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Testosterone Replacement, Low T, HCG, & Beyond
Testosterone Basics & Questions
Official Natesto Thread
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<blockquote data-quote="madman" data-source="post: 213524" data-attributes="member: 13851"><p><strong>NatestoTM, a novel testosterone nasal gel, normalizes androgen levels in hypogonadal men (2015)</strong></p><p><strong></strong></p><p><strong></strong></p><p><strong>Study procedures </strong></p><p></p><p>Randomization occurred on Day 1 via the ClinTrakTM Interactive Voice Response System (Medpace, Inc.; Cincinnati, OH), with <strong><em>subjects randomly assigned in a 3:1 ratio to the titration or the fixed-dose arm, respectively (Fig. 2).</em></strong> Following randomization, all subjects were instructed on the use of the medication dispenser and then received their first dose in the clinic at 2100 h. <strong><em>Subjects assigned to the titration arm were instructed to take 1 actuation (5.5 mg) per nostril of study medication at 0700 h and 2100 h (b.i.d., total dose 22 mg/day), while subjects assigned to the fixed-dose arm took 5.5 mg per nostril at 0700 h, 1300 h, and 2100 h (t.i.d, total dose 33 mg/ day).</em></strong> <strong><em>Subjects in the titration arm having an estimated serum total testosterone average concentration (Cavg) of <300 ng/dL (measured at Day 30) were up-titrated to t.i.d. on Day 45.</em></strong> Subjects continued treatment through the 90-day Treatment Period and, as applicable, through both Safety Extension Periods out to 1 year (Supplemental Data S1).</p><p></p><p></p><p><strong>RESULTS</strong></p><p><strong></strong></p><p><strong><em>Figure 3 shows a plot of 24-h serum total testosterone concentration-time curves at Day 90 by treatment regimen.</em></strong> The mean total testosterone Cavg increased from 200.8 ng/dL at baseline into the normal range in all groups after 90 days of treatment (Table 3).<strong><em> Mean total testosterone Cavg were 375 and 421 ng/dL for b.i.d and t.i.d. regimens, respectively. Among subjects whose Cavg value was in the normal range, the mean values were 415 ng/dL for the b.i.d. and 428 ng/dL for the t.i.d. regimens.</em></strong> Geometric mean total testosterone Cmax values did not exceed the upper limit of normal (ULN) for the b.i.d. and t.i.d. regimens at Day 90.</p><p></p><p></p><p><strong>DISCUSSION</strong></p><p></p><p>In the case of testosterone nasal gel, 90% of hypogonadal subjects in the fixed-dose arm and 68% of subjects in the titration arm (ITT) were in the eugonadal range (300–1050 ng/dL) after 90 days of treatment with testosterone nasal gel. <strong><em>Subject’s mean total testosterone Cavg level after 90 days was 415 ng/dL when taking the b.i.d. dose and 428 ng/dL when receiving the t.i.d. dose.</em></strong> These levels are consistent with the mean Cavg (418 ng/dL) reported for a large, population-based epidemiological survey of healthy adult males aged 30–79 years (Litman et al., 2006). <strong><em>After considering the protocol violations, the PP percentage of subjects achieving normal serum testosterone is 91% in the fixed-dose arm and 71% in the titration arm.</em> <em>Protocol violations included failure to up-titrate subjects upon the direction of the physician or at patient request (<u>b.i.d. being adequate for symptoms</u>) despite estimated Cavg values <300 ng/dL. <u>Notably, the percentage of PP subjects in the normal range on the b.i.d. dose of the titration arm was 75%</u> (95% CI, 66–83%).</em></strong></p><p></p><p><em><strong>Each individual dose of nasal gel provides a reproducible short-acting peak that returns near to baseline by the time of the next dose. </strong></em>While there are up to three peaks per profile, Cmax values were consistently below 1500 mg/d and only 3.3% of subjects had values of 1800–2500 ng/dL. While one subject showed a Cmax >2500 ng/dL (3570 ng/dL); this subject would appear to have violated the protocol by continuing finasteride treatment. No safety concerns were identified for this subject</p><p></p><p><strong><em><u>The peaks-and-troughs PK profile did not appear to have a negative impact on symptomatology</u>.</em></strong> There were statistically significant improvements because of treatment in mean values for the erectile function and mood, and positive trends in improvement for body composition and BMD when compared to pretreatment baseline values.</p><p></p><p></p><p><em><strong>*Some limitations of this study should be noted. The pharmacokinetic analysis is the key primary endpoint to determine the efficacy of testosterone therapies. The study was not blinded and did not include an active comparator or a placebo control limiting the usefulness of a variety of measures including secondary efficacy endpoints (IIEF, PANAS, and BMD) which were analyzed against baseline values and between the b.i.d. and t.i.d. regimens and are only indicators. </strong></em></p><p><em><strong></strong></em></p><p><em><strong>*</strong></em><strong>Subjects with nasal disorders were excluded from the study (exclusion criteria).</strong> <em><strong>Single-dose pharmacokinetics of nasal testosterone administration was determined in subjects with active seasonal rhinitis (unpublished results) and treated with oxymetazoline; the <u>results showed a relative decrease in testosterone absorption</u>. <u>It is recommended that patients consult their doctor when nasal inflammation occurs</u>.</strong></em></p><p></p><p></p><p></p><p></p><p><strong>Table 2 Primary efficacy measure: percentage of testosterone nasal gel-treated subjects with serum total testosterone Cavg in the normal range at Day 90 of the treatment period by treatment and by population.</strong></p><p><strong>[ATTACH=full]18552[/ATTACH]</strong></p><p><strong></strong></p><p><strong></strong></p><p><strong>Figure 3 Plot of 24-h total testosterone concentration-time curves by treatment regimen and time point at Day 90 in the intent-to-treat population. Data are shown for the b.i.d. dosing (n = 141) (A), and the t.i.d. dosing (n = 77) (B).</strong></p><p><strong>[ATTACH=full]18553[/ATTACH]</strong></p><p><strong>[ATTACH=full]18554[/ATTACH]</strong></p><p><strong></strong></p><p><strong></strong></p><p><strong>Table 3 Pharmacokinetics of serum total testosterone by treatment regimen at Day 90 of the treatment period in the intent-to-treat population.</strong></p><p><strong>[ATTACH=full]18555[/ATTACH]</strong></p></blockquote><p></p>
[QUOTE="madman, post: 213524, member: 13851"] [B]NatestoTM, a novel testosterone nasal gel, normalizes androgen levels in hypogonadal men (2015) Study procedures [/B] Randomization occurred on Day 1 via the ClinTrakTM Interactive Voice Response System (Medpace, Inc.; Cincinnati, OH), with [B][I]subjects randomly assigned in a 3:1 ratio to the titration or the fixed-dose arm, respectively (Fig. 2).[/I][/B] Following randomization, all subjects were instructed on the use of the medication dispenser and then received their first dose in the clinic at 2100 h. [B][I]Subjects assigned to the titration arm were instructed to take 1 actuation (5.5 mg) per nostril of study medication at 0700 h and 2100 h (b.i.d., total dose 22 mg/day), while subjects assigned to the fixed-dose arm took 5.5 mg per nostril at 0700 h, 1300 h, and 2100 h (t.i.d, total dose 33 mg/ day).[/I][/B] [B][I]Subjects in the titration arm having an estimated serum total testosterone average concentration (Cavg) of <300 ng/dL (measured at Day 30) were up-titrated to t.i.d. on Day 45.[/I][/B] Subjects continued treatment through the 90-day Treatment Period and, as applicable, through both Safety Extension Periods out to 1 year (Supplemental Data S1). [B]RESULTS [I]Figure 3 shows a plot of 24-h serum total testosterone concentration-time curves at Day 90 by treatment regimen.[/I][/B] The mean total testosterone Cavg increased from 200.8 ng/dL at baseline into the normal range in all groups after 90 days of treatment (Table 3).[B][I] Mean total testosterone Cavg were 375 and 421 ng/dL for b.i.d and t.i.d. regimens, respectively. Among subjects whose Cavg value was in the normal range, the mean values were 415 ng/dL for the b.i.d. and 428 ng/dL for the t.i.d. regimens.[/I][/B] Geometric mean total testosterone Cmax values did not exceed the upper limit of normal (ULN) for the b.i.d. and t.i.d. regimens at Day 90. [B]DISCUSSION[/B] In the case of testosterone nasal gel, 90% of hypogonadal subjects in the fixed-dose arm and 68% of subjects in the titration arm (ITT) were in the eugonadal range (300–1050 ng/dL) after 90 days of treatment with testosterone nasal gel. [B][I]Subject’s mean total testosterone Cavg level after 90 days was 415 ng/dL when taking the b.i.d. dose and 428 ng/dL when receiving the t.i.d. dose.[/I][/B] These levels are consistent with the mean Cavg (418 ng/dL) reported for a large, population-based epidemiological survey of healthy adult males aged 30–79 years (Litman et al., 2006). [B][I]After considering the protocol violations, the PP percentage of subjects achieving normal serum testosterone is 91% in the fixed-dose arm and 71% in the titration arm.[/I] [I]Protocol violations included failure to up-titrate subjects upon the direction of the physician or at patient request ([U]b.i.d. being adequate for symptoms[/U]) despite estimated Cavg values <300 ng/dL. [U]Notably, the percentage of PP subjects in the normal range on the b.i.d. dose of the titration arm was 75%[/U] (95% CI, 66–83%).[/I][/B] [I][B]Each individual dose of nasal gel provides a reproducible short-acting peak that returns near to baseline by the time of the next dose. [/B][/I]While there are up to three peaks per profile, Cmax values were consistently below 1500 mg/d and only 3.3% of subjects had values of 1800–2500 ng/dL. While one subject showed a Cmax >2500 ng/dL (3570 ng/dL); this subject would appear to have violated the protocol by continuing finasteride treatment. No safety concerns were identified for this subject [B][I][U]The peaks-and-troughs PK profile did not appear to have a negative impact on symptomatology[/U].[/I][/B] There were statistically significant improvements because of treatment in mean values for the erectile function and mood, and positive trends in improvement for body composition and BMD when compared to pretreatment baseline values. [I][B]*Some limitations of this study should be noted. The pharmacokinetic analysis is the key primary endpoint to determine the efficacy of testosterone therapies. The study was not blinded and did not include an active comparator or a placebo control limiting the usefulness of a variety of measures including secondary efficacy endpoints (IIEF, PANAS, and BMD) which were analyzed against baseline values and between the b.i.d. and t.i.d. regimens and are only indicators. *[/B][/I][B]Subjects with nasal disorders were excluded from the study (exclusion criteria).[/B] [I][B]Single-dose pharmacokinetics of nasal testosterone administration was determined in subjects with active seasonal rhinitis (unpublished results) and treated with oxymetazoline; the [U]results showed a relative decrease in testosterone absorption[/U]. [U]It is recommended that patients consult their doctor when nasal inflammation occurs[/U].[/B][/I] [B]Table 2 Primary efficacy measure: percentage of testosterone nasal gel-treated subjects with serum total testosterone Cavg in the normal range at Day 90 of the treatment period by treatment and by population. [ATTACH type="full" alt="1639545074766.png"]18552[/ATTACH] Figure 3 Plot of 24-h total testosterone concentration-time curves by treatment regimen and time point at Day 90 in the intent-to-treat population. Data are shown for the b.i.d. dosing (n = 141) (A), and the t.i.d. dosing (n = 77) (B). [ATTACH type="full" alt="Screenshot (9757).png"]18553[/ATTACH] [ATTACH type="full" alt="Screenshot (9758).png"]18554[/ATTACH] Table 3 Pharmacokinetics of serum total testosterone by treatment regimen at Day 90 of the treatment period in the intent-to-treat population. [ATTACH type="full" alt="Screenshot (9759).png"]18555[/ATTACH][/B] [/QUOTE]
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Testosterone Replacement, Low T, HCG, & Beyond
Testosterone Basics & Questions
Official Natesto Thread
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