scholarly journals FRI0430 THE NOVEL, INTRA-ARTICULAR CLK/DYRK1A INHIBITOR LORECIVIVINT (LOR; SM04690), WHICH MODULATES THE WNT PATHWAY, IMPROVED RESPONDER OUTCOMES IN SUBJECTS WITH KNEE OSTEOARTHRITIS: A POST HOC ANALYSIS FROM A PHASE 2B TRIAL

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 813.2-814
Author(s):  
Y. Yazici ◽  
S. Kennedy ◽  
C. Swearingen ◽  
J. Tambiah
Keyword(s):  
Wnt Pathway ◽  
Rating Scale ◽  
Womac Pain ◽  
Phase 3 ◽  
Post Hoc Analysis ◽  
Threshold Response ◽  
Knee Oa ◽  
Womac Function ◽  
Patient Reported ◽  
Post Hoc

Background:Lorecivivint (LOR; SM04690) is a small-molecule, intra-articular (IA) CLK/DYRK1A inhibitor that modulates the Wnt pathway1and has demonstrated some beneficial effects on patient-reported outcomes (PROs) relative to placebo (PBO) in two Phase 2 knee OA trials. With subjective measures such as PROs, meaningful benefits may be better characterized by representation as discrete threshold responses rather than by changes in mean point estimates.Objectives:To conduct a post hoc analysis of subjects in a 24-week Phase 2b study by measuring the proportions of subjects treated with LOR and placebo (PBO) who achieved 30%, 50%, or 70% threshold responses of improvement over baseline in Pain Numeric Rating Scale (NRS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Function, and Patient Global Assessment (PtGA) at Week 12. Results from the Phase 3-selected dose of 0.07 mg LOR are presented here.Methods:Subjects had ACR-defined knee OA, Kellgren-Lawrence (KL) grades 2–3, and Pain NRS scores ≥4 and ≤8 in the target knee and <4 in the contralateral knee. A single 2mL IA injection of 0.03 mg, 0.07 mg, 0.15 mg, or 0.23 mg LOR, or vehicle PBO was given in the target knee at baseline. The proportion of subjects meeting 30%, 50%, or 70% threshold responses over baseline in the weekly average of daily Pain NRS [0–10], WOMAC Pain [0–100], WOMAC Function [0–100], and PtGA [0–100] at Week 12 was determined. The odds ratios (OR [95% CI]) of achieving each threshold response level were calculated and compared between LOR and PBO.Results:In total, 635 subjects (91.4%) completed the study (mean age 59.0±8.5 years, BMI 29.0±4.0 kg/m2, female 58.4%, KL grade 3 57.3%). At Week 12, treatment with 0.07 mg LOR significantly (P<0.05) increased the odds of a 30% threshold response in Pain NRS (OR 2.47 [1.45, 4.19]) and WOMAC Function (OR 1.86 [1.10, 3.12]) and a 50% threshold response in WOMAC Pain (OR 1.79 [1.06, 3.03]) and PtGA (OR 2.28 [1.25, 4.16]). Numerically, more (not statistically significant) subjects achieved a 70% threshold response in all PROs. All improvements were maintained through Week 24.Conclusion:In this post hoc analysis, LOR-treated subjects reported greater improvements in PRO threshold responses versus PBO from Week 12 through Week 24. LOR demonstrated significantly higher odds of achieving and maintaining improvements in PROs at 30% and 50% thresholds. Phase 3 studies of 0.07 mg LOR are ongoing.References:[1]Deshmukh V, et al.Osteoarthr Cartil. 2019.Disclosure of Interests:Yusuf Yazici Shareholder of: Samumed, LLC, Grant/research support from: Bristol-Myers Squibb, Celgene, and Genentech, Consultant of: Celgene and Sanofi, Employee of: Samumed, LLC, Sarah Kennedy Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, Christopher Swearingen Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, Jeyanesh Tambiah Shareholder of: Samumed, LLC, Employee of: Samumed, LLC

Comparing Patient-Reported Outcomes From Sham and Saline-Based Placebo Injections for Knee Osteoarthritis: Data From a Randomized Clinical Trial of Lorecivivint

2022 ◽  
pp. 036354652110672
Author(s):  
Jeyanesh R.S. Tambiah ◽  
Ismail Simsek ◽  
Christopher J. Swearingen ◽  
Sarah Kennedy ◽  
Brian J. Cole ◽  
...  
Keyword(s):  
Knee Osteoarthritis ◽  
Patient Reported Outcomes ◽  
Rating Scale ◽  
Numeric Rating Scale ◽  
Womac Pain ◽  
Time Points ◽  
Knee Oa ◽  
Patient Reported ◽  
Mean Differences ◽  
Numeric Rating

Background: Durable, meaningful symptom responses to intra-articular saline placebo injections are observed in knee osteoarthritis (OA) trials, but it is unclear if these are due to physiological effects. Purpose: To perform a prospective comparison of patient-reported outcome responses among participants with knee OA who underwent intra-articular injection of saline-based placebo or sham (dry needle). Study Design: Randomized controlled trial; Level of evidence, 2. Methods: From a 24-week randomized double-blind trial, participants with moderate to severe knee OA received 2-mL intra-articular injections of saline-based placebo (PBO; 99.45% PBS) or sham (dry needle) to the target knee. Least squares mean differences of changes from baseline to week 24 were compared between the PBO and sham groups for the following: pain Numeric Rating Scale; Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, stiffness, and function; and patient global assessment. Bang Blinding Index was used to evaluate all-group blinding on day 1 and week 24. Results: In total, 116 and 117 participants were randomized to the PBO and sham groups, respectively. Within the full trial population, the mean ± SD age and body mass index were 59.0 ± 8.5 years and 28.97 ± 4.01, respectively. An overall 406 (58.4%) were female, and 394 (57.3%) had Kellgren-Lawrence grade 3 target knee OA. The PBO and sham groups demonstrated clinically meaningful improvements (≥10%) from baseline in all patient-reported outcomes at all time points (ie, weeks 4-24). Mean differences (95% CI) at week 24 between the PBO and sham groups were as follows: pain Numeric Rating Scale, –0.10 (–0.79 to 0.59; P = .78); WOMAC pain, –2.89 (–9.70 to 3.92; P = .40); WOMAC stiffness, –2.37 (–9.37 to 4.63; P = .51); and WOMAC function, –1.39 (–8.06 to 5.29; P = .68). Bang Blinding Index indicated that blinding was maintained. Conclusion: PBO and sham groups demonstrated equivalent patient-reported outcomes at all time points through week 24, suggesting that responses attributed to saline were contextual (ie, to the procedure) and not physiological. Registration: NCT03122860 (ClinicalTrials.gov identifier).

scholarly journals POS1088 EFFICACY OF SUBCUTANEOUS TANEZUMAB FOR THE TREATMENT OF OSTEOARTHRITIS OF THE KNEE OR HIP: A POST-HOC SUBGROUP ANALYSIS OF PATIENTS FROM A RANDOMIZED, NSAID-CONTROLLED STUDY WITH A HISTORY OF DEPRESSION, ANXIETY, OR INSOMNIA

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 823-824
Author(s):  
P. J. Mease ◽  
T. Mallick-Searle ◽  
E. Johnston ◽  
L. Viktrup ◽  
D. Menuet ◽  
...  
Keyword(s):  
Pain Relief ◽  
Physical Function ◽  
Controlled Study ◽  
Womac Pain ◽  
Phase 3 ◽  
Post Hoc Analysis ◽  
Oral Nsaid ◽  
History Of ◽  
Post Hoc ◽  
History Of Depression

Background:Tanezumab is a monoclonal antibody directed against nerve growth factor. It is in development for the treatment of moderate to severe chronic pain associated with osteoarthritis (OA) in adult patients for whom other treatments are ineffective or not appropriate. Phase 3 clinical trials have demonstrated the efficacy of subcutaneous tanezumab versus placebo for pain and function outcomes over various timepoints. Largely similar change from baseline was demonstrated in an oral nonsteroidal anti-inflammatory drug (NSAID)-controlled study.1,2,3,4 The efficacy of some other OA therapies can be dampened in patients with depression, anxiety, or insomnia.5,6,7Objectives:A post-hoc analysis to explore the efficacy of subcutaneous tanezumab after 16 weeks treatment, as compared to oral NSAID, in patients with OA and a history of depression, anxiety, or insomnia at baseline.Methods:Subgroup analysis of data from a randomized, double-blind, double-dummy, active-controlled phase 3 study of subcutaneous tanezumab (2.5 mg or 5 mg every 8 weeks) vs twice daily oral NSAID in patients (≥18 years) with radiographically-confirmed moderate to severe hip or knee OA (Kellgren-Lawrence grade ≥2; NCT02528188).4 Co-primary efficacy endpoints were change from baseline to week 16 in Western Ontario and McMaster Universities OA Index (WOMAC*) Pain and Physical Function subscale scores (both ≥5/10 at randomisation; increasing score indicates increasing pain/disability), and Patient’s Global Assessment of OA (PGA-OA, ≥3/5 at randomisation; increasing score indicates poorer condition). Enrolled patients had a history of inadequate pain relief with acetaminophen; inadequate pain relief with/intolerance to/contraindication to tramadol or opioids; or an unwillingness to take opioids. Patients were on a stable dose of NSAID for ≥30 days before screening. Data are presented as least squares (LS) mean change from baseline to week 16 for the whole population and for subgroups of patients with/without a history of depression, anxiety, or insomnia at baseline. Exploratory statistical analysis was conducted by analysis of covariance. P values were not adjusted for multiplicity. This exploratory post-hoc analysis was not part of the pre-specified hypothesis testing plan or included in any sample size calculations; therefore, comparisons between treatment arms or patient subgroups should be interpreted with caution.Results:Overall, 2996 patients were randomized and received at least one dose of study treatment (subcutaneous tanezumab 2.5 mg: n=1002; subcutaneous tanezumab 5 mg: n=998; oral NSAID: n=996). In this population (comprising patients with or without a history of anxiety, depression or insomnia), all treatments were associated with notable and largely similar magnitude improvements in WOMAC Pain, WOMAC Physical Function, and PGA-OA at week 16 (Figure 1). Across treatment groups, differences in LS mean change from baseline in patients with and without a history of depression, anxiety or insomnia ranged between 0 - 0.34 for WOMAC Pain and Physical Function and 0 - 0.19 for PGA-OA.Conclusion:Patients with a history of depression, anxiety, or insomnia did not appear to experience dampened improvements in pain or function with tanezumab or NSAID, as compared to those without.References:[1]Schnitzer T, et al. JAMA. 2019;322(1):37-48;[2]Berenbaum F, et al. Ann Rheum Dis. 2020;79(6):800-10;[3]Schnitzer T, et al. Semin Arthritis Rheum. 2020;50(3):387-93;[4]Hochberg M, et al. Arthritis Rheumatol. In Press;[5]Sharma A, et al. Open Access Rheumatol. 2016;31(8):103-13;[6]Mallen C, et al. PLoS Med. 2017;14(4):e1002273;[7]Campbell C, et al. Arthritis Care Res. 2015;67(10):1387-96.Acknowledgements:Study sponsored by Pfizer and Eli Lilly and Company. Editorial support was provided by Jennifer Bodkin of Engage Scientific Solutions and funded by Pfizer and Eli Lilly and Company.Disclosure of Interests:Philip J Mease Speakers bureau: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Janssen, Eli Lilly and Company, Novartis, Pfizer, UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Galapagos, Gilead, GlaxoSmithKline, Janssen, Eli Lilly and Company, Novartis, Pfizer, Sun, UCB, Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Janssen, Eli Lilly and Company, Novartis, Pfizer, Sun, UCB, Theresa Mallick-Searle Speakers bureau: Allergan, Abbvie, Eli Lilly and Company, Salix, Consultant of: Pfizer, Eli Lilly and Company, Elizabeth Johnston Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Lars Viktrup Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Dominique Menuet Employee of: Pfizer, Ruoyong Yang Employee of: Pfizer, Robert J Fountaine Shareholder of: Pfizer, Employee of: Pfizer.

FRI0380 ITEMS DRIVING WOMAC PAIN SUBSCORE CHANGES DUE TO LORECIVIVINT, A POTENTIAL DISEASE-MODIFYING TREATMENT FOR KNEE OSTEOARTHRITIS: A POST HOC ANALYSIS OF PHASE 2B TRIAL DATA

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 787-788
Author(s):  
S. Kennedy ◽  
C. Swearingen ◽  
I. Simsek ◽  
J. Tambiah
Keyword(s):  
Effect Size ◽  
Target Population ◽  
Effect Sizes ◽  
Primary Study ◽  
Womac Pain ◽  
Widespread Pain ◽  
Post Hoc Analysis ◽  
Knee Oa ◽  
Post Hoc ◽  
Disease Modifying Treatment

Background:Knee osteoarthritis (OA) is a disease characterized by pain, loss of function, and structural deformities, leading to a heterogeneous disease state that can confound patient-reported outcomes (PROs). The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain subscore addresses this reporting variability by capturing multiple pain items related to ‘active’ and ‘static’ subject states. We hypothesize that measurement of these ‘active’ versus ‘static’ pain items may demonstrate differential effect sizes when assessing treatment benefit. Lorecivivint (LOR; SM04690), a small-molecule, intra-articular CLK/DYRK1A inhibitor that modulates the Wnt pathway, is currently in development as a potential disease-modifying treatment for knee OA.1,2Objectives:To test the hypothesis, a post hoc analysis of Pain NRS, the WOMAC Pain subscore, and individual WOMAC PROs (items A1–A5) from a Phase 2b LOR trial was performed to examine effect size (ES) changes.Methods:The original 24-week Phase 2b trial has been previously reported. In this study, pain was assessed using the weekly average of daily Pain NRS and WOMAC Pain subscore. In the post hoc analysis, items A1–A5 (pain walking on a flat surface? [A1], going up/downstairs? [A2], at night in bed? [A3], sitting or lying down? [A4], and while standing? [A5]) were individually analyzed for subjects treated with 0.07 mg LOR and compared with the primary study outcomes of mean Pain NRS and summed mean WOMAC Pain subscore at Week 12. Baseline-adjusted analysis of covariance for WOMAC A1–A5 scores was conducted on LOR-treated subjects compared with placebo (PBO) in 1) the Full Analysis Set (FAS) of all dosed subjects and 2) a target population of subjects with fixed baseline joint space width (JSW) [2–4] mm without widespread pain (Widespread Pain Index [WPI] ≤4, Symptom Severity Score Question 2≤2).Results:In this analysis, 231 subjects (KL grade 3 63.2%) were included. The primary study analysis demonstrated efficacy of LOR compared with PBO for Pain NRS and WOMAC Pain, with respective effect sizes of 0.450 and 0.293 (Figure). In the target population, Pain NRS and WOMAC A effect sizes increased (0.637 and 0.410, respectively). Each WOMAC A item showed less of an effect size than Pain NRS at Week 12. Treatment with 0.07 mg LOR compared with PBO showed significant improvements in effect sizes of WOMAC A1 (FAS: ES=0.315,P=0.028; target population: ES=0.421,P=0.035) and A2 (FAS: ES=0.392,P=0.006; target population: ES=0.510,P=0.011). A3–A5 did not show statistical improvement for LOR compared with PBO.Figure.Effect sizes for 0.07 mg LOR compared with PBO for the FAS and target population at Week 12.Conclusion:In the post hoc analysis, Pain NRS exhibited the greatest effect size of tested PROs after treatment with 0.07 mg LOR compared with PBO. These effect sizes were enhanced in the target population with fixed baseline JSW and without widespread pain for all scores relative to the FAS. WOMAC ‘active’ questions demonstrated greater effect sizes with LOR treatment than ‘static’ questions and the full WOMAC Pain domain, providing support for the hypothesized dimensional constructs in knee OA pain assessment.References:[1]Deshmukh V, et al.Osteoarthritis Cartilage. 2017.[2]Deshmukh V, et al.Osteoarthritis Cartilage. 2019.Disclosure of Interests:Sarah Kennedy Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, Christopher Swearingen Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, Ismail Simsek Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, Jeyanesh Tambiah Shareholder of: Samumed, LLC, Employee of: Samumed, LLC

scholarly journals Exploring the Relationship between Disease Awareness and Outcomes in Patients with Chronic Obstructive Pulmonary Disease

Respiration ◽  
2021 ◽  
Vol 100 (4) ◽  
pp. 291-297
Author(s):  
Ilaria Baiardini ◽  
Marco Contoli ◽  
Angelo Guido Corsico ◽  
Carla Scognamillo ◽  
Fabio Ferri ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Treatment Satisfaction ◽  
Illness Perception ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Post Hoc Analysis ◽  
Disease Awareness ◽  
Patient Reported ◽  
Post Hoc

Background: Disease awareness is a challenge in the management of chronic obstructive pulmonary disease (COPD). Objectives: The aim of this analysis was to explore the association between COPD optimal and suboptimal awareness, clinical parameters, and the following patient-reported outcomes: modified Medical Research Council (mMRC), Treatment Satisfaction Questionnaire (TSQM-9), COPD Assessment Test (CAT), Morisky Medication-Taking Adherence Scale (MMAS-4), and Brief Illness Perception Questionnaire (B-IPQ). Methods: This post hoc analysis of the SAT study included all enrolled patients for whom awareness (Disease Awareness in COPD Questionnaire – DACQ) was assessed at baseline and 12 months. DACQ scores ≥80 were considered an indicator of an optimal awareness. Results: 367 patients (25.8% women, median age 72 years) were included in the analysis. At enrollment, 74 patients (20.2%) had a DACQ score ≥80. Patients with suboptimal awareness, compared to those in which awareness was optimal, had higher median scores for CAT (p = 0.0001) and mMRC (p = 0.0031), a lower median TSQM-9 global score (p < 0.0001), and higher median B-IPQ score (p < 0.0001). The proportion of patients who had exacerbations during the previous year was higher in patients with suboptimal COPD awareness than in those with DACQ score ≥80 (42.8 vs. 21.4%, p = 0.0009). During the 12-month observation period, illness perception, adherence, and treatment satisfaction were found to be independent factors significantly associated with level of disease awareness. Conclusion: The results of our post hoc analysis suggest that patients’ awareness of their COPD disease is related to both clinical outcomes and how they perceive and manage their condition.

scholarly journals Itch and Sleep Improvements with Baricitinib in Patients with Atopic Dermatitis: A Post Hoc Analysis of 3 Phase 3 Studies

2021 ◽  
Author(s):  
Timo Buhl ◽  
David Rosmarin ◽  
Esther Serra-Baldrich ◽  
Pablo Fernandez-Peñas ◽  
Atsuyuki Igarashi ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Phase 3 ◽  
Post Hoc Analysis ◽  
Post Hoc
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