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The American Journal of Geriatric... Feb 2020Elderly patients with major depression have a poorer prognosis, are less responsive to treatment, and show greater functional decline compared with younger patients,... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Elderly patients with major depression have a poorer prognosis, are less responsive to treatment, and show greater functional decline compared with younger patients, highlighting the need for effective treatment.
METHODS
This phase 3 double-blind study randomized patients with treatment-resistant depression (TRD) ≥65 years (1:1) to flexibly dosed esketamine nasal spray and new oral antidepressant (esketamine/antidepressant) or new oral antidepressant and placebo nasal spray (antidepressant/placebo). The primary endpoint was change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to day 28. Analyses included a preplanned analysis by age (65-74 versus ≥75 years) and post-hoc analyses including age at depression onset.
RESULTS
For the primary endpoint, the median-unbiased estimate of the treatment difference (95% CI) was -3.6 (-7.20, 0.07); weighted combination test using MMRM analyses z = 1.89, two-sided p = 0.059. Adjusted mean (95% CI) difference for change in MADRS score between treatment groups was -4.9 (-8.96, -0.89; t = -2.4, df = 127; two-sided nominal p = 0.017) for patients 65 to 74 years versus -0.4 (-10.38, 9.50; t = -0.09, two-sided nominal p = 0.930) for those ≥75 years, and -6.1 (-10.33, -1.81; t = -2.8, df = 127; two-sided nominal p = 0.006) for patients with depression onset <55 years and 3.1 (-4.51, 10.80; t = 0.8, two-sided nominal p = 0.407) for those ≥55 years. Patients who rolled over into the long-term open-label study showed continued improvement with esketamine following 4 additional treatment weeks.
CONCLUSIONS
Esketamine/antidepressant did not achieve statistical significance for the primary endpoint. Greater differences between treatment arms were seen for younger patients (65-74 years) and patients with earlier onset of depression (<55 years).
Topics: Administration, Oral; Age Factors; Aged; Aged, 80 and over; Antidepressive Agents; Depressive Disorder, Treatment-Resistant; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Ketamine; Male; Nasal Sprays; Treatment Outcome
PubMed: 31734084
DOI: 10.1016/j.jagp.2019.10.008 -
Clinical Pharmacology and Therapeutics Feb 2021This post hoc analysis assessed the benefit-risk profile of esketamine nasal spray + oral antidepressant (AD) induction and maintenance treatment in patients with... (Observational Study)
Observational Study Randomized Controlled Trial
This post hoc analysis assessed the benefit-risk profile of esketamine nasal spray + oral antidepressant (AD) induction and maintenance treatment in patients with treatment-resistant depression (TRD). The Benefit-Risk Action Team framework was utilized to assess the benefit-risk profile using data from three induction studies and one maintenance study. Benefits were proportion of remitters or responders in induction studies and proportion of stable remitters or stable responders who remained relapse-free in the maintenance study. Risks were death, suicidal ideation, most common adverse events (AEs), and potential long-term risks. Per 100 patients on esketamine + AD vs. AD + placebo in induction therapy, 5-21 additional patients would remit and 14-17 additional patients would respond. In maintenance therapy, 19-32 fewer relapses would occur with esketamine. In both cases, there was little difference in serious or severe common AEs (primarily dissociation, vertigo, and dizziness). These findings support a positive benefit-risk balance for esketamine + AD as induction and maintenance treatment in patients with TRD.
Topics: Administration, Oral; Adolescent; Adult; Aged; Antidepressive Agents; Depressive Disorder, Treatment-Resistant; Double-Blind Method; Female; Humans; Ketamine; Male; Middle Aged; Nasal Sprays; Prospective Studies; Risk Assessment; Treatment Outcome; Young Adult
PubMed: 32860422
DOI: 10.1002/cpt.2024 -
The Journal of Clinical Psychiatry May 2020To compare esketamine to placebo, each in addition to standard-of-care treatment, for rapidly reducing major depressive disorder symptoms, including suicidal ideation. (Randomized Controlled Trial)
Randomized Controlled Trial
Esketamine Nasal Spray for Rapid Reduction of Major Depressive Disorder Symptoms in Patients Who Have Active Suicidal Ideation With Intent: Double-Blind, Randomized Study (ASPIRE I).
OBJECTIVE
To compare esketamine to placebo, each in addition to standard-of-care treatment, for rapidly reducing major depressive disorder symptoms, including suicidal ideation.
METHODS
This phase 3, double-blind, multicenter study (ASPIRE I), conducted between June 2017 and December 2018, enrolled 226 adults having major depressive disorder based on Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5) criteria, active suicidal ideation with intent, and need for psychiatric hospitalization. Patients were randomized 1:1 to esketamine 84 mg or placebo nasal spray twice-weekly for 4 weeks, each with comprehensive standard-of-care treatment (initial psychiatric hospitalization and newly initiated or optimized oral antidepressant[s] therapy). Change from baseline to 24 hours post-first dose in Montgomery-Asberg Depression Rating Scale (MADRS) total score (primary endpoint) was analyzed using analysis of covariance (ANCOVA), and change in Clinical Global Impression of Severity of Suicidality Revised version (CGI-SS-r; key secondary endpoint) score was analyzed using ANCOVA on ranks with treatment difference estimated using the Hodges-Lehmann estimate.
RESULTS
Greater improvement in MADRS total score was observed with esketamine + standard-of-care versus placebo + standard-of-care at 24 hours (least-squares mean difference [SE]: -3.8 [1.39]; 95% CI, -6.56 to -1.09; 2-sided P = .006), as well as at earlier (4 hours) and later time points during 4-week double-blind treatment. The difference between groups in the severity of suicidality was not statistically significant (median of treatment difference [95% CI]: 0.0 [-1.00 to 0.00]; 2-sided P = .107). The most common adverse events among esketamine-treated patients were dizziness, dissociation, headache, nausea, and somnolence.
CONCLUSIONS
These findings demonstrate rapid and robust efficacy of esketamine nasal spray in reducing depressive symptoms in severely ill patients with major depressive disorder who have active suicidal ideation with intent.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT03039192.
Topics: Administration, Intranasal; Adolescent; Adult; Antidepressive Agents; Depressive Disorder, Major; Double-Blind Method; Female; Humans; Ketamine; Male; Middle Aged; Nasal Sprays; Suicidal Ideation; Young Adult
PubMed: 32412700
DOI: 10.4088/JCP.19m13191 -
The International Journal of... Jan 2021Patients with major depressive disorder (MDD) having active suicidal ideation with intent require immediate treatment. (Randomized Controlled Trial)
Randomized Controlled Trial
Esketamine Nasal Spray for Rapid Reduction of Depressive Symptoms in Patients With Major Depressive Disorder Who Have Active Suicide Ideation With Intent: Results of a Phase 3, Double-Blind, Randomized Study (ASPIRE II).
BACKGROUND
Patients with major depressive disorder (MDD) having active suicidal ideation with intent require immediate treatment.
METHODS
This double-blind study (ASPIRE II) randomized adults (aged 18-64 years) with MDD having active suicidal ideation with intent to esketamine 84 mg or placebo nasal spray twice weekly for 4 weeks, given with comprehensive standard of care (hospitalization ≥5 days and newly initiated or optimized oral antidepressant[s]). Change from baseline to 24 hours post-first dose in Montgomery-Asberg Depression Rating Scale total score (primary efficacy endpoint) was analyzed using ANCOVA. Clinical Global Impression-Severity of Suicidality-revised (key secondary endpoint) was analyzed using ANCOVA on ranks of change.
RESULTS
Of 230 patients who were randomized (115 per arm), 227 received study drug and were included in efficacy/safety analyses; 184 (80.0%) completed double-blind treatment. Greater improvement in Montgomery-Asberg Depression Rating Scale total score was observed with esketamine (mean [SD]: -15.7 [11.56]) vs placebo (-12.4 [10.43]), each with standard of care, at 24 hours (least-squares mean difference [SE]: -3.9 [1.39], 95% CI: -6.60, -1.11; 2-sided P = .006). This was also noted at the earlier (4-hour) timepoint (least-squares mean difference -4.2, 95% CI: -6.38, -1.94). Patients in both treatment groups experienced rapid reduction in Clinical Global Impression-Severity of Suicidality-revised score; the between-group difference was not statistically significant. The most common adverse events among esketamine-treated patients were dizziness, dissociation, nausea, dysgeusia, somnolence, headache, and paresthesia.
CONCLUSION
This study confirmed rapid and robust reduction of depressive symptoms with esketamine nasal spray in severely ill patients with MDD who have active suicidal ideation with intent. Trial Registration: Clinical Trials.gov identifier: NCT03097133.
Topics: Administration, Intranasal; Adolescent; Adult; Antidepressive Agents; Depressive Disorder, Major; Double-Blind Method; Female; Humans; Ketamine; Male; Middle Aged; Nasal Sprays; Outcome Assessment, Health Care; Patient Acuity; Suicidal Ideation; Young Adult
PubMed: 32861217
DOI: 10.1093/ijnp/pyaa068 -
The Journal of Clinical Psychiatry Apr 2020To evaluate long-term safety and efficacy of esketamine nasal spray plus a new oral antidepressant (OAD) in patients with treatment-resistant depression (TRD).
Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2).
OBJECTIVE
To evaluate long-term safety and efficacy of esketamine nasal spray plus a new oral antidepressant (OAD) in patients with treatment-resistant depression (TRD).
METHODS
This phase 3, open-label, multicenter, long-term (up to 1 year) study was conducted between October 2015 and October 2017. Patients (≥ 18 years) with TRD (DSM-5 diagnosis of major depressive disorder and nonresponse to ≥ 2 OAD treatments) were enrolled directly or transferred from a short-term study (patients aged ≥ 65 years). Esketamine nasal spray (28-mg, 56-mg, or 84-mg) plus new OAD was administered twice a week in a 4-week induction (IND) phase and weekly or every-other-week for patients who were responders and entered a 48-week optimization/maintenance (OP/MAINT) phase.
RESULTS
Of 802 enrolled patients, 86.2% were direct-entry and 13.8% were transferred-entry; 580 (74.5%) of 779 patients who entered the IND phase completed the phase, and 150 (24.9%) of 603 who entered the OP/MAINT phase completed the phase. Common treatment-emergent adverse events (TEAEs) were dizziness (32.9%), dissociation (27.6%), nausea (25.1%), and headache (24.9%). Seventy-six patients (9.5%) discontinued esketamine due to TEAEs. Fifty-five patients (6.9%) experienced serious TEAEs. Most TEAEs occurred on dosing days, were mild or moderate in severity, and resolved on the same day. Two deaths were reported; neither was considered related to esketamine. Cognitive performance generally either improved or remained stable postbaseline. There was no case of interstitial cystitis or respiratory depression. Treatment-emergent dissociative symptoms were transient and generally resolved within 1.5 hours postdose. Montgomery-Åsberg Depression Rating Scale total score decreased during the IND phase, and this reduction persisted during the OP/MAINT phase (mean [SD] change from baseline of respective phase to endpoint: IND, -16.4 [8.76]; OP/MAINT, 0.3 [8.12]).
CONCLUSIONS
Long-term esketamine nasal spray plus new OAD therapy had a manageable safety profile, and improvements in depression appeared to be sustained in patients with TRD.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT02497287.
Topics: Administration, Intranasal; Administration, Oral; Adolescent; Adult; Aged; Antidepressive Agents; Cognition; Depressive Disorder, Treatment-Resistant; Drug Therapy, Combination; Female; Humans; Ketamine; Male; Middle Aged; Nasal Sprays; Young Adult
PubMed: 32316080
DOI: 10.4088/JCP.19m12891 -
The Journal of Clinical Investigation Mar 2021BACKGROUNDTo understand the features of a replicating vaccine that might drive potent and durable immune responses to transgene-encoded antigens, we tested a... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUNDTo understand the features of a replicating vaccine that might drive potent and durable immune responses to transgene-encoded antigens, we tested a replication-competent adenovirus type 4 encoding influenza virus H5 HA (Ad4-H5-Vtn) administered as an oral capsule or via tonsillar swab or nasal spray.METHODSViral shedding from the nose, mouth, and rectum was measured by PCR and culturing. H5-specific IgG and IgA antibodies were measured by bead array binding assays. Serum antibodies were measured by a pseudovirus entry inhibition, microneutralization, and HA inhibition assays.RESULTSAd4-H5-Vtn DNA was shed from most upper respiratory tract-immunized (URT-immunized) volunteers for 2 to 4 weeks, but cultured from only 60% of participants, with a median duration of 1 day. Ad4-H5-Vtn vaccination induced increases in H5-specific CD4+ and CD8+ T cells in the peripheral blood as well as increases in IgG and IgA in nasal, cervical, and rectal secretions. URT immunizations induced high levels of serum neutralizing antibodies (NAbs) against H5 that remained stable out to week 26. The duration of viral shedding correlated with the magnitude of the NAb response at week 26. Adverse events (AEs) were mild, and peak NAb titers were associated with overall AE frequency and duration. Serum NAb titers could be boosted to very high levels 2 to 5 years after Ad4-H5-Vtn vaccination with recombinant H5 or inactivated split H5N1 vaccine.CONCLUSIONReplicating Ad4 delivered to the URT caused prolonged exposure to antigen, drove durable systemic and mucosal immunity, and proved to be a promising platform for the induction of immunity against viral surface glycoprotein targets.TRIAL REGISTRATIONClinicalTrials.gov NCT01443936 and NCT01806909.FUNDINGIntramural and Extramural Research Programs of the NIAID, NIH (U19 AI109946) and the Centers of Excellence for Influenza Research and Surveillance (CEIRS), NIAID, NIH (contract HHSN272201400008C).
Topics: Adenoviruses, Human; Administration, Oral; Adolescent; Adult; Antibodies, Neutralizing; Antibodies, Viral; Antigens, Viral; Female; Genetic Vectors; Hemagglutinin Glycoproteins, Influenza Virus; Humans; Immunity, Cellular; Immunity, Humoral; Immunity, Mucosal; Influenza A Virus, H5N1 Subtype; Influenza Vaccines; Influenza, Human; Male; Nasal Sprays; Palatine Tonsil; Virus Replication; Virus Shedding; Young Adult
PubMed: 33529172
DOI: 10.1172/JCI140794 -
International Journal of Nursing Studies Jun 2022When a patient emerges from cardiac surgery, they may experience intense thirst and discomfort or even impaired swallowing after endotracheal extubation. This may lead... (Randomized Controlled Trial)
Randomized Controlled Trial
Effects of a spray-based oropharyngeal moisturising programme for patients following endotracheal extubation after cardiac surgery: A randomised, controlled three-arm trial.
BACKGROUND
When a patient emerges from cardiac surgery, they may experience intense thirst and discomfort or even impaired swallowing after endotracheal extubation. This may lead to feelings of suffocation, desperation, fear, and anxiety. Although thirst relief and dysphagia prevention share similar mechanisms, there is limited evidence for a combined intervention to alleviate thirst and prevent dysphagia. Furthermore, no studies to date have targeted postoperative cardiac patients.
OBJECTIVE
To evaluate the safety, feasibility, and effects of a spray-based oropharyngeal moisturising programme for cardiac surgery patients following endotracheal extubation.
DESIGN
A randomised, controlled three-arm trial was conducted from October 2017 to December 2019.
SETTING
Tertiary medical centre cardiac care unit.
PARTICIPANTS
Participants (N = 145) were patients who underwent cardiac surgery and received mechanical ventilation.
METHODS
Participants were randomly assigned to one of three groups: a four-part programme offering spray-based therapy with either a constant low-temperature cold spray (programme A; n = 47) or low-to-normal temperature spray (programme B; n = 49), or those that received usual care (control group; n = 49). Control group patients who complained of thirst were given wet cotton swabs to moisten their mouths. The primary outcomes included discomfort and various levels of thirst intensity; secondary outcomes included dysphagia and adverse events. Outcomes were evaluated at Time 0 (baseline), Time 1 (3 h), Time 2 (6 h) and Time 3 (96 h) post intervention. Repeated-measures analyses was performed using generalised estimating equations.
RESULTS
The baseline evaluation indicated no significant differences between the groups. Participants (average age: 55 years; 53.8% men) underwent cardiac surgery for; valvular heart disease (64.8%), coronary atherosclerotic heart disease (25.5%), or aortic dissection (9.7%). Baseline scores indicated moderately severe thirst (6.24±1.57) and discomfort (9.88±2.23). Post intervention, the thirst intensity in the intervention groups was significantly lower than that of the control group (p<0.001). The generalised estimating equation analysis showed no significant difference in reduced thirst intensity between programmes A and B (adjusted β=0.08, 95% CI: -0.59-0.76, p = 0.810) when controlling for intervention condition and time. Comparable results were found for reduced thirst discomfort (adjusted β=0.36, 95% CI: -0.66-1.38, p = 0.493). The three groups showed no significant differences for dysphagia frequency. No observable adverse events were reported during the intervention period.
CONCLUSIONS
A spray-based oropharyngeal moisturising programme is a practical and effective intervention to alleviate patient thirst after cardiac surgery and tracheal intubation that could be integrated into comfort care for post-surgical patients' critical care management.
TWEETABLE ABSTRACT
A spray-based oropharyngeal moisturising programme for cardiac surgery recipients following endotracheal extubation may alleviate thirst.
Topics: Airway Extubation; Cardiac Surgical Procedures; Deglutition Disorders; Female; Humans; Male; Middle Aged; Mouth; Respiration, Artificial
PubMed: 35421771
DOI: 10.1016/j.ijnurstu.2022.104214