Gary Layton

A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral Sildenafil Citrate in Treatment-Naive Children With Pulmonary Arterial Hypertension

Background— Safe, effective therapy is needed for pediatric pulmonary arterial hypertension. Methods and Results— Children (n=235; weight ≥8 kg) were randomized to low-, medium-, or high-dose sildenafil or placebo orally 3 times daily for 16 weeks in the Sildenafil in Treatment-Naive Children, Aged 1–17 Years, With Pulmonary Arterial Hypertension (STARTS-1) study. The primary comparison was percent change from baseline in peak oxygen consumption (PV[Combining Dot Above]O2) for the 3 sildenafil doses combined versus placebo. Exercise testing was performed in 115 children able to exercise reliably; the study was powered for this population. Secondary end points (assessed in all patients) included hemodynamics and functional class. The estimated mean±SE percent change in PV[Combining Dot Above]O2 for the 3 doses combined versus placebo was 7.7±4.0% (95% confidence interval, −0.2% to 15.6%; P=0.056). PV[Combining Dot Above]O2, functional class, and hemodynamics improved with medium and high doses versus placebo; low-dose sildenafil was ineffective. Most adverse events were mild to moderate in severity. STARTS-1 completers could enter the STARTS-2 extension study; patients who received sildenafil in STARTS-1 continued the same dose, whereas placebo-treated patients were randomized to low-, medium-, or high-dose sildenafil. In STARTS-2 (ongoing), increased mortality was observed with higher doses. Conclusions— Sixteen-week sildenafil monotherapy is well tolerated in pediatric pulmonary arterial hypertension. Percent change in PV[Combining Dot Above]O2 for the 3 sildenafil doses combined was only marginally significant; however, PV[Combining Dot Above]O2, functional class, and hemodynamic improvements with medium and high doses suggest efficacy with these doses. Combined with STARTS-2 data, the overall profile favors the medium dose. Further investigation is warranted to determine optimal dosing based on age and weight. Clinical Trial Registration— http://www.clinicaltrials.gov. Unique identifier: NCT00159913.

Long-term Treatment With Sildenafil Citrate in Pulmonary Arterial Hypertension: The SUPER-2 Study

BACKGROUND The long-term safety and tolerability of sildenafil treatment of pulmonary arterial hypertension (PAH) were assessed. METHODS Two hundred fifty-nine of 277 randomized and treated patients completed a 12-week, double-blind, placebo-controlled trial (SUPER-1 [Sildenafil Use in Pulmonary Arterial Hypertension]) of oral sildenafil in treatment-naive patients with PAH (96% functional class II/III) and entered an open-label uncontrolled extension study (SUPER-2) that continued until the last patient completed 3 years of sildenafil treatment. Patients titrated to sildenafil 80 mg tid; one dose reduction for tolerability was allowed during the titration phase. RESULTS The median duration of sildenafil treatment across SUPER-1 and SUPER-2 was 1,242 days (range, 1-1,523 days); 170 patients (61%) completed both studies, and 89 patients discontinued from SUPER-2. After 3 years, 87% of 183 patients on treatment were receiving sildenafil 80 mg tid. Of patients remaining under follow-up, 3%, 10%, and 18% were receiving a second approved PAH therapy at 1, 2, and 3 years, respectively. At 3 years post-SUPER-1 baseline, 127 patients had an increased 6-min walk distance (6MWD); 81 improved and 86 maintained functional class. Most adverse events were of mild or moderate severity. At 3 years, 53 patients had died (censored, n = 37). Three-year estimated survival rate was 79%; if all censored patients were assumed to have died, 3-year survival rate was 68%. No deaths were considered to be treatment related. CONCLUSIONS Long-term treatment of PAH initiated as sildenafil monotherapy was generally well tolerated. After 3 years, the majority of patients (60%) who entered the SUPER-1 trial improved or maintained their functional status, and 46% maintained or improved 6MWD.

A randomized, controlled, multicentre trial comparing pegvisomant alone with combination therapy of pegvisomant and long-acting octreotide in patients with acromegaly

Objective  For patients with acromegaly who are suboptimally controlled on long‐acting octreotide (LAR), treatment options are to switch to pegvisomant monotherapy (PM) or add pegvisomant to LAR (P‐LAR). Our objective was to evaluate if the safety and efficacy of these regimens differ.

Man Versus Machine: Is There an Optimal Method for QT Measurements in Thorough QT Studies?

Electrocardiographic (ECG) recordings from 3 placebo‐controlled thorough QT healthy volunteer studies were used to compare QT intervals obtained by manual measurement with those generated by ECG machines. The effect of the positive control was compared to placebo at each time point for data obtained from both sources. Both manual and automated techniques consistently demonstrated statistically significant prolongation of QTcF with the positive controls. The proportion of outlier values was small for both methods. The pairwise comparison between manual and automated uncorrected QT intervals demonstrated clear differences, with intervals derived from one machine on average 16 to 19 milliseconds shorter and from the other 7 milliseconds longer than the manually measured QT intervals, but these differences disappeared when analyzing QT change from baseline. Both manual and automated, commercially available QT algorithms demonstrated small statistically significant effects on the QTc interval induced by positive controls.

STARTS-2: Long-Term Survival With Oral Sildenafil Monotherapy in Treatment-Naïve Pediatric Pulmonary Arterial Hypertension

Background— The double-blind, placebo-controlled Sildenafil in Treatment-Naive Children, Aged 1 to 17 Years, With Pulmonary Arterial Hypertension (STARTS-1) study assessed sildenafil in pediatric patients with pulmonary arterial hypertension; improved hemodynamics and exercise capacity occurred in medium- and high-dose groups. STARTS-2 was the extension study. Methods and Results— In STARTS-1, 234 children ≥8 kg were randomly assigned to low-, medium-, or high-dose sildenafil or placebo orally thrice daily; within-group dose depended on weight. In STARTS-2, sildenafil-treated patients continued STARTS-1 dosing; placebo-treated patients were randomized to 1 of the 3 sildenafil dose groups. Patients requiring additional pulmonary arterial hypertension–specific therapy discontinued study treatment; survival follow-up was attempted. As of August 2011, all children received ≥3 years of treatment (unless discontinued) from STARTS-1 baseline; 37 deaths were reported (26 on study treatment), 1 of which occurred within the first year of treatment. Most patients who died (28/37) had idiopathic/heritable pulmonary arterial hypertension (76% versus 33% overall) and baseline functional class III/IV disease (38% versus 15% overall); patients who died had worse baseline hemodynamics. Kaplan-Meier estimated 3-year survival rates from start of sildenafil were 94%, 93%, and 88% for patients randomized to low-, medium-, and high-dose sildenafil, respectively; 87%, 89%, and 80% were known to be alive at 3 years. Hazard ratios for mortality were 3.95 (95% confidence interval, 1.46–10.65) for high versus low and 1.92 (95% confidence interval, 0.65–5.65) for medium versus low dose; however, multiple analyses raised uncertainty about the survival/dose relationship. Conclusions— Although children randomized to higher compared with lower sildenafil doses had an unexplained increased mortality, all sildenafil dose groups displayed favorable survival for children with pulmonary arterial hypertension. Clinical Trial Registration— URL: http://clinicaltrials.gov/ct2/show/NCT00159874 (extension study of NCT00149913). Unique identifier: NCT00159874.Background— The double-blind, placebo-controlled Sildenafil in Treatment-Naive Children, Aged 1 to 17 Years, With Pulmonary Arterial Hypertension (STARTS-1) study assessed sildenafil in pediatric patients with pulmonary arterial hypertension; improved hemodynamics and exercise capacity occurred in medium- and high-dose groups. STARTS-2 was the extension study. Methods and Results— In STARTS-1, 234 children ≥8 kg were randomly assigned to low-, medium-, or high-dose sildenafil or placebo orally thrice daily; within-group dose depended on weight. In STARTS-2, sildenafil-treated patients continued STARTS-1 dosing; placebo-treated patients were randomized to 1 of the 3 sildenafil dose groups. Patients requiring additional pulmonary arterial hypertension–specific therapy discontinued study treatment; survival follow-up was attempted. As of August 2011, all children received ≥3 years of treatment (unless discontinued) from STARTS-1 baseline; 37 deaths were reported (26 on study treatment), 1 of which occurred within the first year of treatment. Most patients who died (28/37) had idiopathic/heritable pulmonary arterial hypertension (76% versus 33% overall) and baseline functional class III/IV disease (38% versus 15% overall); patients who died had worse baseline hemodynamics. Kaplan-Meier estimated 3-year survival rates from start of sildenafil were 94%, 93%, and 88% for patients randomized to low-, medium-, and high-dose sildenafil, respectively; 87%, 89%, and 80% were known to be alive at 3 years. Hazard ratios for mortality were 3.95 (95% confidence interval, 1.46–10.65) for high versus low and 1.92 (95% confidence interval, 0.65–5.65) for medium versus low dose; however, multiple analyses raised uncertainty about the survival/dose relationship. Conclusions— Although children randomized to higher compared with lower sildenafil doses had an unexplained increased mortality, all sildenafil dose groups displayed favorable survival for children with pulmonary arterial hypertension. Clinical Trial Registration— URL: (extension study of [NCT00149913][1]). Unique identifier: [NCT00159874][2]. # CLINICAL PERSPECTIVE {#article-title-32} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00149913&atom=%2Fcirculationaha%2F129%2F19%2F1914.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00159874&atom=%2Fcirculationaha%2F129%2F19%2F1914.atom

Safety, tolerability and pharmacokinetics of an intravenous bolus of sildenafil in patients with pulmonary arterial hypertension

AIMS To assess pharmacokinetics and pharmacodynamics of a 10 mg intravenous sildenafil bolus in pulmonary arterial hypertension (PAH) patients stabilized on 20 mg sildenafil orally three times daily. METHODS Pharmacokinetic parameters were calculated using noncompartmental analysis. RESULTS After an acute increase, plasma concentrations stabilized within the range reported previously for a 20 mg oral tablet. At 0.5 h, mean ± SD changes from baseline were -8.4 ± 11.7 mmHg (systolic pressure), -2.6 ± 7.3 mmHg (diastolic pressure) and -3.5 ± 10.4 beats min(-1) (heart rate). There was no symptomatic hypotension. CONCLUSIONS Although further research is warranted, a 10 mg sildenafil intravenous bolus appears to provide similar exposure, tolerability and safety to the 20 mg tablet.

Activity, pharmacokinetics and safety of lersivirine (UK-453,061), a next-generation nonnucleoside reverse transcriptase inhibitor, during 7-day monotherapy in HIV-1-infected patients.

Objective:To investigate the effects on viral load and assess dose–response relationships, pharmacokinetics, safety and tolerability of lersivirine (UK-453,061), a next-generation nonnucleoside reverse transcriptase inhibitor, in asymptomatic HIV-1-infected patients. Design:Randomized, double-blind, placebo-controlled, parallel group, multicenter phase IIa clinical study. Methods:Forty-eight HIV-1-infected patients were enrolled for the study of once-daily or twice-daily lersivirine at total daily doses ranging from 20 to 1000 mg. The primary endpoint was the change in log10 plasma HIV-1 RNA viral load from baseline to day 8. Secondary endpoints related to pharmacokinetics, safety and tolerability and potential development of viral resistance and genotyping patterns. Results:Patients treated with lersivirine achieved day 8 mean viral load reductions of 0.3, 0.8, 1.3 and 1.6 log10 after receiving 10, 30, 100 and 500 mg twice daily, respectively, and 0.9, 1.7 and 1.8 log10 after receiving 100, 500 and 750 mg once daily, respectively. Mean changes from baseline to day 8 were small in patients receiving placebo. For all dose regimens, plasma exposure increased approximately in line with lersivirine dose. Median plasma concentrations of lersivirine at steady state were above the IC90 for lersivirine at once-daily doses of at least 500 mg and twice-daily doses of at least 100 mg. The most commonly reported treatment-emergent adverse events were headache, fatigue and nausea. Conclusion:Seven-day monotherapy with lersivirine achieved mean viral load reductions up to 1.8 log10. Lersivirine was safe and well tolerated. Further studies of lersivirine in combination with other antiretroviral drugs to assess long-term durability of antiviral response, safety and tolerability are warranted.

Effect of single doses of maraviroc on the QT/QTc interval in healthy subjects

AIMS To assess the effect of a single dose of maraviroc on the QTc interval in healthy subjects and to evaluate the QTc interval-concentration relationship. METHODS A single-dose, placebo- and active-controlled, five-way crossover study was conducted to investigate the effects of maraviroc (100, 300, 900 mg) on QTc in healthy subjects. Moxifloxacin (400 mg) was used as the active comparator. The study was double-blind with respect to maraviroc/placebo and open label for moxifloxacin. There was a 7-day wash-out period between each dose. QT interval measurements obtained directly from the electrocardiogram (ECG) recorder were corrected for heart rate using Fridericias correction (QTcF). A placebo run-in day was conducted before period 3, when ECGs were collected at intervals while subjects were resting or during exercise. These ECGs plus other predose ECGs were used to evaluate the QT/RR relationship for each subject to enable calculation of an individuals heart rate correction for their QT measurements (QTcI). ECGs were taken at various intervals pre- and postdose in each study period. Pharmacokinetic parameters were determined for each maraviroc dose. The end-points that were evaluated were QTcF at median time to maximum concentration (T(max)) based on the machine readings and QTcI at median T(max) based on manual over-reads of the QT/RR data. A separate analysis of variance was used for each of the pair-wise comparisons for each end-point. The relationship between QTc interval and plasma concentration was also investigated using a mixed-effects modelling approach, as implemented by the NONMEM software system. A one-stage model was employed in which the relationship between QT and RR and the effects of maraviroc plasma concentration on QT were estimated simultaneously. RESULTS The mean difference from placebo in machine-read QTcF at median T(max) for maraviroc 900 mg was 3.6 ms [90% confidence interval (CI) 1.5, 5.8]. For the active comparator, moxifloxacin, the mean difference from placebo in machine-read QTcF was 13.7 ms. The changes from placebo for each of the end-points were similar for men and women. No subjects receiving maraviroc or placebo had a QTcF > or = 450 ms (men) or QTcF > or = 470 ms (women), nor did any subject experience a QTcF increase > or = 60 ms from baseline at any time point. Analysis based on the QTcI data obtained from the manual over-readings of the ECGs gave numerically very similar results. The QT:RR relationship was similar pre- and postdose and was not related to maraviroc concentration. The population estimate of the QT:RR correction factor was 0.324 (95% CI 0.309, 0.338). The population estimate of the slope describing the QT-concentration relationship was 0.97 micros ml ng(-1) (95% CI -0.571, 2.48), equivalent to an increase of 0.97 ms in QT per 1000 ng maraviroc plasma concentration. Most adverse events were mild to moderate in severity. CONCLUSIONS Single doses of maraviroc, up to and including 900 mg, had no clinically relevant effect on QTcF or QTcI. At all maraviroc doses and for both end-points, the mean difference from placebo for QTc was < 4 ms. There was no apparent relationship between QT interval and maraviroc plasma concentration up to 2363 ng ml(-1). This conclusion held in both male and female subjects, and there was no evidence of a change in the QT/RR relationship with concentration.

A comparison of sumanirole versus placebo or ropinirole for the treatment of patients with early Parkinson's disease.

To assess the safety and efficacy of sumanirole, a highly selective dopamine agonist, versus placebo and demonstrate its noninferiority to ropinirole, 614 patients with early Parkinsons disease (PD) were treated with sumanirole, 1 to16 mg/day; ropinirole, 0.75 to 24 mg/day; or placebo. Primary end point in this flexible‐dose, double‐blind, double‐dummy, parallel‐group study of 40 weeks was the change in total sum of the United Parkinsons Disease Rating Scale (UPDRS) Parts II + III scores from baseline to end of maintenance. Approximately half the subjects in the sumanirole and placebo groups withdrew early from the study, most (51.8% and 68.5%, respectively) due to lack of efficacy. Of the ropinirole subjects who withdrew (50.5%), most discontinued because of adverse events. In sumanirole and ropinirole groups, mean changes from baseline of −2.48 and −5.20 in UPDRS II + III mean scores were significant versus 0.38 in the placebo group (P ≤ 0.006). Sumanirole and ropinirole are effective in the treatment of patients with early PD when compared with placebo. Noninferiority of sumanirole to ropinirole was not demonstrated, with a difference of 2.70 (90% CI, 0.92–4.49). Sumanirole was better tolerated than ropinirole.

Effects of Multiple Doses of Voriconazole on the Vision of Healthy Volunteers: A Double-Blind, Placebo-Controlled Study

Purpose: To investigate the effects, and their reversibility, of multiple oral voriconazole doses on a variety of visual tests in healthy male volunteers. Methods: Single-center, double-blind, randomized, placebo-controlled, parallel-group study in 36 volunteers who received voriconazole (n = 18, 400 mg every 12 h on day 1, then 300 mg every 12 h for 27.5 days) or matched placebo (n = 18). Electroretinograms (ERGs) and ophthalmological examinations were performed at screening, throughout the study and at follow-up. Results: Fifteen (83.3%) volunteers treated with voriconazole experienced ≥1 treatment-related visual adverse events (AEs); these included enhanced visual perceptions, blurred vision, color vision changes and photophobia. No serious AEs were reported. Voriconazole reduced from baseline scotopic maximal a- and b-wave amplitude, shortened implicit time and decreased oscillatory potential amplitude compared with placebo. Under photopic conditions, the 30-Hz flicker response amplitude was significantly reduced and was accompanied by a slight but nonsignificant prolongation of peak time. These effects did not progress in degree over the treatment period, and mean changes from baseline in ERG parameters were similar to placebo by day 43 (14 days after end of treatment). In the first week, color vision discrimination was impaired in the tritan axis, although this resolved by end of treatment and was similar to placebo by day 43. Mean deviation in the static visual field indicated increased sensitivity following voriconazole treatment, correlating with decreased amplitude in conjunction with shortened implicit time. Conclusions: Effects of voriconazole on altered visual perception, ERG, color vision and static visual field thresholds are nonprogressive over a treatment period and reversible. It is hypothesized that voriconazole has a pharmacological effect on rod and cone pathways including a possible mechanism of disinhibition that reversibly puts the retina in a more light-adapted state and leads to increased relative contrast sensitivity.