit. Eligible patients were randomly assigned in a 3:1 ratio to either oral TU or a 2% topical T solution. The starting dose for oral TU was 237 mg TU (150 mg of unesterified T equivalents), twice-daily (BID) which was administered immediately prior to a breakfast and dinner meal, approximately 12 hours apart. The starting dose for topical T was 60 mg once daily (QD) in the AM. For dose titrations, serial PK samples over 24 hours were obtained around Days 21 and 56 to determine Cavg for dose titrations that occurred about 14 days after the PK visits. Based on the T Cavg, oral TU doses could be up-titrated sequentially to 316 mg (200 mg T equivalents) and then 396 mg (250 mg T equivalents), or down-titrated to 198 mg (125 mg T equivalents) and then 158 mg (100 mg T equivalents) BID. Similarly, topical T doses could remain unchanged or be increased to 90 or 120 mg or decreased to 30 mg. The primary efficacy endpoint was based on the T Cavg at the final PK visit. A cosyntropin [ACTH[1–23]] stimulation test was conducted on a subset of patients (N = 24 on oral TU and N = 8 on topical T).

Patient Population

Eligible patients were men aged 18–65 years, body mass index <38 kg/m2, with hypogonadism as defined by consistently low morning serum total T <300 ng/dL (blood samples collected between 6:00 and 10:00 AM on 2 separate days approximately 7 days apart) and a history of signs and/or symptoms consistent with hypogonadism. Patients were naïve to androgen-replacement therapy or had a complete washout period of previous androgen replacement therapies [2 wks for oral, topical (gel or patch), intranasal or buccal T; 4 wks for short-acting i.m. T (e.g., T-enanthate, T-cypionate); 20 wks for i.m. TU; and 6 months for s.c. T-pellets]. Patients were excluded if they had significant uncontrolled intercurrent disease of any type, hematocrit (Hct) <35% or >48%, history of polycythemia, untreated, severe obstructive sleep apnea, abnormal digital rectal exam, prostate-specific antigen (PSA) >4.0 ng/mL, International Prostate Symptom Score >19 or history of prostate cancer. Prohibited medications included those that could affect T levels, T metabolism, or levels of T metabolites (e.g., antiandrogens, 5-alpha-reductase inhibitors, estrogens, long-acting opioid analgesics or human growth hormone). Patients participating in a cosyntropin stimulation sub-study were not allowed treatment with corticosteroids (oral or inhaled) and were excluded if they had a pituitary abnormality (e. g., hypopituitarism, post-surgery, post-radiotherapy, or history of abnormalities on imaging such as an adenoma).

Primary and Other Secondary Endpoints

The primary efficacy endpoint was mean T concentration (Cavg) after two dose-adjustment cycles with the objective being to demonstrate that at least 75% (with a lower 95% CI of 65%) of patients treated with oral TU (JATENZO®) achieved a T Cavg in the eugonadal range of 252 to 907 ng/dL (9 to 31 nmol/L) for blood collected in NaF-EDTA tubes. A topical T solution (i.e., Axiron®) was used as the active T comparator.

Peak T concentrations (Cmax) were also measured over 24 hours at several points during the study and formed the basis of a secondary efficacy assessment based on FDA criteria. Specifically, T-replacement products must yield a Cmax response that is in close alignment with the following targets: ≥85% of patients with a Cmax < 1500 ng/dl (52 nmol/L); ≤ 5% of patients with Cmax between 1800–2500 ng/dL (62–87 nmol/L); and no patients with a Cmax > 2500 ng/dL) (87 nmol/L). These Cmax categories were ostensibly based on the upper eugonadal limit in serum of 1000 ng/dL (35 nmol/L). However, the eugonadal T range in NaF-EDTA plasma when assayed by LC/MS-MS only extended to 907 ng/dL; therefore, Cmax was also evaluated (post hoc) in light of a second set of Cmax categories based on T assays in this matrix, namely, ≥ 85% of patients with a Cmax ≤ 1361 ng/dL (47 nmol/L); ≤ 5% of patients with Cmax between 1633–2268 ng/dL (57–79 nmol/l); and no patients with a Cmax > 2268 ng/dL (79 nmol/L).

Pharmacokinetic and Efficacy Assessments

The efficacy endpoints of the trial were based on PK of NaF-EDTA plasma T in patients treated with oral TU. Blood samples for total T, dihydrotestosterone (DHT), and estradiol were collected in plain tubes that were allowed to clot for 30 minutes at room temperature (for serum) and NaF-EDTA-containing tubes (BD vacutainer) that were placed on ice for 30 minutes (for NaF-EDTA plasma) prior to centrifugation on study PK days (namely, prior to the 2 dose titration visits and final study visit). Samples from patients in the oral TU group were obtained at -30 minutes and 0, 2, 4, 6, 9, and 12 hours after AM dose and 0 (i.e.,12 hours after AM dose), 2, 4, 6, 9, and 12 hours after PM dose. For patients in the topical T group blood samples were collected at -30 minutes and 0, 2, 4, 6, 9, 12, 14, 16, 18, 21, and 24 hours after AM dose.

Total T and DHT in NaF-EDTA plasma samples were measured using a previously reported validated liquid chromatography tandem-mass spectrometry (LC-MS/MS) assay.[17] Serum total T concentrations for screening and comparative results for the final PK visit were determined using validated measurements by LC-MS/MS as previously described.[12,13] Estradiol was assayed using a validated LC-MS/MS assay[18] in serum using samples collected at the last study visit.

The concentrations of total T and DHT were analyzed to derive the PK parameters of Cmax, time to maximal T concentration (Tmax), area under the plasma concentration-time curve (AUC) and Cavg for both the morning and evening dosing intervals (oral TU only), as well as the entire 24-hour period (oral TU and topical T). The concentrations of estradiol collected at the final visit were similarly analyzed. Free T concentrations were calculated using the Vermeulen formula[19] based on T, sex hormone binding globulin (SHBG), and albumin concentrations.

The Psychosexual Daily Questionnaire (PDQ)[20] was used to assess sexual function and mood changes. Patients were asked to complete the questionnaire every day for 7 consecutive days before Day 1 and the last study day (end of study). Each domain of the PDQ (sexual desire, enjoyment and performance, mood, and sexual activity score) was evaluated.

Safety Assessments

Safety was assessed by recording serious adverse events (SAEs), treatment-emergent adverse events (TEAEs), and routine clinical chemistry and hematology laboratory measurements (particularly hematocrit, PSA and lipid profile). Prostate symptoms were assessed using the International Prostate Symptom Score (I-PSS).[21] Vital signs were measured following published guidelines for accurate measurement of BP[22] in triplicate in the office by an automated oscillometric device. The average of the 3 office measurements was used for data analyses. In addition, 24-hour blood pressure (BP) and heart rate values were acquired every 20 minutes through ambulatory BP monitoring (ABPM) (Spacelabs, Inc, Redmond, WA) performed on the day before the baseline visit and again 1–3 days prior to the final PK Visit.

Data Analyses

Efficacy/Pharmacokinetic Analyses. Efficacy was assessed based on the percentage of treated patients whose T Cavg was in the eugonadal range. The T Cavg was separately summarized for those receiving oral TU and topical T, respectively, without a formal comparison between the treatment groups. The Cavg was calculated by non-compartmental PK methods using actual sample collection times relative to dosing using a modified intent-to-treat population (mITT). In the efficacy analysis, patients who dropped out prior to final study day due to a possible treatment-related cause (e.g., an AE), were counted as treatment failures, while patients who dropped out for other causes (e.g., site closure not related to study conduct) had their T Cavg imputed using last observation carried forward (LOCF) methodology. A 95% Clopper-Pearson binomial confidence interval (CI) for the proportion was reported along with the estimated proportion.

Standard descriptive PK for the oral TU and topical T, as calculated using non-compartmental methods, were presented for total T, free T (calculated), DHT and estradiol. In addition, changes from the pretreatment baseline to end-of-study were presented for the endogenous molecules LH, FSH, and SHBG.

Psychosexual Daily Questionnaire Analyses. The Psychosexual Daily Questionnaire weekly average subscale scores were computed using the daily scores collected during the visit period as previously described,[20] but only if the daily questionnaire had been completed on at least 3 of the 7 consecutive days in the period.

Cosyntropin Stimulation Test. To ensure that the new oral TU formulation did not cause a reduction in cortisol levels, a cosyntropin [ACTH[1–23]] stimulation sub-study was conducted at a select number of centers in this study to evaluate the effect of testosterone on the hypothalamic-pituitary-adrenal axis and determine if chronic oral TU or topical T treatment suppressed cortisol secretion. At the initial study visit (before administration of oral TU or topical T) and at the last study visit study (i.e., the day after collection of final 24-hr PK samples), a baseline blood sample was drawn followed by intravenous injection of 0.25 mg cosyntropin. Blood samples for serum cortisol assay by liquid chromatography tandem mass spectrometry (LC-MS/MS) were subsequently collected 30 and 60 minutes after the injection. For each treatment group, the adrenal response to cosyntropin was evaluated by estimating the proportion of patients whose maximum cortisol value was normal (18 mcg/dL) at the pre-treatment visit and again at the final.

Evaluation of Food Effect. This sub-study was conducted only in oral TU patients. At the start of the study, patients were offered several meal choices during confinement, without disclosing the nutritional content of the various meal options. The patients were asked to select the meal that best reflected what they would typically eat for breakfast and dinner (meals at which oral TU dosing occurred). After the meal selection, the same meal was served at all PK visits during the study. The meal choices had defined amounts of fat (15 g, 30 g, or 45 g). The unconsumed parts of the meal were recorded to estimate actual fat intake. In this way, a more real-world setting for oral TU use was integrated into the design of the study.

The food-effect analysis included all patients on each PK day for which the subject was evaluable for testosterone concentrations for AUCAM, AUCPM, and AUC24. The AM- and PM-specific PK parameters were examined for a dependence on AM or PM meal type, respectively. The comparisons were examined using dose normalized AUCx values. Pearson's correlation coefficients between the fat intake and the dose normalized AUCx values were calculated.

The distribution of final titrated dose by the various meal compositions at earlier study visits were examined to ascertain if meal type played a significant role in the dose to which patients were titrated. This was done using a cross-tabulation and a Pearson's chi-square association test. Dose distributions were examined for the breakfast and dinner meals separately.

PK Simulation/Modeling and Concordance Analyses. Two approaches were taken to determine the optimal time for the assessment of circulating T on the basis of a single blood sample after the morning oral TU dose in order to provide dosing guidance for oral TU in real world clinical settings where T response to TRT is determined from a single blood sample. First, extensive simulation and modeling of PK data was used to identify a discrete blood sampling range (e.g., 4 to 6 hours after oral TU) that would consistently yield a T value in close agreement with the actual T Cavg based on serial PK samples. The population PK of T following oral TU dosing were modeled with a 1-compartment model with first order absorption following a time lag, a central volume of distribution, and first order clearance. Inter-subject and inter-occasion variability were incorporated into the time-lag, absorption, volume and clearance parameters. Testing of each candidate status sample collection time and choice of cut-off thresholds utilized 1000 simulated patients run through the protocol- designated TU dose titration schedule and maintenance treatment period. The aforementioned sources of inter-occasion variability introduced random variability among the multiple T concentration assessments (i.e., each titration visit and end of study) made for each simulated subject. Second, concordance analysis was performed to identify the best post-dose T assay time-point to guide any necessary dose-adjustment in oral TU patients. Concordance is defined herein to describe the extent of agreement between a decision to adjust the oral TU dose (up or down) when a single circulating T concentration in remains in the hypogonadal range [i.e., <252 ng/dl (9 nmol/L) for this study] or supraphysiological range [i.e., >907 ng/dL (31 nmol/L) for this study] and the desired outcome of that decision (i.e., a circulating T level in the eugonadal range) is achieved. Although a predefined concordance result was not established for this study, the goal was to demonstrate as high a total concordance as possible (e.g., at least 85%).

Derivation of a Conversion Factor to Allow use of Serum for T measurements after Oral TU Administration

In this study, plasma samples were collected in NaF-EDTA tubes to minimize ex-vivo conversion of TU to T. However, in clinical practice serum T is routinely collected from blood drawn into in plain tubes. Because the post-collection conversion rate of TU to T is higher in serum (blood collected in plain tubes) compared to plasma (blood collected in NaF-EDTA tubes),[15,16] a Phase 1 study (CLAR-18019, ClinicalTrials.gov identifier: NCT03973840) provided data for calculation of the conversion factor between T levels measured in blood collected in NaF-EDTA tubes and plain tubes from men who received oral TU.

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