Single therapeutic and supratherapeutic doses of corifollitropin alfa, a sustained follicle stimulant, do not prolong the QTcF-interval in healthy postmenopausal volunteers.

OBJECTIVE: Corifollitropin alfa (Elonva®) is the first hybrid follicle-stimulating hormone molecule with demonstrated sustained follicle-stimulating activity after a single subcutaneous injection. This trial evaluated if corifollitropin alfa is associated with QT/QTc prolongation and/ or proarrhythmic potential as compared to placebo in healthy post-menopausal women. MATERIALS: Participants were healthy, postmenopausal women. Study treatments were corifollitropin alfa 150 µg, corifollitropin alfa 240 µg, and moxifloxacin 400 mg with placebo. METHODS: This randomized, double blind, double-dummy, 4-period crossover trial compared single doses of corifollitropin alfa 150 µg (therapeutic dose), corifollitropin alfa 240 µg (supratherapeutic dose), and moxifloxacin 400 mg (positive control) with placebo. Corifollitropin alfa was administered on day 1 and moxifloxacin on day 2. RESULTS: The largest time-matched mean QTcF difference versus placebo for the therapeutic dose of corifollitropin alfa was 1.4 ms (upper limit of 1-sided 95% confidence interval (UL 95% CI) = 3.4 ms), and for the supratherapeutic dose was 1.2 ms (UL 95% CI = 3.6 ms). CONCLUSIONS: For both the therapeutic and the supratherapeutic dose of corifollitropin alfa and at all time points, the UL 95% CI for the time matched QTcF differences compared with placebo was below 10 ms, the threshold of relevance defined by the ICH E14 guideline. Single therapeutic and supratherapeutic doses of corifollitropin alfa are not associated with clinically relevant QT/QTc-interval prolongation in healthy post-menopausal women.

Intercycle variability of the ovarian response in patients undergoing repeated stimulation with corifollitropin alfa in a gonadotropin-releasing hormone antagonist protocol.

OBJECTIVE: To determine whether individual subject variation in ovarian response between repeated cycles with the same ovarian stimulation protocol can be predicted. DESIGN: Retrospective data analysis. SETTING: Multicenter, open-label, uncontrolled clinical trial. PATIENT(S): Women aged 18-39 from a phase 3, open-label, uncontrolled trial with complete data across all cycles (n = 176). INTERVENTION(S): Up to three cycles of a single injection of 150 µg corifollitropin alfa for 7 days, then daily recombinant FSH/hMG until three follicles reached ≥17 mm. Gonadotropin-releasing hormone antagonist from stimulation day 5 until day of hCG administration. MAIN OUTCOME MEASURE(S): Numbers of follicles ≥11 mm on day of hCG in cycles 1-3, transition in ovarian response type between cycles from low (0-<6), normal (6-<18), and high (≥18), and serum FSH concentrations and antral follicle count (AFC) at each cycle start. RESULT(S): The mean (SD) numbers of follicles ≥11 mm on day of hCG were 13.4 (6.2), 13.3 (5.4), and 13.8 (6.4) in cycles 1, 2 and 3, respectively. Between cycles 1 and 2, 11.9% switched from normal to low or high response, and 12.5% switched from low or high to normal response; 75.6% remained in the same category. Between cycles 2 and 3, 15.9% switched from normal to low or high response, and 10.2% switched from low or high to normal response; 73.9% remained in the same category. These shifts are symmetrical in nature, in that the percentage of subjects who shift from normal to low or high response is comparable to the percentage of subjects who shift from low or high to normal response. Baseline FSH and AFC did not significantly predict transition in ovarian response. CONCLUSION(S): The variability in ovarian responses between repeated cycles using the same protocol was not explained by baseline FSH and AFC. CLINICAL TRIAL REGISTRATION NUMBER: NCT00696878 Protocol P05714.

The effect of therapeutic and supratherapeutic oral doses of nomegestrol acetate (NOMAC)/17ß-estradiol (E2) on QTcF intervals in healthy women: results from a randomized, double-blind, placebo- and positive-controlled trial.

BACKGROUND AND OBJECTIVE: Nomegestrol acetate (NOMAC)/17ß-estradiol (E2) is a monophasic oral contraceptive that contains a progesterone-derived progestogen (NOMAC), and E2, a bio-identical estrogen. The primary objective of this thorough QT/QTc study was to investigate whether once-daily administration of therapeutic (2.5/1.5 mg) and supratherapeutic (12.5/7.5 mg) doses of NOMAC/E2 were associated with prolongation of the mean Fridericia-corrected QT (QTcF) interval in electrocardiograms at steady-state concentrations of NOMAC/E2 versus placebo. The co-primary objective was to establish assay sensitivity after a single dose of moxifloxacin (positive control). METHODS: This was a randomized, double-blind, parallel-group trial comparing 2.5/1.5 mg of NOMAC/E2 (therapeutic dose), 12.5/7.5 mg of NOMAC/E2 (supratherapeutic dose), placebo, and moxifloxacin 400 mg. Double-blind study medication was administered from day -1 to 14. Healthy women aged 18-50 years were randomized. RESULTS: The largest time-matched mean QTcF difference compared with placebo for the therapeutic dose of NOMAC/E2 was 1.6 ms, with an upper limit (UL) of a one-sided 95% confidence interval (CI) of 5.2 ms, and 3.1 ms with an UL 95% CI of 7.0 ms for the supratherapeutic dose. The UL for the time-matched QTcF differences compared with placebo were below the 10 ms threshold defined in the ICH E14 guideline for all time points, both for the therapeutic and the supratherapeutic dose. For moxifloxacin, assay sensitivity was demonstrated. CONCLUSIONS: This thorough QT/QTc study showed that therapeutic and supratherapeutic doses of NOMAC/E2 were not associated with clinically relevant QTc interval prolongation in healthy women after a 2-week period of dosing.

Half-life prolongation of therapeutic proteins by conjugation to ATIII-binding pentasaccharides: a first-in-human study of CarboCarrier® insulin.

AIM: Conjugation to antithrombin III ATIII-binding pentasaccharides has been proposed as a novel method to extend the half-life of therapeutic proteins. We aim to validate this technological concept in man by performing a first-in-human study using CarboCarrier® insulin (SCH 900948) as an example. A rising single dose phase 1 study was performed assessing safety, tolerability, pharmacokinetics and relative bioactivity of CarboCarrier® insulin. Safety, tolerability and pharmacokinetics (PK) of single doses of CarboCarrier® insulin in healthy volunteers were explored, and the dose-response relationship and relative bioactivity of CarboCarrier® insulin in subjects with type 2 diabetes were investigated. METHODS: After an overnight fast, subjects were randomized to a treatment sequence. PK and pharmacodynamic (glucose, insulin and C-peptide) samples were obtained for up to 72 h post-dose. Effects of CarboCarrier® insulin were compared with those of NPH-insulin. RESULTS: CarboCarrier® insulin was safe and well-tolerated and no consistent pattern of adverse events occurred. CarboCarrier® insulin exposure (Cmax and AUC) increased proportionally with dose. The mean terminal elimination half-life ranged between 3.11 and 5.28 h. All CarboCarrier® insulin dose groups showed decreases in the mean change from baseline of plasma glucose concentrations compared with the placebo group. CONCLUSIONS: CarboCarrier® insulin is pharmacologically active showing features of insulin action in man. The elimination half-life of the molecule was clearly extended compared with endogenous insulin, indicating that conjugation to ATIII-binding pentasaccharides is a viable approach to extend the half-life of therapeutic proteins in humans. This is an important step towards validation of the CarboCarrier® technology by making use of CarboCarrier® insulin as an example.

Sugammadex is not associated with QT/QTc prolongation: methodology aspects of an intravenous moxifloxacin-controlled thorough QT study.

OBJECTIVE: Sugammadex is a novel γ-cyclodextrin and the first selective relaxant binding agent to be developed for the reversal of rocuronium and vecuroniuminduced neuromuscular blockade. According to International Conference on Harmonization (ICH) E14, a thorough QT/QTc study is required for most new compounds to assess the potential to cause QT prolongation, because a delay in cardiac repolarization may create an electrophysiological environment that favors the development of cardiac arrhythmias, most notably Torsade de Pointes. Therefore a thorough QTc study was conducted to evaluate the effect of sugammadex on the individually corrected QTc interval (QTcI). METHODS: Following two baseline electrocardiogram (ECG) days (Day -2 and Day -1), in this randomized, double-blind, cross-over study, healthy volunteers received a sequence of four treatments comprising single intravenous doses of placebo, moxifloxacin 400 mg (positive control, open label), sugammadex 4 mg/kg and sugammadex 32 mg/kg. ECGs were recorded in triplicate at 12 time points up to ~ 24 h after study drug administration, and the QT intervals were evaluated manually under blinded conditions. The pre-specified primary endpoint was the largest time-matched mean QTcI difference compared with placebo across all time points. RESULTS: A total of 62 subjects received treatment, of which 58 completed the study. After intravenous moxifloxacin, QTcI prolongations compared with placebo exceeded the ICH E14 safety margin of 10 msec and the one-sided 95% lower confidence limit exceeded 5 msec, confirming assay sensitivity. For both sugammadex doses, the one-sided 95% upper confidence limits for the largest time-matched mean QTcI differences compared with placebo were ≤ 5.3 msec at each timepoint and thus considerably below the 10 msec safety margin. Unexpectedly, the two full-day baseline ECGs indicated systematically prolonged QTc values when comparing the first baseline with the second baseline day, reaching a maximum mean difference of 3.8 msec. CONCLUSION: Single therapeutic (4 mg/kg) and supra-therapeutic (32 mg/kg) intravenous doses of sugammadex are not associated with clinically important QTc prolongation.

Effects of sugammadex doses up to 32 mg/kg alone or in combination with rocuronium or vecuronium on QTc prolongation: a thorough QTc study.

BACKGROUND: Sugammadex reverses the effects of rocuronium- and vecuronium-induced neuromuscular blockade, which are achieved by encapsulation. It is known that some non-antiarrhythmic drugs have the potential to delay cardiac repolarization and it is therefore recommended that the effects of all new drugs on the QT interval are assessed. OBJECTIVE: This thorough corrected QT (QTc) study evaluated the effect of sugammadex alone and in combination with rocuronium or vecuronium on the individually corrected QTc interval (QTcI). METHODS: This was a randomized, double-blind, six-period crossover, placebo-controlled study, with an open-label active-controlled component (moxifloxacin). The study was designed according to International Conference on Harmonization (ICH) E14 guidelines. The study was conducted in a clinical research unit from November 2006 to April 2007. Healthy male and female subjects (n = 84) were enrolled in the study. Subjects were randomized to six treatment sequences comprising single intravenous doses of placebo, moxifloxacin 400 mg (positive control), sugammadex 4 mg/kg, sugammadex 32 mg/kg, sugammadex 32 mg/kg with rocuronium 1.2 mg/kg and sugammadex 32 mg/kg with vecuronium 0.1 mg/kg. Triplicate ECGs were recorded at 13 timepoints up to 23.5 hours after study drug administration and QT intervals were evaluated manually under blinded conditions. The primary outcome was the largest time-matched mean difference in QTcI change from baseline compared with placebo across the 13 timepoints up to 23.5 hours after study drug administration. Blood samples were also collected for pharmacokinetic analysis. RESULTS: Of the 84 randomized healthy subjects, 80 completed the study. After moxifloxacin, QTcI prolongations were observed compared with placebo; the lower limit of the one-sided 95% confidence interval (CI) for the largest time-matched mean difference in QTcI change compared with placebo was 20.8 msec (90% CI 18.5, 23.1), thus exceeding the ICH E14 safety margin of 5 msec and demonstrating assay sensitivity. In contrast, the largest time-matched mean difference in QTcI (msec) from placebo with sugammadex treatments ranged from 2.1 (sugammadex 4 mg/kg alone) to 4.3 (sugammadex 32 mg/kg with vecuronium 0.1 mg/kg). For the largest time-matched mean difference in QTcI change compared with placebo the corresponding upper limit of the one-sided 95% CI was well below the 10 msec margin for both sugammadex doses. Telemetry results revealed that one subject experienced a non-sustained ventricular tachycardia 4 hours after sugammadex 32 mg/kg, which was self-terminating after 20 beats and considered unlikely to be drug related. Pharmacokinetic-QTc analysis showed a statistically significant (p < 0.01) relationship between sugammadex plasma concentration and QTcI; however, at mean maximum plasma concentrations of the therapeutic and supra-therapeutic sugammadex dose, the predicted one-sided upper 95% CI for the largest time-matched QTcI difference from placebo was below 10 msec. Rocuronium or vecuronium co-administration did not affect the relationship between sugammadex concentrations and QTc. CONCLUSIONS: Based on the results of this study of healthy subjects, it can be concluded that sugammadex alone or in combination with rocuronium or vecuronium is not associated with QTc prolongation.

Reversal of rocuronium-induced neuromuscular blockade with sugammadex in pediatric and adult surgical patients.

BACKGROUND: Sugammadex reverses neuromuscular blockade by chemical encapsulation of rocuronium. This phase IIIA study explored efficacy and safety of sugammadex in infants (28 days to 23 months), children (2-11 yr), adolescents (12-17 yr), and adults (18-65 yr). METHODS: Anesthetized patients (American Society of Anesthesiologists class 1-2) received 0.6 mg/kg rocuronium and were randomized to receive sugammadex (0.5, 1.0, 2.0, or 4.0 mg/kg) or placebo at reappearance of T2. Neuromuscular monitoring was performed using acceleromyography. Primary endpoint was time from sugammadex/placebo administration to recovery of the train-of-four ratio to 0.9. Adverse events and electrocardiograms were recorded, and blood samples were collected for safety and determination of sugammadex and rocuronium plasma concentrations. RESULTS: A dose-response relation was demonstrated in children (n = 22), adolescents (n = 28), and adults (n = 26), but not infants because of the small sample size (n = 8). After placebo, median recovery time of train-of-four to 0.9 was 21.0, 19.0, 23.4, and 28.5 min in infants, children, adolescents, and adults, respectively. After 2.0 mg/kg sugammadex train-of-four 0.9 was attained in 0.6, 1.2, 1.1, and 1.2 min, respectively. The sugammadex plasma concentrations were similar for the children, adolescent, and adult age groups across the dose range. Sugammadex was well tolerated: No reoccurrence of blockade, inadequate reversal, significant QT prolongation, or other abnormalities were observed. CONCLUSIONS: Sugammadex is a new reversal agent that rapidly, effectively, safely, and with similar recovery times reverses rocuronium-induced neuromuscular blockade in children, adolescents, adults, and the small number of infants studied.

Induction of spermatogenesis by recombinant follicle-stimulating hormone (puregon) in hypogonadotropic azoospermic men who failed to respond to human chorionic gonadotropin alone.

A multicenter, open-label, randomized efficacy and safety study was performed with combined human chorionic gonadotropin (hCG) and recombinant follicle-stimulating hormone (recFSH) (Puregon(R)) treatment to induce spermatogenesis in hypogonadotropic hypogonadal male patients. Patients were pretreated for 16 weeks with hCG to normalize testosterone levels. A total of 30 of 49 (61%) subjects had normalized testosterone levels but were still azoospermic after the hCG-alone phase. These patients were randomized into 2 treatment schemes with recFSH (2 x 225 IU recFSH per week [group A] or 3 x 150 IU recFSH per week [group B]), in combination with hCG for a period of 48 weeks. Total testosterone increased during the hCG-alone period from 1.08 and 1.22 ng/mL to 6.26 and 4.52 ng/mL for groups A and B, respectively. Combined gonadotropin treatment was effective in inducing spermatogenesis (sperm count >/=1 x 10(6)/mL) in 14 of 30 subjects (47%) and this was achieved after a median duration of treatment of approximately 5.5 months. Treatment time necessary for first sperm cells to appear in the ejaculate was related to the initial testicular volume. Subjects with a history of maldescended testes (11 of 30 subjects, 37%) showed a lower mean response to treatment as indicated by the relatively lower number of subjects reaching levels of at least 1 x 10(6) sperm cells per milliliter. Combined testicular volume increased during combined gonadotropin treatment from 11.4 to 24.0 mL. Although subjects with a history of maldescended testes had a lower starting testicular volume, subjects with and without a history of maldescended testes showed approximately the same relative increase in testicular volume. Total testosterone levels showed only a minor further increase during the combined gonadotropin treatment period. In conclusion, a weekly dose of 450 IU (3 x 150 IU or 2 x 225 IU) recFSH, in addition to hCG, was able to induce spermatogenesis in many hypogonadotropic azoospermic men who failed to respond to treatment with hCG alone.