Long-term safety and effectiveness of roflumilast cream 0.3% in adults with chronic plaque psoriasis: A 52-week, phase 2, open-label trial.

BACKGROUND: Efficacy and/or safety profiles limit topical psoriasis treatments. OBJECTIVE: Evaluate long-term effects of once-daily roflumilast cream 0.3% in patients with psoriasis. METHODS: In this open-label phase 2 trial, adult patients (N = 332) with psoriasis who completed the phase 2b parent trial or were newly enrolled applied roflumilast once-daily for 52 weeks. Safety and effectiveness were assessed. RESULTS: Overall, 244 patients (73.5%) completed the trial; 13 patients (3.9%) discontinued due to adverse events (AEs) and 3 (0.9%) due to lack of efficacy. Twelve patients (3.6%) reported treatment-related AEs; none were serious. ≥97% of patients had no irritation. No tachyphylaxis was observed with 44.8% of the patients achieving Investigator Global Assessment (IGA) Clear or Almost Clear at Week 52. LIMITATIONS: Intertriginous-IGA and Psoriasis Area and Severity Index (PASI) were not evaluated in all patients. CONCLUSIONS: In this long-term trial, once-daily roflumilast cream was well-tolerated and efficacious up to 64 weeks in patients in the earlier trial, suggesting it is suitable for chronic treatment, including the face and intertriginous areas.

Roflumilast foam 0.3% for adolescent and adult patients with seborrheic dermatitis: A randomized, double-blinded, vehicle-controlled, phase 3 trial.

BACKGROUND: The topical phosphodiesterase 4 inhibitor roflumilast has been studied in several dermatologic conditions. OBJECTIVE: Roflumilast foam 0.3% is being investigated as a topical treatment for seborrheic dermatitis (SD). METHODS: In this phase 3, double-blinded trial, patients with SD were randomly assigned (2:1 ratio) to once-daily roflumilast foam 0.3% or vehicle foam for 8 weeks. The primary efficacy outcome was Investigator Global Assessment (IGA) Success at week 8, defined as IGA of 0 (Clear) or 1 (Almost Clear) plus ≥2-point improvement from baseline. Safety was also assessed. RESULTS: 79.5% of roflumilast-treated and 58.0% of vehicle-treated patients met the primary endpoint (P < .001); statistically significant differences in IGA Success also favored roflumilast at week 2 (roflumilast: 43.0%; vehicle: 25.7%; P < .001) and week 4 (roflumilast: 73.1%; vehicle: 47.1%; P < .001). Roflumilast was well-tolerated with a low rate of treatment-emergent adverse events. LIMITATIONS: Study limitations include the 8-week treatment period for this chronic condition. CONCLUSIONS: Once-daily roflumilast foam was superior to vehicle in leading to IGA of Clear or Almost Clear plus ≥2-point improvement from baseline at 8 weeks in patients with SD. Longer trials are needed to determine durability and safety of roflumilast foam in SD.

Once-daily roflumilast foam 0.3% for scalp and body psoriasis: a randomized, double-blind, vehicle-controlled phase IIb study.

BACKGROUND: Scalp psoriasis affects most patients with psoriasis, but it can be difficult to treat. OBJECTIVES: To evaluate the efficacy and safety of once-daily roflumilast foam 0.3% on scalp and body psoriasis. METHODS: In a phase IIb randomized controlled trial, adults and adolescents aged ≥ 12 years with scalp and body psoriasis were randomized (2 : 1) to roflumilast foam 0.3% or vehicle for 8 weeks. The primary efficacy endpoint was scalp Investigator Global Assessment (S-IGA) success (score of 'clear' or 'almost clear' plus ≥ 2-grade improvement from baseline) at week 8. Safety and tolerability were also evaluated. RESULTS: Significantly more roflumilast-treated patients (59.1%) than vehicle-treated patients (11.4%) achieved S-IGA success at week 8 (P < 0.001); differences favoured roflumilast as early as the first postbaseline visit at week 2 (P < 0.001). Significant improvements were also seen for secondary endpoints, including body IGA success, Scalp Itch Numeric Rating Scale and the Psoriasis Scalp Severity Index. The safety of roflumilast was generally similar to vehicle. Patients treated with roflumilast experienced low rates of treatment-emergent adverse events (AEs), with few discontinuations due to an AE. Few patients with skin of colour (11%) and few adolescents (0.7%) were included. CONCLUSIONS: The results support the further development of roflumilast foam for treating scalp and body psoriasis.

Efficacy of Roflumilast Foam, 0.3%, in Patients With Seborrheic Dermatitis: A Double-blind, Vehicle-Controlled Phase 2a Randomized Clinical Trial.

Importance: Current topical treatment options for seborrheic dermatitis are limited by efficacy and/or safety. Objective: To assess safety and efficacy of roflumilast foam, 0.3%, in adult patients with seborrheic dermatitis affecting the scalp, face, and/or trunk. Design, Setting, and Participants: This multicenter (24 sites in the US and Canada) phase 2a, parallel group, double-blind, vehicle-controlled clinical trial was conducted between November 12, 2019, and August 21, 2020. Participants were adult (aged ≥18 years) patients with a clinical diagnosis of seborrheic dermatitis for a 3-month or longer duration and Investigator Global Assessment (IGA) score of 3 or greater (at least moderate), affecting 20% or less body surface area, including scalp, face, trunk, and/or intertriginous areas. Data analysis was performed from September to October 2020. Interventions: Once-daily roflumilast foam, 0.3% (n = 154), or vehicle foam (n = 72) for 8 weeks. Main Outcomes and Measures: The main outcome was IGA success, defined as achievement of IGA score of clear or almost clear plus 2-grade improvement from baseline, at week 8. Secondary outcomes included IGA success at weeks 2 and 4; achievement of erythema score of 0 or 1 plus 2-grade improvement from baseline at weeks 2, 4, and 8; achievement of scaling score of 0 or 1 plus 2-grade improvement from baseline at weeks 2, 4, and 8; change in Worst Itch Numeric Rating Scale (WI-NRS) score from baseline; and WI-NRS success, defined as achievement of 4-point or greater WI-NRS score improvement in patients with baseline WI-NRS score of 4 or greater. Safety and tolerability were also assessed. Results: A total of 226 patients (mean [SD] age, 44.9 [16.8] years; 116 men, 110 women) were randomized to roflumilast foam (n = 154) or vehicle foam (n = 72). At week 8, 104 (73.8%) roflumilast-treated patients achieved IGA success compared with 27 (40.9%) in the vehicle group (P < .001). Roflumilast-treated patients had statistically significantly higher rates of IGA success vs vehicle at week 2, the first time point assessed. Mean (SD) reductions (improvements) on the WI-NRS at week 8 were 59.3% (52.5%) vs 36.6% (42.2%) in the roflumilast and vehicle groups, respectively (P < .001). Roflumilast was well tolerated, with the rate of adverse events similar to that of the vehicle foam. Conclusions and Relevance: The results from this phase 2a randomized clinical trial of once-daily roflumilast foam, 0.3%, demonstrated favorable efficacy, safety, and local tolerability in the treatment of erythema, scaling, and itch caused by seborrheic dermatitis, supporting further investigation as a nonsteroidal topical treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT04091646.

Sequential administration of Prevnar 13™ and PNEUMOVAX™ 23 in healthy participants 50 years of age and older.

In most countries worldwide, pneumococcal conjugate vaccines have been included in the infant immunization program, resulting in a significant reduction in the burden of pneumococcal disease in children and adults. Shifting serotype distribution due to the indirect effect of infant vaccination with the 13-valent pneumococcal conjugate vaccine (PCV13) may continue to increase the gap between 23-valent pneumococcal polysaccharide vaccine (PPSV23) and PCV13 serotype coverage for older adults in the coming years. This clinical study (V110-029; NCT02225587) evaluated the safety and immunogenicity of sequential administration of PCV13 followed approximately 8 weeks later, or approximately 26 weeks later, by PPSV23 in healthy adults ≥50 years of age. Both dosing intervals were generally well tolerated as measured by the nature, frequency, and intensity of reported adverse events (AEs) in both vaccination groups. Serotype-specific opsonophagocytic activity (OPA) geometric mean titers (GMTs) measured 30 days following receipt of PPSV23 in either group and at Week 30 were generally comparable between the 2 groups for 6 serotypes unique to PPSV23 and 12 serotypes shared between PCV13 and PPSV23, regardless of the interval between receipt of PCV13 and PPSV23. In addition, administration of PPSV23 given either 8 weeks or 26 weeks following PCV13 did not negatively impact immune responses induced by PCV13. Furthermore, administration of PPSV23 given either 8 weeks or 26 weeks after PCV13 elicited serotype-specific OPA GMTs to serotypes unique to PPSV23, which could provide earlier protection against pneumococcal disease caused by these serotypes in comparison with the current Advisory Committee on Immunization Practices recommended interval of at least 12 months.

Evidence of plasticity in the pontocerebellar conditioned stimulus pathway during classical conditioning of the eyeblink response in the rabbit.

Electrical stimulation thresholds required to elicit eyeblinks with either pontine or cerebellar interpositus stimulation were measured before and after classical eyeblink conditioning with paired pontine stimulation (conditioned stimulus, CS) and corneal airpuff (unconditioned stimulus, US). Pontine stimulation thresholds dropped dramatically after training and returned to baseline levels following extinction, whereas interpositus thresholds and input-output functions remained stable across training sessions. Learning rate, magnitude of threshold change, and electrode placements were correlated. Pontine projection patterns to the cerebellum were confirmed with retrograde labeling techniques. These results add to the body of literature suggesting that the pons relays CS information to the cerebellum and provide further evidence of synaptic plasticity in the cerebellar network.

The time to onset and overall analgesic efficacy of rofecoxib 50 mg: a meta-analysis of 13 randomized clinical trials.

OBJECTIVE: To determine the time to onset of analgesia of rofecoxib based on a patient-level meta-analysis of randomized, placebo-controlled, postoperative oral surgery pain studies. METHODS: A search on MEDLINE and of Merck data on file was conducted to identify studies that met the inclusion criteria. Meta-analysis inclusion criteria required that patients were treated with a single oral dose of rofecoxib 50 mg when they experienced moderate or severe pain after surgical extraction of > or = 2 third molars; study design involved patient randomization, double-blinding, and matching placebo, and onset data from individual patients were available. The meta-analysis of time to onset also required that studies used the two-stopwatch method. Eleven studies fulfilled the onset criteria and included patients who received a single dose of rofecoxib 50 mg (N = 1220) or placebo (N = 483). These studies were analyzed to determine time to onset of analgesia, time to perceptible pain relief, percentage of patients achieving onset of analgesia, and duration of analgesia. Six of the 11 studies included a nonselective nonsteroidal anti-inflammatory drug (N = 303) and were included in the onset meta-analysis for comparison. The meta-analysis of overall efficacy also required that data on total pain relief scores over 8 hours were available. Over-all effectiveness of analgesia was based on analysis of 13 studies involving 1330 rofecoxib patients and 570 placebo patients on the endpoints of total pain relief scores over 8 hours and patient global assessment of response to therapy at 24 hours. Eight of the 13 studies with a nonselective nonsteroidal anti-inflammatory drug comparator (N = 391) were included for the efficacy meta-analysis. RESULTS: Patient demographics and baseline characteristics were similar across treatment groups in each study. Median time to onset of analgesia for rofecoxib was 34 minutes (95% CI, 31-38 minutes), significantly faster than placebo, which did not achieve onset within the 4 hours the assessment was conducted (P < 0.001). Duration of analgesia for rofecoxib 50 mg was > 24 hours. Rofecoxib achieved a greater mean total pain relief score over 8 hours than placebo (17.4 versus 4.4; P < 0.001) and a greater patient response rate on patient global assessment of response to therapy at 24 hours than placebo (73% versus 16%; P < 0.001). Outcomes were similar between the rofecoxib group and the nonselective nonsteroidal anti-inflammatory drug group. CONCLUSION: In this meta-analysis of over 1200 rofecoxib-treated patients, a single dose of rofecoxib 50 mg demonstrated a rapid onset of analgesia in approximately half an hour combined with sustained effectiveness, supporting its use as a treatment of acute pain.

Layer-specific somatosensory cortical activation during active tactile discrimination.

Ensemble neuronal activity was recorded in each layer of the whisker area of the primary somatosensory cortex (SI) while rats performed a whisker-dependent tactile discrimination task. Comparison of this activity with SI activity evoked by similar passive whisker stimulation revealed fundamental differences in tactile signal processing during active and passive stimulation. Moreover, significant layer-specific functional differences in SI activity were observed during active discrimination. These differences could not be explained solely by variations in ascending thalamocortical input to SI. Instead, these results suggest that top-down influences during active discrimination may alter the overall functional nature of SI as well as layer-specific mechanisms of tactile processing.

Onset of pain relief with rofecoxib in chronic low back pain: results of two four-week, randomized, placebo-controlled trials.

OBJECTIVE: We recently reported the efficacy of rofecoxib in two randomized controlled trials in chronic low back pain (CLBP). The objectives of this report are to present data regarding the onset of efficacy of rofecoxib from these trials and propose methods for reporting onset. RESEARCH DESIGN AND METHODS: Patients were aged 18-75, with non-radicular CLBP for >or= 3 months. Patients were randomized to rofecoxib 25mg, 50 mg, or placebo once daily for 4 weeks. Assessments included Low Back Pain and Bothersomeness scales every morning and Relief from Starting Pain after the first dose at 0.5, 1, 2, 3, 4 h, bedtime, and next morning. Onset of meaningful relief was measured by Time to Confirmed 50% Reduction in Pain and Time to Confirmed 'Slightly' or 'Not At All' Bothersome Pain. Onset of perceptible pain relief was measured by Time to At Least 'A Little' Confirmed Pain Relief. RESULTS: 690 patients entered. Significantly more patients treated with rofecoxib had compared with 1/3 receiving placebo. Median meaningful relief compared to placebo: 60.4, 58.4, and 34.7% for rofecoxib 25mg, 50 mg, and placebo (p< 0.001). Median time to meaningful relief for rofecoxib was 2 days, 1 day sooner than placebo. Rofecoxib was superior to placebo by bedtime after the first dose. CONCLUSIONS: Approximately 2/3 of patients achieved meaningful pain relief with rofecoxib time to onset of meaningful relief was about 2 days, but superior relief over placebo was seen by bedtime after the first dose. Onset of perceptible pain relief was within 2 h. We propose that measures of onset of analgesic effect include the proportion of patients who achieve meaningful pain relief and in this subgroup, the time-to-onset of confirmed meaningful reduction in pain intensity, time-to-onset of confirmed pain relief, and time to first separation from placebo in the proportion of patients who achieve meaningful pain relief.

Inhibiting the expression of a classically conditioned behavior prevents its extinction.

The underlying neuronal substrates and behavioral properties that might mediate extinction of the classically conditioned eye-blink response (CR) were examined. Four groups of rabbits were trained to perform the CR. Two of the groups then received either three or six sessions of tone-alone extinction training while the motor nuclei that mediate expression of the CR (facial nucleus and accessory abducens) were reversibly inactivated with microinjections of the GABA agonist muscimol. After these inactivation extinction sessions, rabbits received four more extinction sessions without inactivation. Two groups of controls received either three or six extinction sessions while saline vehicle was infused into the motor nuclei, followed by four sessions with no infusions. Saline infusions had no effect on extinction, and controls extinguished the CR normally over the first three to four sessions. In contrast, muscimol inactivation of the motor nuclei completely prevented any performance of CRs during the three or six inactivation extinction sessions. At the start of the four extinction sessions without inactivation, rabbits performed CRs at the same rate and amplitude as controls on their first extinction sessions. The muscimol rabbits then extinguished the CR normally over the four sessions without inactivation. In short, inactivation of the motor nuclei completely prevented any extinction of the eye-blink CR with no effect on subsequent extinction without inactivation. These results are discussed in terms of possible neuroanatomical loci that might mediate the extinction process as well as how effects of manipulating CR performance during extinction may affect the extinction process.

Efficacy and safety of rofecoxib in patients with chronic low back pain: results from two 4-week, randomized, placebo-controlled, parallel-group, double-blind trials.

STUDY DESIGN: Two replicate, 4-week, randomized, double-blind, placebo-controlled, trials of rofecoxib 25 and 50 mg versus placebo for chronic low back pain. OBJECTIVES: To determine the efficacy and safety of two doses of rofecoxib compared to placebo in the treatment of chronic low back pain. SUMMARY OF BACKGROUND DATA: Although nonsteroidal anti-inflammatory drugs are commonly prescribed for chronic low back pain, their efficacy is unproven and toxicity can be serious. These studies evaluated the efficacy and tolerability of rofecoxib, a selective COX-2 inhibitor, in the treatment of chronic low back pain. METHODS: Patients with chronic low back pain were randomized 1:1:1 to rofecoxib 25 mg, 50 mg, or placebo once daily. Primary endpoint: Low Back Pain Intensity. Secondary endpoints: Pain Bothersomeness, Global Assessments of Response to Therapy, Global Assessment of Disease Status, Roland-Morris Disability Questionnaire, SF-12 Health Survey, Use of Rescue Acetaminophen, and Discontinuations Due to Lack of Efficacy. RESULTS: Combining both studies, 690 patients were randomized to placebo (N = 228), rofecoxib 25 mg (N = 233), or rofecoxib 50 mg (N = 229). Mean (+/- SD) age was 53.4 (+/- 12.9) years, pain duration 12.1 (+/- 11.8) years, 62.3% female. Both rofecoxib groups improved significantly. Mean differences from placebo in pain intensity were -13.50 mm, -13.81 mm (25, 50 mg doses) respectively (P < 0.001). Both regimens were superior to placebo in eight of nine secondary endpoints. Fifty mg provided no advantage over 25 mg. Both rofecoxib regimens were well tolerated, although 25 mg had a slightly better safety profile. CONCLUSIONS: Rofecoxib significantly reduced chronic low back pain in adults and was well tolerated.

A randomized, placebo controlled, multicenter study to evaluate the safety and efficacy of rofecoxib in the treatment of chronic nonbacterial prostatitis.

PURPOSE: We determine the effects of treatment with rofecoxib and placebo in patients with chronic prostatitis. MATERIALS AND METHODS: Patients diagnosed with chronic nonbacterial prostatitis were randomized to 6 weeks of 25 or 50 mg., rofecoxib or placebo in a double-blind multicenter study with a 1-week run in of placebo. End points included the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) (average pain score item 4 primary end point), and patient global assessment questions of pain, disease activity and response to therapy. RESULTS: A total of 161 patients were randomized in the study. The NIH-CPSI total, domain and pain scores significantly decreased from baseline in all groups and, although the mean scores numerically favored the rofecoxib groups, the difference was not significantly different among groups. There was a trend for the percentage of patients with a 25% (or 6 point) improvement in total score being superior on rofecoxib versus placebo with the difference being significantly different (p <0.05) for the 50 mg. rofecoxib group. Patient global assessment of pain, response to therapy and disease activity also favored rofecoxib over placebo (p <0.05, p = 0.07, p = 0.06, respectively). Of the patients 79% on 50 mg. rofecoxib versus 59% on placebo reported no or mild pain, and 56% of patients on 50 mg. rofecoxib versus 27% on placebo experienced significant improvement in quality of life (p <0.005). Rofecoxib was generally well tolerated. CONCLUSIONS: To our knowledge this study is the first to evaluate rofecoxib versus placebo in patients with prostatitis and the first large multicenter treatment study to use the NIH-CPSI. Subjective assessment with patient global questions may be more sensitive to change than the NIH-CPSI and, therefore, may be a better tool to use in future therapeutic trials. Although 6 weeks of rofecoxib treatment appear to benefit many men diagnosed with chronic prostatitis/chronic pelvic pain syndrome further studies are needed.

A comparison of adverse renovascular experiences among osteoarthritis patients treated with rofecoxib and comparator non-selective non-steroidal anti-inflammatory agents.

BACKGROUND: Non-selective non-steroidal anti-inflammatory drugs (NSAIDs) inhibit both cyclo-oxygenase (COX) isoenzymes, i.e. COX-1 and COX-2. Rofecoxib, an agent that selectively inhibits COX-2, has been shown to provide equivalent anti-inflammatory and analgesic efficacy to comparator non-selective NSAIDs in osteoarthritis (OA) and other pain models with a significant improvement in gastrointestinal (GI) safety and tolerability. Based on renal physiology studies, it was predicted that rofecoxib would have renovascular effects similar to those observed with non-selective NSAIDs--specifically edema, blood pressure elevation, attenuation of the effects of ACE inhibitors, and (in rare circumstances), acute renal failure might be manifest in a small percentage of patients. OBJECTIVE: To assess the renovascular safety profile of rofecoxib in OA patients compared to that of non-selective NSAID comparators. METHODS: Renovascular adverse experiences (AEs) in over 5,000 participants in Phase IIb/III OA clinical trials were reviewed and compared between rofecoxib and non-selective NSAID comparators (ibuprofen 800mg tid, diclofenac 50 mg tid, nabumetone 1,500 mg qd). RESULTS: The incidence of lower extremity edema (LEE) AEs was generally similar between rofecoxib 12.5 mg/day, rofecoxib 25 mg/day, and non-selective comparator NSAIDs. Treatment discontinuations due to LEE AEs and clinically significant weight gain (> or = 2 kg) associated with LEE AEs were infrequent and generally similar in all active treatment groups. Congestive heart failure (CHF) was rare in all treatment groups. The incidence of hypertension AEs was low in all active treatment groups. Discontinuations due to hypertension AEs and hypertension AEs requiring a change or adjustment in blood pressure medications were similar and uncommon in all treatment groups. There was only a single report of acute renal failure (in the ibuprofen treatment group). CONCLUSIONS: In the rofecoxib phase IIb/III OA database, the renal safety profile for rofecoxib, a selective inhibitor of COX-2, was generally similar to that of the comparator, non-selective NSAIDs which were studied.

Integration of bilateral whisker stimuli in rats: role of the whisker barrel cortices.

Recently, we demonstrated that neural responses within the whisker region of the primary somatosensory cortex (SIw) of rats are profoundly influenced by the spatiotemporal attributes of ipsilateral, as well as contralateral, whisker stimuli. As inactivation of one SIw eliminates in the intact SIw both ipsilaterally evoked responses and the influence of ipsilateral stimulation on contralaterally evoked activity, we proposed that interhemispheric interactions between the SIws may be important for integrating bilateral whisker information. To test whether rats can recognize the bilateral nature of a whisker stimulus, we developed a tactile discrimination task that required rats to conjointly determine distances to a left and a right discriminandum as equidistant or non-equidistant using only their facial whiskers. All rats trained in this task achieved performance levels indicative of an ability to integrate bilateral whisker information. Testing during unilateral, as well as bilateral, inactivation of the SIws indicated that rats rely on both SIws for detecting the bilateral nature of a whisker stimulus. Rats were unable to perform the task without both sets of whiskers, a fact that indicates that the whiskers (and not other modalities) were used to perform this task. The findings presented here indicate that rats can solve a task that requires the conjoint detection of left and right whisker-mediated distance information and implicate the SIws as central to this ability.