A hypotonic aqueous nasal spray of ciclesonide is indicated for the treatment of allergic rhinitis (AR). A new nasal aerosol formulation of ciclesonide containing a hydrofluoroalkane propellant ...delivered via a metered-dose inhaler (CIC-HFA) is currently in clinical development as a potential treatment for AR.
To study the efficacy and safety of once-daily administration of CIC-HFA 80 or 160 μg compared with placebo in subjects 12 years and older with seasonal AR (SAR).
Subjects 12 years and older with a ≥ 2-year history of SAR were randomized in a placebo-controlled, double-blind, parallel-group, multicenter study to receive CIC-HFA 80 or 160 μg or placebo once daily in the morning for 2 weeks. Changes from baseline in reflective total nasal symptom scores (rTNSSs), instantaneous TNSSs (iTNSSs), and reflective total ocular symptom scores (rTOSSs) in subjects with a baseline rTOSS of ≥ 5.00 were evaluated. Treatment-emergent adverse events were monitored throughout the study.
Seven hundred seven subjects were randomized. From baseline, CIC-HFA 80 or 160 μg demonstrated 15.1% and 16.0% reductions in rTNSSs (P < .0001, 3.7% for placebo), 14.3% and 15.4% reductions in iTNSSs (P < .0001, 3.9% for placebo), and 15.7% and 15.0% reductions in rTOSSs (P < .001, 6.8% for placebo). The overall incidence of treatment-emergent adverse events was low and comparable between the CIC-HFA and placebo groups.
In this study, once-daily treatment with CIC-HFA 80 or 160 μg demonstrated statistically significant improvements in nasal and ocular symptoms of SAR. Both doses of active treatment were well tolerated.
The cat flea (Ctenocephalides felis) is the most common flea species parasitising both domestic cats and dogs globally. Fleas are known vectors of zoonotic pathogens such as vector-borne Rickettsia ...spp. and Bartonella spp. and could theoretically transmit Coxiella burnetii, the causative agent of Q fever. A total of 107 fleas were collected from 21 cats and 14 dogs in veterinary clinics, a feline rescue organisation and a grooming salon in New South Wales, Australia, to undergo PCR detection of Bartonella spp., Rickettsia spp. and C. burnetii DNA. Morphological identification confirmed that the cat flea (C. felis) is the most common flea in New South Wales, Australia, with only a single stick fast flea, Echidnophaga gallinacea recorded. The examined fleas (n = 35) at the cox1 locus revealed five closely related C. felis haplotypes (inter-haplotype distance < 0.5%). Multiplex TaqMan qPCR targeting the gltA (Rickettsia spp.) and ssrA (Bartonella spp.) genes was positive in 22.9% (95% CI: 11.8–39.3%) and 11.4% (95% CI: 3.9–26.6%) of samples, respectively. None of the DNA isolated from fleas was positive on TaqMan qPCRs targeting the C. burnetii IS1111, Com1 and htpAB genes. Co-infection of C. felis with Bartonella henselae and Bartonella clarridgeiae was demonstrated using gltA and ssrA Illumina next-generation amplicon sequencing. These findings reinforce the importance of flea control on domestic dogs and cats to effectively control the transmission of Rickettsia felis and Bartonella spp. The flea, however, is unlikely to be a vector of C. burnetii between companion animals and humans.
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•The cat flea (Ctenocephalides felis) is the flea species on cats and dogs in New South Wales Australia.•Absence of Coxiella burnetii DNA in flea extract, but presence of Rickettsia felis.•Detection of Bartonella DNA using gltA and ssrA Illumina next-generation amplicon sequencing.
ITCA 650 (exenatide in osmotic mini-pump) continuously delivers exenatide subcutaneously for 3-6 months. Two doses of ITCA 650 were compared with placebo in patients with uncontrolled type 2 ...diabetes.
This 39-week, phase 3, double-blind, placebo-controlled trial randomized 460 patients aged 18-80 years with glycated hemoglobin (HbA
) 7.5-10% 58-86 mmol/mol 1:1:1 to placebo, ITCA 650 40 μg/day, or ITCA 650 60 μg/day. Primary end point was change in HbA
at 39 weeks.
Least squares (LS) mean change from baseline HbA
was -1.1% -12.2 mmol/mol and -1.2% -13.2 mmol/mol for ITCA 650 40 and 60 μg/day, respectively (
< 0.001 vs. placebo -0.1% -1.3 mmol/mol). In a prespecified analysis, greater HbA
reductions occurred in patients not receiving sulfonylureas (SUs) versus those receiving SUs (-1.7% vs. -1.2% -18.6 and -13.1 mmol/mol). At week 39, HbA
<7% 53 mmol/mol was attained in 37%, 44%, and 9% of ITCA 650 40 μg/day, ITCA 650 60 μg/day, and placebo groups, respectively (
< 0.001 each dose vs. placebo). LS mean change from baseline body weight was -2.3 kg and -3.0 kg for ITCA 650 40 and 60 μg/day, respectively (
≤ 0.015 vs. placebo -1.0 kg). Nausea was the most common adverse event (AE) and subsided over time. Discontinuation for gastrointestinal AEs occurred in 7.2% with ITCA and 1.3% with placebo. Most AEs associated with procedures to place and remove ITCA 650 were mild and transient.
ITCA 650 significantly reduced HbA
and weight compared with placebo and was well tolerated in patients with uncontrolled type 2 diabetes on oral antidiabetes medications.
Children with acute myeloid leukemia (AML) are commonly treated using a daunorubicin-cytarabine ±etoposide (DA/ADE) backbone as developed by the Medical Research Council (MRC) AML 12 trial and since ...adopted by the Children's Oncology Group (COG). This regimen is an anthracycline-intensive regimen, incorporating mitoxantrone in the consolidation phase, with a stated cumulative cardiotoxic exposure of ~444 mg/m 2 doxorubicin equivalents, though recent data suggests mitoxantrone is more cardiotoxic than previously considered (~10x more cardiotoxic than doxorubicin instead of 3x). The MRC AML15 trial randomized DA/ADE versus fludarabine-cytarabine-idarubicin (FLAG-Ida) and found superior event-free survival (EFS) from FLAG-Ida, with fewer cycles of intensive chemotherapy (4 vs 5), and less than half the cardiotoxic exposure, potentially reducing acute and long-term morbidity. Experience with FLAG-Ida as frontline therapy in children with de novo AML is limited. Following MRC 15, minimal residual disease (MRD) monitoring has become standard of care for risk stratification in AML, but MRD data for the FLAG-Ida regimen in children has not yet been reported.
We collected data from 30 pediatric patients (age 0.3-20.0 years) with newly diagnosed de novo AML (no preceding myelodysplastic syndrome, secondary AML, or prior malignancy) and no underlying genetic disease (e.g., Trisomy 21, Fanconi Anemia, Kostmann Syndrome, Shwachman-Diamond Syndrome) treated at our institution with MRC 15-style FLAG-Ida between 2014 and 2021 (Table 1). Each case was characterized by cytogenetics, chromosomal microarray analysis (since 2015, in 29/30), and a proprietary molecular testing panel (since 2017, in 21/30); AML risk category was assigned at diagnosis using the contemporary COG classification (AAML1831). Following Induction I and II, MRD was measured in each patient by multiparameter flow cytometry using a ‘difference from normal’ approach (MRD+ defined by contemporary COG threshold, MRD≥0.05%). Patients with poor disease response (MRD+) or high-risk cytogenetics proceeded to hematopoietic stem cell transplantation (HSCT) in first remission. Patients routinely received antimicrobial prophylaxis with sulfamethoxazole-trimethoprim, an azole or echinocandin, and levofloxacin. The study was approved by the Institutional Review Board.
Following Induction I, 28/30 (93%) patients were MRD negative, and 30/30 (100%) patients following Induction II. Only 1/20 (5%) patients without high-risk AML required HSCT for slow-responding disease; 1/30 (3%) patients were unable to proceed to consolidation (prolonged myelosuppression). No patient developed treatment-related mortality (TRM) during pre-HSCT chemotherapy (2 subsequent to HSCT). Cardiac evaluation in surviving patients was normal (LVSF>28%) post-therapy in 23/24 (96%). Median survival for patients alive at last follow-up was 2.3 years with overall 3-year EFS and overall survival (OS) of 73±9% and 80±8%, respectively (Figure 1A). Survival for patients in the low-risk subset is depicted (Figure 1B, 1C); all low-risk patients were alive at last follow-up.
FLAG-Ida was well tolerated and effective in our pediatric AML population with no TRM, excellent early disease response by MRD, and encouraging albeit early EFS and OS. This compares favorably with the adult MRC AML 15 experience as well as with the COG DA/ADE regimen, particularly for MRD response (in AAML0531, ~30% patients were MRD+ following Induction I Brodersen et al 2020). These data support our continued use of FLAG-Ida in pediatric AML alone or in combination with targeted and/or molecular therapies. Further study of FLAG-Ida as frontline therapy in children with AML is warranted.
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Gaynon: Takeda pharmaceuticals: Other: member of DSMC committee. Orgel: Jazz Pharmaceuticals: Consultancy.
ITCA 650 consists of a small titanium osmotic mini-pump that is subdermally placed in the abdominal wall during a brief office procedure. As an investigational product for the treatment of type 2 ...diabetes (T2D), ITCA 650 provides a continuous subcutaneous infusion of exenatide over 3 or 6 months. An integrated analysis of efficacy and safety was conducted from 2 double-blind, randomized, Phase 3 studies, which evaluated pooled data with ITCA 650 20/60 mcg/d vs. placebo or sitagliptin for the treatment of patients with T2D, inadequately controlled on antidiabetic drugs. The efficacy endpoints were mean change from baseline at Week 39 for HbA1c, body weight, composite endpoints of HbA1c and weight loss, and proportion achieving HbA1c <7%. The incidence of treatment-emergent adverse events (TEAEs) was also reported. Significant and clinically meaningful improvements at 39 weeks were observed with ITCA 650 20/60 mcg/d for all these endpoints. The higher incidence of TEAEs with ITCA 650 vs. comparators was explained by the higher incidence of GI TEAEs. Similar proportions of patients in each group discontinued for TEAEs. The results are consistent with results observed from individual Phase 3 studies, which demonstrated that ITCA 650 is effective for lowering HbA1c and weight, for achieving a composite of HbA1c/weight reduction and target HbA1c <7%, and is well tolerated.
Disclosure
L.L. Kjems: Employee; Self; Intarcia Therapeutics, Inc.. Stock/Shareholder; Self; Intarcia Therapeutics, Inc.. P. Prabhakar: None. B. Schwartz: Employee; Self; Intarcia Therapeutics, Inc.. H. Huang: None. M.A. Baron: Employee; Self; Intarcia Therapeutics, Inc..
ITCA 650 consists of a small titanium osmotic mini—pump that is subdermally placed in the abdominal wall during a brief in-office procedure. As an investigational product for the treatment of type 2 ...diabetes (T2D), ITCA 650 provides a continuous subcutaneous infusion of exenatide over 3 or 6 months. Pooled 39-week data from two double-blind, randomized, Phase 3 studies were used to evaluate the efficacy of ITCA 650 20/60 mcg/d in patients with T2D inadequately controlled by oral antidiabetic drugs (OADs). Results in the overall population (N=683) and in subgroups according to age, gender, BMI, ethnicity, time since diagnosis, baseline HbA1c, GI adverse events, presence of anti-drug antibodies, and renal function are reported. As shown in the Figure, the overall mean (standard deviation SD) reduction in HbA1c (%) was 1.5% (1.2) with clinically meaningful reductions in HbA1c consistently observed irrespective of age, gender, BMI, ethnicity, time from T2D diagnosis, eGFR and background OADs (data not shown). Patients with a higher baseline HbA1c had a greater response. Mean weight loss was 3.4 kg (SD 4.7), and 40.7% (95% CI 0.36-0.46) of patients achieved a composite endpoint of HbA1c/weight reduction of >0.5%/≥2 kg. Similar changes were likewise seen consistently across subgroups. ITCA 650 demonstrated consistent efficacy across a wide spectrum of patients with T2D.
Disclosure
P. Prabhakar: None. L.L. Kjems: Employee; Self; Intarcia Therapeutics, Inc.. Stock/Shareholder; Self; Intarcia Therapeutics, Inc.. H. Huang: None. B. Schwartz: Employee; Self; Intarcia Therapeutics, Inc. M.A. Baron: Employee; Self; Intarcia Therapeutics, Inc..
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Background: Patients (pts) with metastatic EGFR-mutated NSCLC who have progressed on osimertinib have limited treatment options. Dual EGFR with HER2 blockade results in complete and long-term ...reversal of osimertinib resistance in preclinical models. Methods: This is an investigator-initiated, single arm, open label phase 1b/2 study to identify the recommended phase 2 dose (RP2D), safety, tolerability, and preliminary efficacy of the combination of osimertinib, necitumumab, and trastuzumab (ONT) in adults with histologically confirmed, metastatic NSCLC with an activating and sensitizing EGFR mutation who have progressed on osimertinib as their most recent treatment. Study pts receive daily oral osimertinib in conjunction with necitumumab and trastuzumab intravenously every other week. In phase 1b, a 3+3 dose-escalation design is used to determine the RP2D (Table 1). In phase 2, if ≥ 2 responses are seen out of 10 pts treated at the RP2D, an additional 10 pts will be accrued. Patient reported outcomes (PRO-CTCAE) and quality of life (FACT-L) data are collected prospectively. Efficacy is assessed as objective response rate (ORR) based on RECIST 1.1 criteria. Results: 22 pts (median age = 63; range = 40-82) have been enrolled and treated. The most commonly observed treatment-related AEs seen at any DL included acneiform rash (63.6%), headache (45.5%), nausea (40.9%), dry skin (36.4%), diarrhea (31.8%), paronychia (27.3%), oral mucositis (27.3%), vomiting (22.7%), fatigue (18.2%), chills (18.2%), and anorexia (18.2%). Grade 3 treatment-related toxicities were acneiform rash (22.7%), diarrhea (4.5%), decreased lymphocyte count (4.5%) and hypertension (4.5%). There were no treatment-related Grade ≥ 4 AEs. 12 evaluable pts were enrolled in phase 1b 3 at Dose Level (DL) 1, 3 at DL 2, and 6 at DL 3; 3 non-evaluable pts were replaced. Pts treated at DL 1 and DL 2 had no dose-limiting toxicities (DLTs) and 1/6 pts at DL 3 had a DLT (persistent grade 3 rash). Due to grade 2 and 3 rash and paronychiae occurring after cycle 1 at DL 3, DL2 was determined to be the RP2D.The proportion of evaluable phase 1b pts achieving partial response or stable disease was 58.3% (7/12). Seven pts have been enrolled at DL2. Conclusions: ONT toxicities are manageable, and the combination has promising preliminary efficacy in refractory EGFR-mutated metastatic NSCLC. Evaluation of phase 2, stage 1 is expected to be completed by April 2023 and will be reported at the meeting. Clinical trial information: NCT04285671 . Table: see text
Health care transition (HCT) planning supports adolescents as they move from pediatric to adult health care and is recommended for all youth. HCT planning uptake remains low, with little known about ...HCT in the adolescent well child check (WCC) setting. We sought to increase rates of HCT planning at WCCs by adapting best practices for HCT from specialty and chronic care.
This quality improvement initiative at 12 to 17-year-old WCCs at four Internal Medicine-Pediatrics primary care clinics, was based on the first three of the “Six Core Elements” of HCT framework and integrated into the electronic health record. Two uptake measures were assessed via chart review after three plan-do-study-act (PDSA) cycles, with two provider surveys and an implementation science analysis further informing interpretation.
By the final PDSA cycle, the percentage of 14 to 17-year-old WCCs at which HCT planning was discussed and a screening tool completed increased from 5% to 31%, and the percentage of 12 to 13-year-old WCCs at which the HCT policy was discussed increased from 6% to 47%. Provider survey results revealed endorsement of HCT goals, but time and technological barriers, which were further elucidated in the implementation science analysis.
This quality improvement initiative increased rates of HCT planning during adolescent WCCs. While limited to three Core Elements and Internal Medicine-Pediatrics clinics, strengths include measures capturing all WCCs, contextualized by provider surveys and an implementation science framework. Lessons from this effort can inform future tailored HCT initiatives at adolescent WCCs.
ITCA 650 is an investigational titanium osmotic mini pump that is subdermally placed in the abdominal wall during a brief office procedure to continuously deliver exenatide over 3 and 6-month periods ...and has the potential to improve medication adherence because patients do not self-administer. In this 26 week, open-label phase 3b study, 136 patients with T2D receiving liraglutide (1.2 to 1.8 mg/d) and metformin (≥1000 mg/d) were randomized to either the standard ITCA 650 dose regimen used in phase 3 trials of 20 mcg/d for 13 weeks followed by a 60 mcg/d maintenance dose (for 13 weeks in this study) or starting directly with the maintenance dose of 60 mcg/d for 26 weeks. The last injection of liraglutide occurred 2 days prior to randomization. The primary endpoint compared the incidence of nausea (N) and vomiting (V) between the two dose regimens. Switching from liraglutide to either dose regimen of ITCA 650 had a similar incidence of transient mild to moderate N/V (Table). Of note, 3 sites, which recruited 25% of the study population, accounted for 47% and 68% of the total N/V seen in the study. 4 patients discontinued due to GI AEs. Glycemic control remained stable in both groups. At Week 26, significant weight reduction was observed in both groups (p<0.vs. baseline).
In conclusion, patients on stable liraglutide therapy can be switched to ITCA 650 60 mcg/d without the need for up-titration from a lower dose.
Disclosure
N. Rasouli: Consultant; Self; AstraZeneca, Intarcia Therapeutics, Inc. J. Rosenstock: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company. Research Support; Self; Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc.. Advisory Panel; Self; Sanofi. Consultant; Self; Sanofi. Advisory Panel; Self; Janssen Pharmaceuticals, Inc.. Consultant; Self; Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Intarcia Therapeutics, Inc.. Consultant; Self; Intarcia Therapeutics, Inc.. Research Support; Self; Merck & Co., Inc., Pfizer Inc., Sanofi, Novo Nordisk Inc., Bristol-Myers Squibb Company, Eli Lilly and Company, Intarcia Therapeutics, Inc., Genentech, Inc.. S. Nakhle: None. B. Schwartz: Employee; Self; Intarcia Therapeutics, Inc.. P. Prabhakar: None. S.L. Kruger: None. H. Huang: None. M.A. Baron: Employee; Self; Intarcia Therapeutics, Inc..
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