Change In Total Symptom Score Research Articles

The long-term efficacy of intra-cervical lymphatic immunotherapy on adults with allergic rhinitis: A randomized controlled study.

The efficacy and safety of the novel immunotherapy method, intra-cervical lymphatic immunotherapy (ICLIT), need to be investigated. Comparing it with subcutaneous immunotherapy (SCIT), we clarified the long-term efficacy and safety of intra-cervical lymphatic immunotherapy on allergic rhinitis (AR), and investigated the improvement of clinical efficacy of the booster injection at 1year after ICLIT treatment. Ninety adult patients with dust mite allergy were randomly divided into 3 groups: 30 in the SCIT group, 30 in the ILCLIT group, and 30 in ICLIT booster group. Changes in total symptom score (TSS), nasal symptom score (TNSS), ocular symptom score (TOSS) and total medication score (TMS) were evaluated in the three groups. Adverse reactions were recorded, and serum dust mite specific IgE (sIgE) and specific IgG4 were assessed in the ICLIT group and ICLIT booster group. TSS, TNSS, TOSS, and TMS scores were significantly lower in the three groups at 36months after treatment (p<0. 05). And at 36months the ICLIT-booster group showed results similar to SCIT and superior to ICLIT (p<0. 05). Serum specific IgE decreased in all three groups at 12 and 36months after treatment, p<0.01. The ICLIT group and the ICLIT booster group showed a significant increase in sIgG4, p<0.01. None of the patients in the three groups had any serious systemic adverse effects during the 3-year follow-up. The ICLIT treatment is effective and safe on AR. One booster injection of allergens at 1year can greatly improve its long-term efficacy. Clinical trial registration number: ChiCTR1800017130.

Assessment of Minimal Clinically Important Difference in Patient-Reported Myelofibrosis-Associated Symptoms Using an Anchor-Based Analysis Based on MANIFEST Arm 3 Data

Background Myelofibrosis (MF) is a life-threatening hematologic neoplasm that can arise as a primary condition or as a progression from polycythemia vera or essential thrombocythemia. The MF Symptom Assessment Form (MFSAF) v4.0 is a seven-item questionnaire that assesses symptom severity from the patients' (pts) perspective. Each item is rated on a scale from 0 (Absent) to 10 (Worst Imaginable). The MFSAF Total Symptom Score (TSS) ranges from 0 to 70, with higher scores indicating worse symptoms. A ≥50% reduction in TSS (TSS50) is a commonly used binary endpoint in clinical trials. However, the clinical meaningfulness of the dichotomization of response at 50% cutoff across the spectrum of responses remains uncertain. The relevance of considering TSS as a continuous endpoint in MF studies is assessed here to capture the full spectrum of symptom changes, enabling a potentially more accurate assessment of treatment effects. Pelabresib (CPI-0610) is an investigational oral small-molecule BET inhibitor, while the Janus kinase inhibitors (JAKis) ruxolitinib or fedratinib are the current standard of care for intermediate- or high-risk pts with MF.InArm 3 of the Phase 2 MANIFEST trial of JAKi treatment-naïve pts with MF treated with pelabresib and ruxolitinib, 56% achieved TSS50 response at Week (Wk) 24. Aims This anchor-based analysis aims to determine the minimal clinically important difference (MCID) of change in TSS as a continuous endpoint, based on data from JAKi treatment-naïve pts with MF treated with pelabresib and ruxolitinib, to better evaluate the incremental clinical benefit of treatment effects. Methods Data from Arm 3 of the MANIFEST Phase 2 study of treatment-naïve pts with MF treated with pelabresib combined with ruxolitinib were used (July 29, 2022 data cut). Anchor-based methods compare the change in a scale-based outcome measure with that of an established patient-reported outcome (PRO). These methods are commonly used to establish the MCID, defined as the smallest difference in score that pts consider beneficial. In this analysis, the Patient Global Impression of Change (PGIC), a seven-point scale reflecting overall improvement compared with baseline (BL), was used as the anchor PRO. On the PGIC, pts rated their change from ‘very much improved’ to ‘very much worse’ (Table 1). The relationship between TSS changes (percentage and absolute) at Wk 24 and PGIC categories was examined using correlation and graphical analyses. Linear and quantile regressions were applied to assess the impact of a one-point difference in PGIC score on TSS change at Wk 24, adjusting for BL TSS score. Only pts with available TSS and PGIC data at Wk 24 were included, with no imputation for missing values. Results In Arm 3 of the MANIFEST trial, 78 of 84 pts treated with pelabresib and ruxolitinib had complete TSS data and PGIC at Wk 24. At BL, mean TSS was 16.4 (SD=8.4), and median TSS was 15.5 (range 2.0-38.3). A -58.8% and -7.7 median percentage and absolute reduction in TSS at Wk 24 was observed, respectively. For PGIC at Wk 24 (Table 1), only six pts (7.7%) scored in the three worsening PGIC categories. Percentage and absolute changes in TSS, and the percentage TSS50 responders for each PGIC category are shown in Table 1. Linear regression demonstrated that a one-category increase in PGIC (indicating worsening) corresponded to an 11.89% increase (95% CI 3.12-20.65) in TSS (indicating worsening) at Wk 24. The quantile regression estimate for this relationship was 11.36% (3.53-19.19). For absolute change at Wk 24, a one-category increase in PGIC resulted in a 1.67 (range 0.74-2.60) increase in mean TSS, with a 1.87 (range 0.62-3.12) increase in median TSS. Conclusion Assuming a one-category change in the seven-category PGIC represents a clinically meaningful difference, the analyses suggest that the MCID in TSS for JAKi treatment-naïve pts with MF could be approximately 11-12% for percentage change from BL and approximately 1.5-2 points for absolute change from BL. These findings provide valuable guidance for assessing treatment outcomes and evaluating symptom improvements' clinical significance in this patient population. Further exploration of these findings requires larger data sets, which will be addressed in the forthcoming Phase 3 MANIFEST-2 study evaluating pelabresib and ruxolitinib versus placebo and ruxolitinib in JAKi treatment-naïve pts with MF.

Transform-1: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, International Phase 3 Study of Navitoclax in Combination with Ruxolitinib Versus Ruxolitinib Plus Placebo in Patients with Untreated Myelofibrosis

Background: Janus kinase inhibitors (JAKis) provide symptom improvement and spleen volume reduction in patients with primary, post-polycythemia vera, and post-essential thrombocythemia myelofibrosis (MF). There remains a substantial unmet need for therapies that alter disease trajectory, improve outcomes, and enhance survival. The COMFORT-1 and -2 studies established JAKi monotherapy as standard-of-care with spleen volume reduction of ≥35% at Week 24 (SVR 35W24) of 42% and SVR 35W48 of 29%, respectively. In combination with the JAKi ruxolitinib, navitoclax, an orally available inhibitor of antiapoptotic B-cell lymphoma 2 proteins (BCL-X L, BCL-2, BCL-W), was shown to have pronounced antitumor activity in patients with MF in the phase 2 REFINE trial (NCT03222609). TRANSFORM-1 is an ongoing, phase 3, double-blind, placebo-controlled, multicenter, international study evaluating the safety and efficacy of navitoclax plus ruxolitinib (NAV + RUX) compared with placebo plus ruxolitinib (PBO + RUX) in JAK2i-naïve adults with MF. Methods: TRANSFORM-1 (NCT04472598) enrolled adult patients with intermediate-2 or high-risk MF with measurable splenomegaly, evidence of MF-related symptoms, no prior JAK2i treatment, and ECOG Performance Score ≤2. Patients were randomized 1:1 to receive NAV (starting dose of 200 mg [platelet {PLT} &amp;gt;150 × 10 9/L] or 100 mg escalated to 200 mg once daily if tolerated after ≥7 days [PLT ≤150 × 10 9/L]) or PBO, plus RUX at label dose, based on stratification factors of intermediate-2 vs high-risk MF and PLT ≤200 × 10 9/L vs &amp;gt;200 × 10 9/L. The primary endpoint was SVR 35W24. Secondary endpoints included change in total symptom score at Week 24 (TSS W24) assessed using 7-item MFSAF v4.0 (scale 0-70), SVR 35 at any time, duration of SVR 35, anemia response (per International Working Group criteria), reduction in marrow fibrosis, overall survival, leukemia-free survival, reduction in PROMIS Fatigue scale, and improvement in EORTC QLQ-C30 physical functioning scale. Exploratory endpoints include progression-free survival. Results: At data cutoff, April 13, 2023, 252 patients were enrolled with a median (range) follow-up of 14.9 (0.0-29.5) months; 125 patients were randomized to receive NAV + RUX and 127 to receive PBO + RUX. Most patients were male (57%), median (range) age was 69 (37-87) years, and patient demographics were similar between treatment arms ( Table 1). TRANSFORM-1 met its primary endpoint, with 79 patients (63.2%) in the NAV + RUX arm achieving SVR 35W24 compared with 40 patients (31.5%) in the PBO + RUX arm ( P&amp;lt;0.0001). Notably, SVR 35 at any time was achieved by 96 patients (77%) with NAV + RUX compared with 53 patients (42%) with PBO + RUX. Median (range) time to SVR 35 response was 12.3 (10.1-48.3) weeks with NAV + RUX versus 12.4 (11.3-72.3) weeks with PBO + RUX. Median duration of SVR 35 was not reached (NR) in the NAV + RUX arm compared with 19.4 months (95% CI 16.8, NR) in the PBO + RUX arm. At Week 24, the mean change in TSS from baseline was -9.7 (95% CI: -11.8, -7.6) with NAV + RUX compared with -11.1 (95% CI: -13.2, -9.1) with PBO + RUX arm ( P=0.2852). Grade ≥3 adverse events (AEs) were experienced by 85% of patients with NAV + RUX and 70% with PBO + RUX. The most common AEs (&amp;gt;30% of patients receiving NAV; Table 2) were thrombocytopenia, anemia, diarrhea, and neutropenia. Serious AEs were experienced by 26% of patients with NAV + RUX and 32% with PBO + RUX, including anemia (NAV + RUX: n=2; PBO + RUX: n=1), thrombocytopenia (NAV + RUX: n=2), and neutropenia (NAV + RUX: n=1). With NAV + RUX, AEs led to NAV dose reduction in 101 (81%) patients and NAV interruption in 87 (70%) patients of which 83 (67%) and 65 (52%) were due to thrombocytopenia, respectively. Of all enrolled patients, 83 (33%) discontinued study treatment; most common (&amp;gt;5% total patients) reason for NAV/PBO discontinuation were AEs (n=32; 39% of discontinuations) and physician decision (n=14; 17% of discontinuations). In each arm, 13 (10%) patients died; 6 with NAV + RUX and 5 with PBO + RUX died ≤30 days post-final dose. Conclusions: This first randomized trial in JAKi-naïve MF with NAV + RUX combination led to an SVR 35W24 rate that was twice as high as PBO + RUX ( P&amp;lt;0.0001). The responses were durable; AEs of thrombocytopenia and anemia were common but manageable with dose modification without any clinically significant sequalae. Additional evaluation is ongoing.

Effectiveness and Tolerability of Ectoin® Mouth and Throat Spray Althaea Honey (ERS09) for Sore Throat due to Acute Pharyngitis and Dry Cough: A Multicentre, Actively Controlled, Open Label Study in Germany.

Acute pharyngitis can cause sore throat. This multicentre, active-controlled, randomised, open-label, and parallel-group study, conducted according to the German Medical Devices Act, compared the effectiveness and tolerability of ERS09 mouth and throat spray with a well-established device for the treatment of sore throat caused by acute pharyngitis and dry cough. Patients were randomised 1:1 into ERS09/comparator groups (EMSER® Sore Throat Spray) for 7 ± 2 days. Patients and investigators reported effectiveness (change in total symptom score [TSS]) and safety endpoints (incidence of adverse events [AEs]; adverse device effects [ADEs]). A total of 186 patients were included (ERS09: n = 92; comparator: n = 94). The baseline-adjusted mean TSS over 7 days was -90.14 and -74.91 in the ERS09 and comparator groups, respectively (p < 0.05). The majority of patients reached a 50% reduction in symptoms by day 6 (ERS09 = 78.85; comparator = 75.8%). Most patients reported a soothing effect within five minutes (ERS09 = 82%; comparator = 71%). Improvements in individual symptoms were similar with no significant differences between groups; more patients in the ERS09 group reported an improvement in pharyngeal redness/swelling. Three AEs unrelated to medication, one ADE following ERS09, and no serious AE/ADE were reported. ERS09 was as well tolerated and effective as the established device, showing greater improvement in the management of some symptoms and greater patient preference.

Efficacy and safety of fixed-dose combination of Bilastine-Montelukast in adult patients with allergic rhinitis: a phase III, randomized, multi-center, double-blind, active controlled clinical study

Background Histamine and cysteinyl leukotrienes (CysLTs) are potent inflammatory mediators in allergic rhinitis (AR). Studies involving other combinations of antihistaminics (Levocetirizine) and highly selective leukotriene receptor antagonist (LTA) (Montelukast) combination have shown additive benefits and are widely prescribed for AR. Objective Evaluate the efficacy and safety of Bilastine 20 mg and Montelukast 10 mg fixed-dose combination (FDC) therapy in patients with AR. Methods A randomized, double-blind, comparative, parallel, phase III study was conducted to evaluate efficacy and safety of Bilastine 20 mg and Montelukast 10 mg FDC at 16 tertiary care otolaryngology centres in India. Adult patients with AR for one year with IgE antibody positive and 12-h NSS score >36 in 3 days were randomized to receive either Bilastine 20 mg and Montelukast 10 mg or Montelukast 10 mg & Levocetirizine 5 mg tablets for 4 weeks. The change in total symptom score (nasal symptom scores (NSS) & non-nasal symptom scores (NNSS)) from baseline to week 4 was assessed as primary endpoint. Secondary endpoints included changes in TSS, NSS, NNSS, individual symptom scores (ISS), Rhinoconjunctivitis Quality of Life (RQLQ), discomfort due to rhinitis (VAS), and clinical global impression (CGI) scores. Results The change in mean TSS from baseline to week 4 in Test group (16.6 units) was comparable to reference group (17 units) (p= 0.8876). The difference in change in mean NSS, NNSS and ISS from baseline to day 7, 14, 28 were comparable. RQLQ improved from baseline to Day 28. Significant improvements were observed in discomfort due to AR measured by VAS and CGI scores from baseline to day 14 and 28. The safety and tolerability of patients were comparable between the groups. All adverse events (AEs) were mild to moderate in severity. No patient discontinued due to AEs. Conclusions The FDC of Bilastine 20 mg and Montelukast 10 mg was efficacious and well tolerated in Indian patients with AR.

Improvement in Individual Symptoms and Total Symptom Score (TSS) and Matching-Adjusted Indirect Comparison (MAIC) Analysis to Compare TSS As a Continuous Endpoint in Patients with Myelofibrosis Treated with Pelabresib in Combination with Ruxolitinib Versus Janus Kinase Inhibitor Monotherapy

Background: Pelabresib (CPI-0610; PELA) is a bromodomain and extraterminal domain (BET) inhibitor in development for the treatment of myelofibrosis (MF). PELA combined with ruxolitinib (RUX) has shown a 56% response rate for ≥50% reduction in total symptom score (TSS) at Wk 24 from baseline (BL; TSS50) in Janus kinase inhibitor (JAKi) treatment-naïve patients (pts) with intermediate or high-risk MF in Arm 3 of the open-label Phase 2 MANIFEST study (NCT02158858). TSS50 is a standard measure of symptom improvement; however, the 50% response threshold does not capture clinical benefit in pts with TSS reduction <50% or pts who achieve TSS50 but could benefit from further symptom improvement (Dueck A, et al. European Hematology Association 2017. Poster E1331). Here, we present percentage change in TSS and subdomains as a continuous endpoint from Arm 3 of MANIFEST and indirect comparisons with historical double-blind JAKi trials in MF. Aims: To assess clinically meaningful changes in TSS with PELA in combination with RUX. TSS subdomains were analyzed to assess the underlying impact of PELA + RUX on symptom scores. In the absence of head-to-head studies of PELA + RUX vs JAKi monotherapy, naïve and matching-adjusted indirect comparison (MAIC) analysis (correcting for potential imbalances in baseline characteristics) were used to investigate improvement in TSS as a continuous endpoint in pts treated with PELA + RUX in Arm 3 of the MANIFEST study with historical double-blind Phase 3 JAKi trials: COMFORT-I (RUX), SIMPLIFY-1 (RUX, momelotinib [MOM]) and JAKARTA (fedratinib [FED]). Methods: In MANIFEST, percentage change in TSS and subdomains (fatigue, night sweats, itching, abdominal discomfort, pain under ribs, feeling of fullness and bone pain) from BL at Week (Wk) 12, 24, 36 and 48 were calculated. Pts with BL score = 0 were excluded. For the MAIC analysis, individual pt level data were available for MANIFEST Arm 3, and study-level data were extracted from published waterfall plots using WebPlotDigitizer (Rohatgia A. https://automeris.io/) for COMFORT-I, SIMPLIFY-1 and JAKARTA (FED 400 mg arm). Unanchored MAIC was conducted, whereby pts were reweighted to adjust for imbalances in key prognostic BL characteristics: gender, MF subtype, International Prognostic Scoring System risk status (IPSS), previous hydroxyurea use, platelet count, hemoglobin levels, spleen volume and JAK2V617F status; as a result, bias due to potential unmeasured differences is unlikely. The weights were used to calculate the effective sample size. Pts with IPSS intermediate-1 were excluded from the analysis. Weighted and unweighted treatment effects in terms of difference in least square (LS) means with their 95% confidence intervals using robust sandwich estimators for variance are presented. Studies used different TSS questionnaire versions; however, variations are subtle, and so comparisons across versions are valid (Dueck A, et al.Blood 2017;130:2168). Results: Comparable mean BL TSS scores were observed: 16.1 in MANIFEST Arm 3 and 17.5-19.4 across comparator Phase 3 studies. In MANIFEST Arm 3, a median reduction from BL of >50% was observed for TSS and all subdomains, and this reduction remained consistent across Wk 12 to Wk 48. TSS distribution in MANIFEST at Wk 24 showed greater median and mean reductions from BL vs JAKi monotherapy studies (Figure 1 shows comparison with RUX in SIMPLIFY-1). Complete summary level balance was achieved in the weighted distributions of the prognostic factors in MANIFEST Arm 3 versus comparators. After adjusting for imbalances, >20% greater reduction in LS mean percentage change in TSS from BL at Wk 24 was observed for all comparisons of MANIFEST Arm 3 vs historical studies, as shown in Figure 2. P values for all MAIC analyses were statistically significant. Conclusions: Analyzing TSS as a continuous endpoint in addition to responder analysis overcomes limitations of using TSS50 alone. TSS50 rates in MANIFEST Arm 3 were higher than all comparator MF studies, and clinically relevant improvements in TSS and its subdomains were observed as early as Wk 12 and were durable over time. When indirectly comparing Arm 3 of the Phase 2 MANIFEST study with historical Phase 3 MF studies using MAIC analysis, improved estimates of changes in TSS with PELA + RUX vs RUX, MOM or FED monotherapy were observed. A randomized Phase 3 MANIFEST-2 study of PELA + RUX vs RUX monotherapy in JAKi-naïve pts is ongoing (NCT04603495). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Add-on Parsaclisib to Ruxolitinib Therapy in Myelofibrosis Patients With Suboptimal Response to Ruxolitinib: Final Results From a Phase 2 Study

Background: Ruxolitinib (RUX) is a potent JAK1/JAK2 inhibitor and is effective in patients (pts) with myelofibrosis (MF). However, suboptimal or declining responses to RUX occur in a subset of pts, possibly due to persistent PI3K pathway activation with chronic JAK inhibitor therapy. Parsaclisib is a potent and highly selective next-generation PI3Kδ inhibitor. We conducted a phase 2 study (NCT02718300) evaluating add-on parsaclisib to stable doses of RUX, for pts with MF who experienced a suboptimal response to RUX (Yacoub A. HemaSphere 2021;5 Suppl 2:512). Here we report efficacy and safety results from the completed study. Methods: Eligible pts had primary or post-essential thrombocythemia/post-polycythemia vera MF with suboptimal response (palpable spleen >10 cm below left subcostal margin [LSM], or palpable splenomegaly 5-10 cm below LSM and presence of 1 symptom score ≥5 or 2 symptom scores ≥3 each using the Screening Symptom Form) after ≥6 months of RUX (5-25 mg twice daily; RUX stable dose, ≥8 wks). Pts remained on their stable RUX dose and were randomized to receive add-on parsaclisib 10 mg or 20 mg once daily (QD) for 8 wks and the same dose once weekly (QW) thereafter (QD/QW group), or parsaclisib 5 mg or 20 mg QD for 8 wks and 5 mg QD thereafter (all QD group) (Figure). Primary efficacy endpoint was change in spleen volume (SV) from baseline to wk 12 by MRI/CT scan. Key secondary endpoints included change in SV to wk 24, change in total symptom score (MFSAF-TSS, MPN-SAF-TSS), and safety. Results: Overall, 32 pts received parsaclisib QD/QW and 42 pts received parsaclisib all QD. Baseline median age was 68.0 (range 41.0-89.0) years and 47.3% of pts were male. The study has been completed. Median treatment duration was 336.5 days; median average daily dose was 5.0 mg/day for parsaclisib and 29.8 mg/day for RUX. Among all pts, 16 (21.6%) were rolled over to continue therapy in an open-label parsaclisib study after ending treatment in the present study. Other common reasons for pts discontinuing treatment were adverse events (13 [17.6%]) and progressive disease (10 [13.5%]); remainder discontinued for physician decision, pt decision, or "Other." Baseline median SV (cm3) was 2414.5 in QD/QW (n=29) and 1877.5 in QD (n=37); median MFSAF-TSS was 10.8 (n=28) and 16.3 (n=32) and median MPN-SAF-TSS was 25.5 (n=28) and 30.0 (n=37), respectively. Median percentage change in SV at wk 12 was −1.6 (n=28) in QD/QW and −15.4 (n=37) in QD, and at wk 24 was −2.5 (n=20) and −19.3 (n=29), respectively. Median percentage change in MFSAF-TSS at wk 12 was −14.0 (n=21) in QD/QW and −32.8 (n=24) in QD, and at wk 24 was −10.0 (n=16) and −44.4 (n=18), respectively. Median percentage change in MPN-SAF-TSS at wk 12 was −19.2 (n=20) in QD/QW and −39.8 (n=30) in QD, and at wk 24 was −43.3 (n=15) and −60.8 (n=26), respectively. Responder analysis for these 3 efficacy variables is shown in the Table. Nonhematologic treatment-emergent adverse events (TEAEs) were primarily grade 1/2. Grade 3/4 nonhematologic TEAEs occurring in >1 pt overall were pneumonia (n=5; 3 QD/QW, 2 QD), fatigue, hypoxia (each n=2; each 1 QD/QW, 1 QD), dyspnea (n=2, all QD), fall, alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, hypocalcemia (each n=2; all QD/QW). New-onset grade 3 thrombocytopenia was observed in 6/32 pts (18.8%) in QD/QW and 11/42 pts (26.2%) in QD; grade 4 thrombocytopenia was observed in 6/32 pts (18.8%) in QD/QW and 3/42 pts (7.1%) in QD. TEAEs of special interest included grade ≥3 ALT and AST (each n=2; all QD/QW), grade ≥2 diarrhea (n=4) and rash (n=1) (all QD/QW), and any-grade herpes simplex (n= 4; 1 QD/QW, 3 QD) and VZV infection (n= 3; 1 QD/QW, 2, QD). No colitis was reported. TEAEs led to parsaclisib interruption in 16/32 pts in QD/QW and 22/42 pts in QD, and RUX interruption in 5/32 and 8/42 pts, respectively. TEAEs led to parsaclisib discontinuation in 5/32 pts in QD/QW and 4/42 pts in QD, and RUX discontinuation in 2/32 and 2/42 pts, respectively. Conclusion: Final results from the phase 2 study demonstrate improvement in symptoms and SV with add-on parsaclisib in patients with MF having a suboptimal response to ruxolitinib. All daily dosing regimens were more efficacious than daily/weekly dosing. Combination therapy was associated with limited grade 3/4 AEs and TEAE-related discontinuations. Phase 3 studies using 5 mg QD parsaclisib together with ruxolitinib in naive MF patients and ruxolitinib-experienced patients are in progress. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Siremadlin, a Human Double Minute-2 (HDM2) Inhibitor, Added to Ruxolitinib after Suboptimal Response to Ruxolitinib Alone in Patients with Myelofibrosis: Results from Part 1 of the Phase 1/2 Adore Study

Introduction Ruxolitinib (RUX), a first-in-class Janus kinase (JAK)1/JAK2 inhibitor, is the standard of care for myelofibrosis (MF). However, ~50% patients (pts) discontinue RUX after ~3 years, including a third due to lack/loss of spleen response. Targeting additional pathogenic signaling pathways may provide superior disease control and potentially address underlying causes of disease. JAK2 mutations in MF induce expression of HDM2, which degrades tumor suppressor protein p53. Siremadlin (SIR), a potent and selective HDM2 inhibitor, restores p53-mediated apoptosis, which may promote clonal regression and spleen volume reduction (SVR). ADORE (NCT04097821) is a three-part phase 1/2 platform study assessing RUX in combination with 5 novel compounds, including SIR. We report results from the Part 1 (phase 1b) dose escalation cohort of SIR added to existing stable dose of RUX after suboptimal response to RUX alone. Methods Eligible pts had a diagnosis of primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF, splenomegaly (a palpable spleen ≥5 cm from the left costal margin or spleen volume ≥450 cm3 by MRI/CT scan), hemoglobin (Hb) level <11 g/dL (earlier protocol: <10 g/dL), and platelet count ≥75 × 109/L. Pts must have received RUX for ≥12 weeks (wks) (earlier protocol: ≥24 wks) and at a stable dose for ≥4 wks (earlier protocol: ≥8 wks) prior to first combination dose. Part 1 objective was to characterize the safety, tolerability, and recommended phase 2 dose (RP2D) of SIR added to RUX. Primary endpoint was incidence and severity of dose-limiting toxicities (DLT) within first 2 cycles; secondary objectives included characterization of the pharmacokinetic (PK) profile. Preliminary efficacy (change in spleen volume by MRI/CT scan from baseline [BL]), total symptom score (TSS) by MFSAF v4.0 and biomarkers were also explored. Pts were allocated to add SIR 20mg, 30mg or 40mg (orally once daily; days 1-5/28-day cycle) to their stable RUX dose (5-25mg twice daily). Adverse events (AEs) were coded by MedDRA and graded by CTCAE v5.0. Results In Part 1 SIR 20mg, 30mg and 40mg cohorts, 1/7, 9/10 and 1/6 pts were ongoing at data cut-off (April 13, 2022) respectively. The number of pts with DLTs after 2 cycles per number of evaluable pts was 0/6 at 20mg, 1/7 at 30mg (grade [G] 4 neutropenia and G4 thrombocytopenia in same pt), and 2/5 at 40mg (G3 and G4 thrombocytopenia). The most common AEs were gastrointestinal (GI) and hematologic (Table). RP2D was SIR 30mg/day. At 30mg, 5 pts experienced SIR-related GI toxicity; all events were G≤2; all lasted ≤4 days except for 1 case controlled with medication; 2 pts required concomitant medication for nausea, however, none discontinued treatment due to GI AEs. The most common hematologic AEs at 30mg were anemia, neutropenia, and thrombocytopenia. Two pts discontinued SIR 30mg due to G3 neutropenia and thrombocytopenia (for 1 pt) and G3 neutropenia (for 1 pt). At 30mg, 4/10 pts had completed a spleen volume assessment at 24 wks at time of data cut-off and all achieved SVR ≥35% from BL. At 20mg, 1/7 pts had SVR ≥35% at 24 wks. At 40mg, 3 pts discontinued prior to or did not complete spleen volume assessment at wk 24, limiting the availability of efficacy data (Figure). Symptom burden was low at BL across cohorts and subsequent TSS changes were highly variable between pts. SIR exposure increased with dose, with no relevant PK interactions between RUX and SIR observed. SIR increased growth/differentiation factor-15 (GDF15) expression, indicating target TP53 engagement. All pts were TP53 wildtype at BL. At data cut-off, SIR treatment resulted in the emergence of TP53 mutant clones in 1/7 pts at 20mg, 0/10 pts at 30mg and 1/6 pts at 40mg, at very low variant allele frequency (0.02-0.06) with unknown clinical significance. At 24 wks, 4/7 SIR-treated pts with available data had a decrease in JAK2 V617F mutational burden from BL (range 1.85-20.0%). Conclusions The RP2D of SIR is established as 30mg orally once daily on days 1-5/28-day cycle when added to the existing stable dose of RUX in pts with suboptimal response to prior RUX treatment. The addition of SIR 30mg was well tolerated, with low-G short-duration GI toxicity in contrast to an expected HDM2 inhibitor class effect. Other AEs were consistent with known RUX safety profile. Good tolerability at 30mg allowed pts to remain on SIR + RUX and to achieve robust spleen volume responses at 24 wks. The study was sponsored by Novartis Pharmaceuticals. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Women benefit from endovenous ablation with fewer complications: Analysis of the Vascular Quality Initiative Varicose Vein Registry

ObjectiveTo evaluate the association between gender and long-term clinician-reported and patient-reported outcomes after endovenous ablation procedures. MethodsThis retrospective cohort study of prospectively collected data from the Vascular Quality Initiative’s Varicose Vein Registry included patients undergoing endovenous ablation procedures on truncal veins with or without treatment of perforating veins between 2015 and 2019. A univariate analysis included comparisons of preprocedural, postprocedural, and periprocedural change in Venous Clinical Severity Score (VCSS) and total symptom score by gender. Rates of complications including deep vein thrombosis, endovenous heat-induced thrombosis, leg pigmentation, blistering, paresthesia, incisional infection, and any postprocedural complications were reported by gender. Multivariable analysis leveraged linear regression to examine how gender affected the relationships between patient characteristics, complication rates, and periprocedural change in VCSS score and total symptom score. ResultsOf 9743 patients who met the inclusion criteria, 3090 (31.7%) were men and 6653 (68.2%) were women. The perioperative change in VCSS score was greater for men than women (average –4.46 for men vs –4.13 for women; P < .0001). Perioperative change in total symptom score was greater for women than for men (average –10.64 for women vs –9.64 for men; P < .0001). Women had lower incidence of any leg complication (6.1% vs 8.6%; P = .001) endovenous heat-induced thrombosis (1.1% vs 2.2%; P = .002), and infection (0.4% vs 0.7%; P = .001). In multivariable analysis, among patients with a body mass index of more than 40, presence of deep reflux, and preoperative Clinical, Etiologic, Anatomic, and Physiologic classification of 2, women had a greater periprocedural change in VCSS score than men. ConclusionsWomen benefited from endovenous ablation similarly as men, with a lower incidence of postprocedural complications. Gender may be useful for patient selection and counseling for endovenous ablation, with particular usefulness among patients with a high body mass index, presence of deep reflux, and preoperative Clinical, Etiologic, Anatomic, and Physiologic classification of 2.

P1041: IMPACT OF FEDRATINIB ON SPLEEN VOLUME AND MYELOFIBROSIS SYMPTOMS IN PATIENTS WITH SUBSTANTIAL SPLENOMEGALY: POST HOC ANALYSES FROM THE JAKARTA AND JAKARTA2 TRIALS

Background: In myelofibrosis (MF), splenomegaly is a marker of disease progression, and larger spleen size (SS) is correlated with poorer survival and debilitating symptoms. Fedratinib (FEDR) is an oral, selective Janus kinase 2 (JAK2) inhibitor approved as first-line (1L) treatment (Tx) of patients (pts) with MF and in pts previously treated with ruxolitinib (RUX). In the phase 3, placebo-controlled JAKARTA trial (NCT01437787) and the phase 2, single-arm JAKARTA2 trial (NCT01523171), pts experienced substantial improvements in spleen volume and MF symptoms after receiving 6 FEDR Tx cycles. Given the prognostic impact of splenomegaly, these analyses explore whether these clinical benefits were influenced by pre-Tx SS. Aims: Investigate the efficacy of FEDR 400 mg/d in JAKARTA and JAKARTA2, in pt subgroups defined by baseline (BL) SS. Methods: The JAKARTA trial assessed FEDR 400 mg/d, FEDR 500 mg/d, and placebo in pts with JAK inhibitor-naïve MF, and the JAKARTA2 trial evaluated FEDR 400 mg/d (starting dose) in pts resistant/intolerant to prior RUX. Both studies enrolled pts with intermediate- or high-risk MF, SS >5 cm from the left costal margin by palpation, platelets ≥50×109/L, and ECOG PS ≤2. These post hoc analyses included pts from both studies who were allocated to receive FEDR 400 mg/d (the approved dosage) in continuous 28-d Tx cycles. Pt subgroups were divided according to BL median SS (mSS) in each trial. Changes from BL in spleen volume and Myelofibrosis Symptom Assessment Form (MFSAF) total symptom score (TSS) were measured at the end of cycle 6 (EOC6). Spleen volume was assessed by MRI/CT scan; MFSAF TSS was the sum of 6 MF symptom scores: night sweats, early satiety, pruritus, pain under ribs-left side, abdominal discomfort, and bone/muscle pain. Eligible pts must have had spleen volume and/or TSS data at BL and EOC6. Results: Overall, 96 pts in JAKARTA and 97 pts in JAKARTA2 received FEDR 400 mg/d; mSS (range) at BL was 16 (5–40) cm and 18 (5–36) cm, respectively. In the JAKARTA <mSS and ≥mSS cohorts, median BL spleen volume was 1771 (316–3396) mL and 3329 (983–6430) mL, respectively, and median TSS was 13.0 (0.0–54.9) and 17.2 (0.4–57.0). In JAKARTA2, median BL spleen volume was 1937 (737–4305) mL and 4002 (1821–7815) mL for pts with <mSS and ≥mSS, respectively; BL TSS was 17.2 (0.7–48.0) and 23.6 (1.0–44.0). Overall, 75 (78%) pts in JAKARTA and 51 (53%) pts in JAKARTA2 had spleen volume data available at BL and EOC6; the <mSS and ≥mSS cohorts, comprised 37 and 38 pts, respectively, in JAKARTA, and 31 and 20 pts in JAKARTA2. Median spleen volume reduction (SVR) from BL was similar between the <mSS and ≥mSS cohorts in each trial, and 97% of pts with ≥mSS in both trials achieved some degree of SVR. In JAKARTA, median SVR at EOC6 was −38% (95% CI, −43 to −31) in the <mSS and −40% (95% CI, −40 to −28) in the ≥mSS cohort; in JAKARTA2, median SVR was −37 (95% CI, −43 to −30) in the <mSS and −38.5% (95% CI, −49 to −14) in the ≥mSS cohort. TSS data were available at BL and EOC6 for 71 (74%) pts in JAKARTA and 51 (53%) pts in JAKARTA2. Changes from BL in TSS at EOC6 were similar in the JAKARTA <mSS and ≥mSS cohorts, with median TSS reductions of −49% and −51%, respectively. Median TSS changes at EOC6 in JAKARTA2 were greater for pts with larger spleens, −36% and −49% in the <mSS and ≥mSS cohorts, respectively. Image:Summary/Conclusion: Pts who completed 6 Tx cycles with FEDR 400 mg/d, whether used as 1L MF Tx or after RUX Tx, experienced substantial improvements in spleen volume and MF symptom severity regardless of the extent of splenomegaly at BL.

Exploring Genotype:Phenotype Correlations at Baseline and at One Year for ET and PV Patients in the Majic Study

Exploring Genotype:Phenotype Correlations at Baseline and at One Year for ET and PV Patients in the Majic Study

Spleen and Symptom Responses with Fedratinib (FEDR) in Patients with Myelofibrosis (MF) and Substantial Splenomegaly

Spleen and Symptom Responses with Fedratinib (FEDR) in Patients with Myelofibrosis (MF) and Substantial Splenomegaly

Abstract CT023: PATHFINDER: Interim analysis of avapritinib (ava) in patients (pts) with advanced systemic mastocytosis (AdvSM)

Abstract Introduction: Systemic mastocytosis is a clonal, hematologic neoplasm driven by KIT D816V mutation in &amp;gt;90% of cases, with limited treatment options. In a phase I study, ava, a potent inhibitor of KIT D816V, induced durable responses which deepened over time in pts with AdvSM, regardless of prior therapy or AdvSM subtype. PATHFINDER (NCT03580655) is a pivotal open-label, single-arm phase II study of ava in pts with AdvSM. Methods: Pts were aged ≥18 years with centrally confirmed diagnosis of an AdvSM subtype. Primary endpoint was overall response rate (ORR) by modified International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis criteria. This pre-specified interim analysis included 32 response-evaluable pts. Secondary endpoints included mean baseline change in AdvSM-Symptom Assessment Form Total Symptom Score (TSS) (Gotlib J et al. ASH 2018) and safety. Results: At June 23, 2020, 62 pts with AdvSM received ava primarily at 200 mg orally once daily (QD). Median age was 69 years (range 31-88), 31% had ECOG PS 2-3, and 68% had prior systemic treatment (55% with midostaurin). At 10.4 months median follow-up, 52/62 (84%) pts remained on treatment. ORR was 75% (95% CI 57-89; P=1.6×10-9) in 32 response-evaluable pts. Complete remission with full or partial hematologic recovery occurred in 19% of pts. Median time to response was 2 months; responses deepened over time. Median overall survival (OS) was not reached; estimated 12-month OS was 87%. There were ≥50% reductions from baseline serum tryptase (87%; n=54), marrow mast cell aggregates (71%; n=44), and KIT D816V allele fraction (53%; n=33). Mean TSS at baseline (n=56) was 18.3; fatigue, spots, itching, flushing, and abdominal pain were the most severe symptoms. Mean change in TSS was -7.7 (1-sided P&amp;lt;0.001) after 6 months of treatment (n=36). Common (≥25%) adverse events (AEs; all grade, Grade ≥3) were peripheral (50%, 3%) and periorbital (35%, 3%) edema, thrombocytopenia (32%, 8%), and anemia (29%,16%). Overall, 5% of pts discontinued due to a treatment-related AE and 5% due to disease progression. There were 3 (5%) deaths, all unrelated to treatment. Seven (11%) pts had cognitive effect AEs (all Grade 1-2). One pt with pre-treatment severe thrombocytopenia (platelets &amp;lt;50×109/L) had Grade 4 subdural hematoma. Subsequent pts with pre-treatment severe thrombocytopenia were excluded, platelet monitoring was intensified, and dose interruption for severe thrombocytopenia was recommended; no intracranial bleeding events occurred in 57 pts without pre-treatment severe thrombocytopenia. Conclusions: The pivotal PATHFINDER study showed that ava 200 mg QD induced rapid responses, which deepened over the course of treatment, and improved symptoms in pts with AdvSM. Ava was generally well tolerated with a manageable safety profile, including effective thrombocytopenia risk mitigation. Citation Format: Daniel J. DeAngelo, Andreas Reiter, Deepti Radia, Michael W. Deininger, Tracy I. George, Jens Panse, Alessandro M. Vannucchi, Madlen Jentzsch, Iván Alvarez-Twose, Andrzej Mital, Olivier Hermine, Ingunn Dybedal, Elizabeth O. Hexner, Lisa K. Hicks, Lambert Span, Ruben Mesa, Prithviraj Bose, Kristen M. Pettit, Mark L. Heaney, Stephen Oh, Jayita Sen, Hui-Min Lin, Brenton G. Mar, Jason Gotlib. PATHFINDER: Interim analysis of avapritinib (ava) in patients (pts) with advanced systemic mastocytosis (AdvSM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT023.

PCN19 Beyond a Binary Endpoint: Longitudinal and Individual Symptom Analyses from the Simplify-1 Study Demonstrate Clinically Comparable Symptomatic Benefit of Momelotinib to Ruxolitinib in JAK Inhibitor Naive Myelofibrosis Patients

Clinical trials investigating JAK1/JAK2 inhibitors for myelofibrosis subjects have measured symptom improvement as a minimum 50% reduction in total symptom score (TSS) at the end of a 24-week treatment period. However, this landmark response analysis is based on post-baseline score changes occurring only between Week 21 (W21) through W24 and does not account for variation in baseline TSS. To better understand the clinical relevance of TSS improvement we applied individual item analyses and Mixed-effect Models for Repeated Measures (MMRM) to SIMPLIFY-1, a phase 3 study which randomized 432 intermediate and high risk JAK inhibitor-naive MF patients 1:1 to momelotinib or ruxolitinib. Analyses were conducted in the intention-to-treat (ITT) population and in symptomatic subjects (baseline TSS ≥ 10). The distributions of TSS items were examined at baseline, and shift in scores at W24 (health state shifts) were determined. Odds ratios from generalized estimating equations for improvement on momelotinib relative to ruxolitinib were calculated for each item of the TSS using multiple predictive imputations for missing data. The MMRM compared mean change in TSS from baseline through W24. The meaningful change threshold (MCT) was determined using Patient Global Impression of Change. While the prespecified non-inferiority endpoint for TSS response rate was not met for momelotinib (28%) vs ruxolitinib (42%), item-level health state shifts and responder analyses showed similar improvements for momelotinib and ruxolitinib. No significant differences on any items were seen; odds ratios for each between-group comparison ranged from 0.74 to 1.20. MMRM mean TSS change score at W24 was 6.35 (momelotinib) vs 7.87 (ruxolitinib) in the ITT and 8.80 (momelotinib) vs 10.46 (ruxolitinib) in the symptomatic subset. TSS improvements were near the within-subject MCT of 8 points in the ITT and exceeded the MCT in the symptomatic subset. Item analyses and MMRM showed clinically important and comparable improvements in TSS.

Longitudinal and individual symptom analyses of momelotinib and ruxolitinib treated myelofibrosis patients from SIMPLIFY-1.

e19040 Background: Clinical trials investigating JAK1/JAK2 inhibitors for myelofibrosis (MF) subjects have measured symptom improvement as a minimum 50% reduction in total symptom score (TSS) at the end of a 24-week treatment period. This landmark analysis is based on post-baseline score changes from Weeks 21 (W21) to 24 and requires vastly different absolute TSS improvements for patients with very high or low baseline (BL) TSS to reach responder status. A phase 3 clinical study, SIMPLIFY-1, randomized 432 intermediate and high risk JAK inhibitor (JAKi) naive MF patients 1:1 to momelotinib (MMB) or ruxolitinib (RUX). Non-inferiority on the MPN-SAF TSS response rate endpoint at W24 was not met (MMB: 28% vs RUX: 42%); however, improvement in each of the 7 TSS items was similar for MMB vs RUX. To understand the discrepancy, we applied item analysis and mixed effect models for repeated measures (MMRM) to SIMPLIFY-1. Methods: Analyses were conducted in the intention-to-treat (ITT) population and in a symptomatic subset (selected as subjects with BL TSS ≥ 10). The distributions of TSS items were examined at BL and shift in scores at W24 (health state shifts) were assessed. GEE models were used to estimate item-level odds ratios using multiple predictive imputations for missing data. MMRM compared mean change in TSS from BL to W24 using data from all visits. The meaningful change threshold (MCT) was determined using Patient Global Impression of Change. Results: BL scores across items were heterogenous in the MMB and RUX groups; the proportion of subjects with no or mild symptoms (0–3 on a 0-10 point scale) ranged from 44% (tiredness) to 81% (itching). Distributions of BL scores were different across arms with 6 out of 7 items in the MMB arm reporting more severe or very severe symptoms (scores of 7-10) at BL. Despite the imbalance in BL scores, item-level health state shifts showed similar improvements for MMB and RUX. Categorical responder analysis showed no significant differences on any items. Odds ratios for each between-group comparison ranged from 0.74 to 1.20. MMRM mean TSS change at W24 was 6.35 (MMB) vs 7.87 (RUX) in the ITT and 8.80 (MMB) vs 10.46 (RUX) in the symptomatic subset. Mean TSS were near the within-subject MCT of 8 points in the ITT and exceeded the MCT in the symptomatic subset. The between-group difference was 1.52 (95% CI: (0.196, 2.847)) in the ITT and 1.67 (95% CI: -0.134, 3.468) in the symptomatic subset. Conclusions: Comparable item health state shifts at W24 and similar improvements in mean TSS as shown by MMRM, with a minimal between-group difference of 1.52 on the 70 point scale in context of an 8-point MCT suggest MMB provides clinically relevant and comparable symptom improvements to RUX; these analyses require further validation in independent data sets. Imbalance in BL symptom scores in MMB subjects may have contributed to the inability to demonstrate non-inferiority in TSS response rate at W24. Clinical trial information: NCT01969838.

A Prospective Study to Compare Clinical Outcomes of Allergic Rhinitis Between Older and Younger Adults: A Potential Effect of Depression in Older Patients.

Although younger patients with allergic rhinitis (AR) have been successfully treated with pharmacotherapy, there are no definitive data on treatment outcomes in older patients with AR. We performed a prospective study of 51 older adults with AR (aged over 65 years) and 101 younger AR patients (aged from 19 to 40 years) to compare clinical outcomes between the 2 groups and to evaluate the impact of depressed mood on treatment outcomes in older AR patients. Changes in total symptom scores (TSS), rhinitis-specific quality of life questionnaire (RQLQ) results, rhinitis control assessment test (RCAT) results and visual analog scale (VAS) scores were evaluated after 4-week treatment according to the Allergic Rhinitis and its Impact on Asthma (ARIA) guideline, and the severity of depressed mood was assessed by using the geriatric depression scale. After 4-week treatment, younger AR patients had greater improvements in clinical scores compared with older adults; differences in least squares mean changes from baseline in older patients vs. younger patients were 1.71 (P = 0.004) for TSS, 10.84 (P < 0.001) for RQLQ, 0.80 (P = 0.275) for RCAT, and 8.60 for VAS score (P = 0.061). Multiple logistic regression analysis showed that the severity of depressed mood was independently associated with severe chronic upper airway disease (adjusted odds ratio, 1.385; P = 0.004). Our results suggest that older AR patients are less responsive to standard treatment compared with younger AR patients and that depressed mood is strongly associated with the increased risk of uncontrolled AR in older AR patients.

Smartphone induced eye strain in young and healthy individuals

Background: Usage of digital devices has become one's basic need. Digital eye strain is repeatedly noticed sequelae in optometry practice.&#x0D; Objectives: This study aims to estimate the different aspects of eye strain.&#x0D; Methodology: Altogether, 55 students with a mean age of 21.25 years, vision (≥6/9) were enrolled. A survey related to common asthenopic (eyestrain) symptoms was carried before and after reading an extract from a novel. Accommodative facility and non-invasive first tear breakup (NTBUT) time were measured before and after the reading. The viewing distance to a smartphone was measured every 20 minute.&#x0D; Results: The total eye strain symptom score was significantly greater post-experiment (score = 7.07±2.84) than pre-experiment (score = 1.54±1.60, p &lt; 0.001). Symptoms of tired eyes, sore eyes, and sleepy eyes increased significantly after 60 min of a smartphone use (p &lt; 0.05). The mean viewing distance while using a smartphone over 60 min was 30.15 ± 3.29 cm. There was a significant correlation between change in total symptom score and change in viewing distance (r = ˗0.301, p = 0.026). The symptom that correlated with a change in viewing distance was ‘sore eyes’ (r = ˗0.382, p = 0.04) and sleepy eyes (r= ˗0.363, p=0.06). There was a significant decrease in monocular and binocular accommodative facilities and NTBUT after 60 min of reading.&#x0D; Conclusion: Closer viewing distance and eyestrain symptoms are obvious after a smartphone reading. Prolonged use of smartphones appears to have important implications for accommodative function, causing ocular symptoms having an impact on quality of life.

The Addition of Navitoclax to Ruxolitinib Demonstrates Efficacy within Different High-Risk Populations in Patients with Relapsed/Refractory Myelofibrosis

The Addition of Navitoclax to Ruxolitinib Demonstrates Efficacy within Different High-Risk Populations in Patients with Relapsed/Refractory Myelofibrosis

Anti–Siglec-8 Antibody for Eosinophilic Gastritis and Duodenitis

BackgroundEosinophilic gastritis and duodenitis are characterized by gastrointestinal mucosal eosinophilia, chronic symptoms, impaired quality of life, and a lack of adequate treatments. Mast-cell activity may contribute to the pathogenesis of the conditions. AK002 (lirentelimab) is an anti–Siglec-8 antibody that depletes eosinophils and inhibits mast cells and that has shown potential in animal models as a treatment for eosinophilic gastritis and duodenitis.MethodsIn this phase 2 trial, we randomly assigned adults who had symptomatic eosinophilic gastritis, eosinophilic duodenitis, or both conditions in a 1:1:1 ratio to receive four monthly infusions of low-dose AK002, high-dose AK002, or placebo. The primary end point was the change in gastrointestinal eosinophil count from baseline to 2 weeks after the final dose; to maximize statistical power, we evaluated this end point in the placebo group as compared with the combined AK002 group. Secondary end points were treatment response (>30% reduction in total symptom score and >75% reduction in gastrointestinal eosinophil count) and the change in total symptom score.ResultsOf the 65 patients who underwent randomization, 43 were assigned to receive AK002 and 22 were assigned to receive placebo. The mean percentage change in gastrointestinal eosinophil count was −86% in the combined AK002 group, as compared with 9% in the placebo group (least-squares mean difference, −98 percentage points; 95% confidence interval [CI], −121 to −76; P<0.001). Treatment response occurred in 63% of the patients who received AK002 and in 5% of the patients who received placebo (difference, 58 percentage points; 95% CI, 36 to 74; P<0.001). The mean change in total symptom score was −48% with AK002 and −22% with placebo (least-squares mean difference, −26 percentage points; 95% CI, −44 to −9; P=0.004). Adverse events associated with AK002 were similar to those with placebo, with the exception of higher percentages of patients having mild-to-moderate infusion-related reactions with AK002 (60% in the combined AK002 group and 23% in the placebo group).ConclusionsIn patients with eosinophilic gastritis or duodenitis, AK002 reduced gastrointestinal eosinophils and symptoms. Infusion-related reactions were more common with AK002 than with placebo. (Funded by Allakos; ENIGMA ClinicalTrials.gov number, NCT03496571.)

Effectiveness and tolerability of formoterol plus glycopyrronium combination in patients with chronic obstructive pulmonary disease: FINE registry

Background: Long-term therapy for chronic obstructive pulmonary disease (COPD) is progressing fast. Dual bronchodilation with long-acting muscarinic antagonist (LAMA) and long-acting β2-agonist (LABA) fixed dose combinations (FDC) have been available over the past few years. To evaluate the real-world tolerability and effectiveness of formoterol plus glycopyrronium FDC inhaler, a post-marketing surveillance study was conducted in Indian population.Methods: This was an open-label, observational registry in which COPD patients, who were prescribed forglyn (a brand of FDC of glycopyrronium 25 mcg and formoterol fumarate dihydrate 6 mcg dry powder inhalation). The effectiveness, safety and tolerability of this LAMA/LABA combination were evaluated for 4, 8 and 12 weeks. The safety and tolerability was assessed based on the incidence of adverse events (AEs). Effectiveness was evaluated based on change in total symptom score from baseline to end of 12 weeks. The forced expiratory volume in 1 second (FEV1) was performed at baseline and end of 12 weeks.Results: Total COPD patients enrolled were 605, of which 78.5% were males and 21.5% were females. Patients showing improvement of symptoms at week 4 were 587 (97.02%).Overall, at the end of 8 week and 12 week 98.34 % and 99.49% patients showed improvement in the total symptoms respectively. About 0.49% did not show any improvement. AEs were reported in 64 (10.64%) patients with no serious AEs. Mean FEV1 of 476 patients before treatment was 1.53±0.68 L at baseline which changed to 1.85±4.74 L at the end of 12 weeks, with was statistically significant (p&lt;0.05).Conclusions: In real-life clinical practice in India, formoterol and glycopyrronium FDC dry powder inhaler was well tolerated in COPD patients, and can be regarded as an effective option for maintenance treatment.