Clinical trials are advancing the treatment of polycystic ovary syndrome (PCOS), an endocrine disorder affecting 8-13% of women. Lifestyle interventions, including nutritional plans, physical activity, and stress management, can improve reproductive hormones and metabolic health. Novel pharmacotherapies targeting hormonal, metabolic, and reproductive abnormalities are being explored for individualized treatment. Combination therapies and lifestyle interventions like acupuncture, high-intensity interval training, and vitamin D3 supplementation are also being explored.
Methods
We conducted a narrative review by searching English-language studies across electronic databases such as PubMed, Science direct, and Google Scholar for articles related to the topics of PCOS and novel drug therapies such as metformin, LIK-066, elagolix, saxenda, exenatide, clomiphene, letrozole, and other diagnostic interventions. Our review excluded preclinical studies and articles not in english.
Findings
In addition to pharmacological treatments, lifestyle interventions such as Tung's acupuncture, high-intensity interval training (HIIT), and vitamin D3 supplementation have proven effective in managing symptoms of PCOS and enhancing overall health outcomes. These interventions offer a complementary approach to traditional medical therapies, emphasizing the importance of integrating lifestyle modifications into the treatment plan for women with PCOS.
Implications
This comprehensive approach underscores the importance of tailored treatments in optimizing clinical outcomes and quality of life for women with PCOS. The aim of this review is to highlight recent advancements in the treatment of PCOS through clinical trials and emerging pharmacotherapies, emphasizing the need for individualized and multifaceted treatment approaches.
{"title":"Recent Advances in Individualized Clinical Strategies for Polycystic Ovary Syndrome: Evidence From Clinical Trials and Emerging Pharmacotherapies","authors":"Murali Krishna Moka PhD , Damal Kandadai Sriram FRCP , Melvin George DM","doi":"10.1016/j.clinthera.2024.11.015","DOIUrl":"10.1016/j.clinthera.2024.11.015","url":null,"abstract":"<div><h3>Purpose</h3><div>Clinical trials are advancing the treatment of polycystic ovary syndrome (PCOS), an endocrine disorder affecting 8-13% of women. Lifestyle interventions, including nutritional plans, physical activity, and stress management, can improve reproductive hormones and metabolic health. Novel pharmacotherapies targeting hormonal, metabolic, and reproductive abnormalities are being explored for individualized treatment. Combination therapies and lifestyle interventions like acupuncture, high-intensity interval training, and vitamin D3 supplementation are also being explored.</div></div><div><h3>Methods</h3><div>We conducted a narrative review by searching English-language studies across electronic databases such as PubMed, Science direct, and Google Scholar for articles related to the topics of PCOS and novel drug therapies such as metformin, LIK-066, elagolix, saxenda, exenatide, clomiphene, letrozole, and other diagnostic interventions. Our review excluded preclinical studies and articles not in english.</div></div><div><h3>Findings</h3><div>In addition to pharmacological treatments, lifestyle interventions such as Tung's acupuncture, high-intensity interval training (HIIT), and vitamin D3 supplementation have proven effective in managing symptoms of PCOS and enhancing overall health outcomes. These interventions offer a complementary approach to traditional medical therapies, emphasizing the importance of integrating lifestyle modifications into the treatment plan for women with PCOS.</div></div><div><h3>Implications</h3><div>This comprehensive approach underscores the importance of tailored treatments in optimizing clinical outcomes and quality of life for women with PCOS. The aim of this review is to highlight recent advancements in the treatment of PCOS through clinical trials and emerging pharmacotherapies, emphasizing the need for individualized and multifaceted treatment approaches.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"47 2","pages":"Pages 158-167"},"PeriodicalIF":3.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.clinthera.2024.11.021
Jian Zhang , Rujiao Liu , Dhruvit Sutaria , Rucha Sane , Minhao Fan , Rui Wang , Grace Song , Kui Chen , Ksenia Arzumanova , Xichun Hu
Purpose
Ipatasertib is a selective inhibitor of Akt, a frequently activated protein kinase that plays a critical role in human cancers. The current clinical trial aimed to assess the pharmacokinetic properties, safety, and tolerability of ipatasertib administered to Chinese patients with locally advanced or metastatic solid tumors.
Methods
A Phase I, single-arm, open-label study was performed in Chinese patients with locally advanced or metastatic solid tumors for whom standard therapy either does not exist or has proven ineffective. Four hundred milligrams of ipatasertib was administered to patients as a single agent, starting with a single dose for 7 days and continuous daily dosing for 21 days, followed by 7 days off schedule. The pharmacokinetic properties of ipatasertib and its major metabolite M1 (GO37220) after single and multiple dose administration were assessed using a validated liquid chromatography–tandem mass spectrometry assay method. Safety was assessed throughout the study, and adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Tumor response was assessed by the investigator using Response Evaluation Criteria in Solid Tumors version 1.1.
Findings
Fourteen patients were enrolled, and all enrolled patients received at least 1 dose of the study treatment. Ipatasertib and M1 exposures were slightly higher than previously reported but comparable with exposures observed within the Asian population. Ipatasertib as a single agent demonstrated a manageable safety profile in Chinese patients, which is aligned with prior observation in global studies. Limited efficacy was observed in these patients with heavily pretreated diverse solid tumors.
Implications
This study of the pharmacokinetic properties, safety, and efficacy of ipatasertib in Chinese patients eventually contributed toward the development of Akt inhibitors in China. ClinicalTrials.gov identifier: NCT04341259.
{"title":"A Phase I Study of the Pharmacokinetics and Safety of Ipatasertib, an Akt Inhibitor in Chinese Patients With Locally Advanced or Metastatic Solid Tumors","authors":"Jian Zhang , Rujiao Liu , Dhruvit Sutaria , Rucha Sane , Minhao Fan , Rui Wang , Grace Song , Kui Chen , Ksenia Arzumanova , Xichun Hu","doi":"10.1016/j.clinthera.2024.11.021","DOIUrl":"10.1016/j.clinthera.2024.11.021","url":null,"abstract":"<div><h3>Purpose</h3><div>Ipatasertib is a selective inhibitor of Akt, a frequently activated protein kinase that plays a critical role in human cancers. The current clinical trial aimed to assess the pharmacokinetic properties, safety, and tolerability of ipatasertib administered to Chinese patients with locally advanced or metastatic solid tumors.</div></div><div><h3>Methods</h3><div>A Phase I, single-arm, open-label study was performed in Chinese patients with locally advanced or metastatic solid tumors for whom standard therapy either does not exist or has proven ineffective. Four hundred milligrams of ipatasertib was administered to patients as a single agent, starting with a single dose for 7 days and continuous daily dosing for 21 days, followed by 7 days off schedule. The pharmacokinetic properties of ipatasertib and its major metabolite M1 (GO37220) after single and multiple dose administration were assessed using a validated liquid chromatography–tandem mass spectrometry assay method. Safety was assessed throughout the study, and adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Tumor response was assessed by the investigator using Response Evaluation Criteria in Solid Tumors version 1.1.</div></div><div><h3>Findings</h3><div>Fourteen patients were enrolled, and all enrolled patients received at least 1 dose of the study treatment. Ipatasertib and M1 exposures were slightly higher than previously reported but comparable with exposures observed within the Asian population. Ipatasertib as a single agent demonstrated a manageable safety profile in Chinese patients, which is aligned with prior observation in global studies. Limited efficacy was observed in these patients with heavily pretreated diverse solid tumors.</div></div><div><h3>Implications</h3><div>This study of the pharmacokinetic properties, safety, and efficacy of ipatasertib in Chinese patients eventually contributed toward the development of Akt inhibitors in China. ClinicalTrials.gov identifier: NCT04341259.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"47 2","pages":"Pages 128-134"},"PeriodicalIF":3.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.clinthera.2024.11.011
Shu-Wei Hsu MS , Shao-Chin Chiang PharmD , Jason C. Hsu PhD , Yu Ko PhD
Background
Breast cancer patients receiving chemotherapy may develop a serious complication called febrile neutropenia (FN). We aimed to validate and compare three existing FN prediction models for breast cancer patients receiving chemotherapy in Taiwan.
Patients and methods
This was a retrospective observational real-world study. Data were acquired from the clinical research databases of three study hospitals. Breast cancer patients who have received at least one antineoplastic chemotherapy drug were chosen for the analysis. For evaluating the occurrence of FN, we used both broad (a body temperature above 38°C with an absolute neutrophil count (ANC) below 0.5 × 109/L or a body temperature above 38°C with a diagnosis of neutropenia) and narrow definitions (having both fever and neutropenia diagnoses or having both neutropenia and infection diagnoses). Sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) were calculated for each selected FN model.
Results
Among the 1903 patients identified, when the broad and narrow definitions of FN were applied, 70 (3.7%) and 60 (3.2%) patients developed FN in the first cycle, respectively. Using the broad FN definition, Aagaard's model was the highest in sensitivity (90.0%), followed by Chantharakhit's (40.0%) and Chen's (7.2%); in specificity, Chen's (93.6%) was the highest. In addition, the accuracy was highest with the Chen model (90.4%). All three models’ PPVs were low, ranging from 0.5% to 4.2%, but all three models’ NPVs were over 96.3%. When the narrow FN definition was used, Chantharakhit's model showed a relatively high improvement in sensitivity (53.3%) and PPV (3.9%) while negligible increases or even slight decreases were seen in the other two models and in the other performance indicators of Chantharakhit's model.
Conclusion
The results of this study provide important information for clinicians when selecting models to identify patients at high-risk of FN. As the model performance observed was less than satisfactory, improving the prediction ability of the models is needed.
{"title":"Validation of Risk Models for Predicting Febrile Neutropenia Among Breast Cancer Patients Receiving Chemotherapy: A Real-World Study","authors":"Shu-Wei Hsu MS , Shao-Chin Chiang PharmD , Jason C. Hsu PhD , Yu Ko PhD","doi":"10.1016/j.clinthera.2024.11.011","DOIUrl":"10.1016/j.clinthera.2024.11.011","url":null,"abstract":"<div><h3>Background</h3><div>Breast cancer patients receiving chemotherapy may develop a serious complication called febrile neutropenia (FN). We aimed to validate and compare three existing FN prediction models for breast cancer patients receiving chemotherapy in Taiwan.</div></div><div><h3>Patients and methods</h3><div>This was a retrospective observational real-world study. Data were acquired from the clinical research databases of three study hospitals. Breast cancer patients who have received at least one antineoplastic chemotherapy drug were chosen for the analysis. For evaluating the occurrence of FN, we used both broad (a body temperature above 38°C with an absolute neutrophil count (ANC) below 0.5 × 10<sup>9</sup>/L or a body temperature above 38°C with a diagnosis of neutropenia) and narrow definitions (having both fever and neutropenia diagnoses or having both neutropenia and infection diagnoses). Sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) were calculated for each selected FN model.</div></div><div><h3>Results</h3><div>Among the 1903 patients identified, when the broad and narrow definitions of FN were applied, 70 (3.7%) and 60 (3.2%) patients developed FN in the first cycle, respectively. Using the broad FN definition, Aagaard's model was the highest in sensitivity (90.0%), followed by Chantharakhit's (40.0%) and Chen's (7.2%); in specificity, Chen's (93.6%) was the highest. In addition, the accuracy was highest with the Chen model (90.4%). All three models’ PPVs were low, ranging from 0.5% to 4.2%, but all three models’ NPVs were over 96.3%. When the narrow FN definition was used, Chantharakhit's model showed a relatively high improvement in sensitivity (53.3%) and PPV (3.9%) while negligible increases or even slight decreases were seen in the other two models and in the other performance indicators of Chantharakhit's model.</div></div><div><h3>Conclusion</h3><div>The results of this study provide important information for clinicians when selecting models to identify patients at high-risk of FN. As the model performance observed was less than satisfactory, improving the prediction ability of the models is needed.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"47 2","pages":"Pages e1-e4"},"PeriodicalIF":3.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.clinthera.2024.11.018
Yabin Zhu MMed , Lin Jiang MMed , Canlin Sun MMed , Yunxiang Li MBBS , Hong Xie MD
Background
Postoperative nausea and vomiting (PONV) is among the most common adverse events, accompanied with impaired prognosis. This study aimed to investigate independent predictors for PONV after laparoscopic surgery for gynecologic cancers and identify a nomogram model.
Methods
Elderly patients who underwent laparoscopic surgery for gynecologic cancers between 2021 and 2024 were retrospectively enrolled. The primary observational endpoint was set as the occurrence of PONV within 72 h after surgery. Independent risk factors associated with PONV were identified by binary logistic regression, and further incorporated into the nomogram prediction mode by R.
Results
Of 337 enrolled patients, 104 experienced PONV with an overall incidence of 30.9%. Multivariate logistic regression analysis indicated body mass index (BMI) ≥ 24.0 (OR: 2.67, 95% CI: 1.37–5.23, P = 0.004), Afpel score (OR: 6.54, 95% CI: 3.52–12.15, P < 0.001), anxiety (OR: 3.14, 95% CI: 1.16–8.50, P = 0.025), 5-hydroxytryptamine (5-HT) (OR: 1.05, 95% CI: 1.02–1.07, P < 0.001), prostaglandin E2 (PGE2) (OR: 1.05, 95% CI: 1.01–1.08, P = 0.007), and albumin/fibrinogen ratio (AFR) (OR: 0.40, 95% CI: 0.28–0.56, P < 0.001) were six independent risk factors for PONV. The nomogram model based on these factors has good predictive value for PONV, with an AUC of 0.898.
Conclusions
This study identified an individual nomogram prediction model to visually represent the regression model for predicting PONV after laparoscopic surgery for gynecologic cancers.
{"title":"A Prediction Model for Postoperative Nausea and Vomiting After Laparoscopic Surgery for Gynecologic Cancers","authors":"Yabin Zhu MMed , Lin Jiang MMed , Canlin Sun MMed , Yunxiang Li MBBS , Hong Xie MD","doi":"10.1016/j.clinthera.2024.11.018","DOIUrl":"10.1016/j.clinthera.2024.11.018","url":null,"abstract":"<div><h3>Background</h3><div>Postoperative nausea and vomiting (PONV) is among the most common adverse events, accompanied with impaired prognosis. This study aimed to investigate independent predictors for PONV after laparoscopic surgery for gynecologic cancers and identify a nomogram model.</div></div><div><h3>Methods</h3><div>Elderly patients who underwent laparoscopic surgery for gynecologic cancers between 2021 and 2024 were retrospectively enrolled. The primary observational endpoint was set as the occurrence of PONV within 72 h after surgery. Independent risk factors associated with PONV were identified by binary logistic regression, and further incorporated into the nomogram prediction mode by R.</div></div><div><h3>Results</h3><div>Of 337 enrolled patients, 104 experienced PONV with an overall incidence of 30.9%. Multivariate logistic regression analysis indicated body mass index (BMI) ≥ 24.0 (OR: 2.67, 95% CI: 1.37–5.23, <em>P</em> = 0.004), Afpel score (OR: 6.54, 95% CI: 3.52–12.15, <em>P</em> < 0.001), anxiety (OR: 3.14, 95% CI: 1.16–8.50, <em>P</em> = 0.025), 5-hydroxytryptamine (5-HT) (OR: 1.05, 95% CI: 1.02–1.07, <em>P</em> < 0.001), prostaglandin E2 (PGE2) (OR: 1.05, 95% CI: 1.01–1.08, <em>P</em> = 0.007), and albumin/fibrinogen ratio (AFR) (OR: 0.40, 95% CI: 0.28–0.56, <em>P</em> < 0.001) were six independent risk factors for PONV. The nomogram model based on these factors has good predictive value for PONV, with an AUC of 0.898.</div></div><div><h3>Conclusions</h3><div>This study identified an individual nomogram prediction model to visually represent the regression model for predicting PONV after laparoscopic surgery for gynecologic cancers.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"47 2","pages":"Pages 143-147"},"PeriodicalIF":3.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.clinthera.2024.11.023
Jonathan D. Santoro MD , Lina Nguyen RN , Nicole A. Nishimori BS , Ruby Ferris BS , Benjamin N. Vogel BS , Natalie K. Boyd BS , Lilia Kazerooni BS , Shermila Pia MD , Mellad M. Khoshnood MD , Saba Jafarpour MD
Purpose
Down syndrome regression disorder (DSRD) is a rare neuropsychiatric condition affecting otherwise healthy individuals with Down syndrome. Multiple studies on DSRD have revealed that immunotherapy with intravenous immunoglobulin (IVIg) is both safe and effective, although site of infusion has never been studied. This study sought to evaluate the safety and tolerability of IVIg in individuals with DSRD receiving home-based infusions.
Methods
A single-center, retrospective chart review evaluating infusion reactions was performed for individuals meeting criteria for DSRD and having received IVIg infusions between 2019 and 2024. Adverse events (AEs) were evaluated for severity and need for alterations in infusion plan. A cohort of individuals receiving home-based infusions was compared with a cohort of individuals receiving infusions at an academic medical center.
Findings
A total of 315 individuals (162 institutional infusions [51%] and 153 home infusions [49%]) met the inclusion criteria. There were no statistical differences between the demographic and clinical features of the cohorts. Individuals receiving home infusions had the same rate of AE during an infusion (P = 0.14), although they did have a lower number of total AEs (P < 0.001). Individuals receiving home infusions experienced a lower number of behavioral issues with infusions (P = 0.03) and had significantly lower discontinuations of infusions secondary to behavioral issues (P = 0.04).
Implications
Rates of AEs and serious AEs in those with DSRD were the same regardless of site of infusion. These data should be considered in policy regarding the appropriateness of home-based infusions as a safe alternative, when suitable for patients and caregivers, for individuals with DSRD.
{"title":"Safety and Tolerability of Home Infusions in Down Syndrome Regression Disorder","authors":"Jonathan D. Santoro MD , Lina Nguyen RN , Nicole A. Nishimori BS , Ruby Ferris BS , Benjamin N. Vogel BS , Natalie K. Boyd BS , Lilia Kazerooni BS , Shermila Pia MD , Mellad M. Khoshnood MD , Saba Jafarpour MD","doi":"10.1016/j.clinthera.2024.11.023","DOIUrl":"10.1016/j.clinthera.2024.11.023","url":null,"abstract":"<div><h3>Purpose</h3><div>Down syndrome regression disorder (DSRD) is a rare neuropsychiatric condition affecting otherwise healthy individuals with Down syndrome. Multiple studies on DSRD have revealed that immunotherapy with intravenous immunoglobulin (IVIg) is both safe and effective, although site of infusion has never been studied. This study sought to evaluate the safety and tolerability of IVIg in individuals with DSRD receiving home-based infusions.</div></div><div><h3>Methods</h3><div>A single-center, retrospective chart review evaluating infusion reactions was performed for individuals meeting criteria for DSRD and having received IVIg infusions between 2019 and 2024. Adverse events (AEs) were evaluated for severity and need for alterations in infusion plan. A cohort of individuals receiving home-based infusions was compared with a cohort of individuals receiving infusions at an academic medical center.</div></div><div><h3>Findings</h3><div>A total of 315 individuals (162 institutional infusions [51%] and 153 home infusions [49%]) met the inclusion criteria. There were no statistical differences between the demographic and clinical features of the cohorts. Individuals receiving home infusions had the same rate of AE during an infusion (<em>P</em> = 0.14), although they did have a lower number of total AEs (<em>P</em> < 0.001). Individuals receiving home infusions experienced a lower number of behavioral issues with infusions (<em>P</em> = 0.03) and had significantly lower discontinuations of infusions secondary to behavioral issues (<em>P</em> = 0.04).</div></div><div><h3>Implications</h3><div>Rates of AEs and serious AEs in those with DSRD were the same regardless of site of infusion. These data should be considered in policy regarding the appropriateness of home-based infusions as a safe alternative, when suitable for patients and caregivers, for individuals with DSRD.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"47 2","pages":"Pages e27-e33"},"PeriodicalIF":3.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.clinthera.2024.11.019
Andrea Greco MSc , Geert W.J. Frederix PhD , Lotty Hooft PhD , Renske M.T. Ten Ham PhD
<div><h3>Purpose</h3><div>Managed Entry Agreements (MEAs) are agreements between firms and competent authorities for pricing and reimbursement, designed to enable coverage of new medicines while managing uncertainties around their financial impact or performance. Although these agreements can facilitate patient access, their complexity and costs seem to dampen enthusiasm for implementation. Nevertheless, MEAs remain a potential route, particularly for high-cost drugs with uncertain value claims. Given their pivotal role in bridging Advanced Therapy Medicinal Products (ATMPs) to patients, their foreseeable future implementation calls for a specific investigation of their associated challenges and opportunities. Therefore, this work aims to identify challenges and opportunities in implementing MEAs specifically for ATMPs.</div></div><div><h3>Methods</h3><div>A systematic literature review was conducted on PubMed, MEDLINE, Scopus, and Google Scholar, based on the updated Preferred Reporting Items for Systematic Review and Meta-Analysis. This has been supplemented by a snowball search. Through the thematic content analysis, opportunities and challenges were identified and grouped into themes and subthemes. Afterward, the subgroup analysis was performed to investigate challenges and opportunities with outcome-based agreements (OBAs) versus financial-based agreements (FBAs), jurisdiction, and ATMP type.</div></div><div><h3>Findings</h3><div>Of the 787 peer-reviewed articles, 42 met the inclusion criteria. Challenges and opportunities were clustered into the mentioned themes: evidence generation and data management, financial and reimbursement, administration and resources, negotiation, and governance, law, and regulations. Of note, no specific challenges or opportunities were found to be cell- or gene-therapy-specific, but certain challenges seem amplified for ATMPs. Several differences emerged per MEA type and jurisdiction. OBAs are described to reward innovative and effective treatments and boost research and development (R&D) returns. FBAs improve cost-effectiveness ratios but can negatively affect curative ATMP's revenues. Still, their versatility facilitates payer engagement in MEA combinations (eg, OBA with spread payments). The US decentralized health care system reported additional implementation challenges to OBAs. Each payer internally decides on reimbursement, and coordination among private payers is hindered by antitrust law. Yet, a new Cell and Gene Therapy Access model has been proposed. This would allow manufacturers to negotiate OBAs directly with the Centers for Medicare & Medicaid Services avoiding individual negotiation with each state. In Europe, there is an evident interest in implementing spread payments, yet accounting rules currently hamper their implementation.</div></div><div><h3>Implications</h3><div>This work offers insights into challenges and opportunities in MEAs implementation for ATMPs by investigating differenc
{"title":"A Systematic Review of Challenges and Opportunities in the Implementation of Managed Entry Agreements for Advanced Therapy Medicinal Products","authors":"Andrea Greco MSc , Geert W.J. Frederix PhD , Lotty Hooft PhD , Renske M.T. Ten Ham PhD","doi":"10.1016/j.clinthera.2024.11.019","DOIUrl":"10.1016/j.clinthera.2024.11.019","url":null,"abstract":"<div><h3>Purpose</h3><div>Managed Entry Agreements (MEAs) are agreements between firms and competent authorities for pricing and reimbursement, designed to enable coverage of new medicines while managing uncertainties around their financial impact or performance. Although these agreements can facilitate patient access, their complexity and costs seem to dampen enthusiasm for implementation. Nevertheless, MEAs remain a potential route, particularly for high-cost drugs with uncertain value claims. Given their pivotal role in bridging Advanced Therapy Medicinal Products (ATMPs) to patients, their foreseeable future implementation calls for a specific investigation of their associated challenges and opportunities. Therefore, this work aims to identify challenges and opportunities in implementing MEAs specifically for ATMPs.</div></div><div><h3>Methods</h3><div>A systematic literature review was conducted on PubMed, MEDLINE, Scopus, and Google Scholar, based on the updated Preferred Reporting Items for Systematic Review and Meta-Analysis. This has been supplemented by a snowball search. Through the thematic content analysis, opportunities and challenges were identified and grouped into themes and subthemes. Afterward, the subgroup analysis was performed to investigate challenges and opportunities with outcome-based agreements (OBAs) versus financial-based agreements (FBAs), jurisdiction, and ATMP type.</div></div><div><h3>Findings</h3><div>Of the 787 peer-reviewed articles, 42 met the inclusion criteria. Challenges and opportunities were clustered into the mentioned themes: evidence generation and data management, financial and reimbursement, administration and resources, negotiation, and governance, law, and regulations. Of note, no specific challenges or opportunities were found to be cell- or gene-therapy-specific, but certain challenges seem amplified for ATMPs. Several differences emerged per MEA type and jurisdiction. OBAs are described to reward innovative and effective treatments and boost research and development (R&D) returns. FBAs improve cost-effectiveness ratios but can negatively affect curative ATMP's revenues. Still, their versatility facilitates payer engagement in MEA combinations (eg, OBA with spread payments). The US decentralized health care system reported additional implementation challenges to OBAs. Each payer internally decides on reimbursement, and coordination among private payers is hindered by antitrust law. Yet, a new Cell and Gene Therapy Access model has been proposed. This would allow manufacturers to negotiate OBAs directly with the Centers for Medicare & Medicaid Services avoiding individual negotiation with each state. In Europe, there is an evident interest in implementing spread payments, yet accounting rules currently hamper their implementation.</div></div><div><h3>Implications</h3><div>This work offers insights into challenges and opportunities in MEAs implementation for ATMPs by investigating differenc","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"47 2","pages":"Pages e16-e26"},"PeriodicalIF":3.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Growing evidence has suggested that the consumption of chia seed can decrease blood pressure and obesity in adults. However, even studies have reported uncertain findings. The current meta-analysis aimed to assess the findings of randomized controlled trials (RCTs) on the efficacy of chia seed supplementation on blood pressure (systolic blood pressure [SBP], diastolic blood pressure [DBP]) and body composition (waist circumference [WC], weight, body mass index [BMI]) in adults.
Methods
A systematic search of the literature was carried out in the PubMed, Web of Knowledge, Scopus, Cochrane Central Library, and EMBASE from inception up to October 2024. Data were extracted and analyzed using a random-effects model, and reported as weighted mean differences (WMD) with 95% confidence intervals (CI).
Findings
A total of eight RCTs involving 372 participants were included in the meta-analysis. The results showed that chia consumption significantly reduced DBP (WMD: -7.49 mmHg; 95% CI: -9.64, -5.34; P < 0.001) and SBP (WMD: -5.61 mmHg; 95% CI: -8.77, -2.44; P = 0.001). Moreover, consuming chia seeds was linked to a notable decrease in WC (WMD: -1.46 cm; 95% CI: -2.68, -0.25; P = 0.01), but it had no significant effect on, BMI (WMD: -0.31 kg/m2; 95% CI: - 0.96, 0.34; P = 0.34) and weight (WMD: 0.09 kg; 95% CI: -0.76, 0.93; P = 0.84).
Implications
Chia consumption can significantly reduce SBP, DBP, and WC in adults, but no significant impact was showed on BMI and weight. To verify these results, more studies involving a greater number of participants are required.
{"title":"The Effects of Chia Seed (Salvia hispanica L.) Consumption on Blood Pressure and Body Composition in Adults: A Systematic Review and Meta-analysis of Randomized Controlled Trials","authors":"Mohamed J. Saadh , Munthar Kadhim Abosaoda , Lalji Baldaniya , Rishiv Kalia , Renu Arya , Shivang Mishra , Ashish Singh Chauhan , Abhinav Kumar , Mohamad Alizadeh","doi":"10.1016/j.clinthera.2024.11.012","DOIUrl":"10.1016/j.clinthera.2024.11.012","url":null,"abstract":"<div><h3>Purpose</h3><div>Growing evidence has suggested that the consumption of chia seed can decrease blood pressure and obesity in adults. However, even studies have reported uncertain findings. The current meta-analysis aimed to assess the findings of randomized controlled trials (RCTs) on the efficacy of chia seed supplementation on blood pressure (systolic blood pressure [SBP], diastolic blood pressure [DBP]) and body composition (waist circumference [WC], weight, body mass index [BMI]) in adults.</div></div><div><h3>Methods</h3><div>A systematic search of the literature was carried out in the PubMed, Web of Knowledge, Scopus, Cochrane Central Library, and EMBASE from inception up to October 2024. Data were extracted and analyzed using a random-effects model, and reported as weighted mean differences (WMD) with 95% confidence intervals (CI).</div></div><div><h3>Findings</h3><div>A total of eight RCTs involving 372 participants were included in the meta-analysis. The results showed that chia consumption significantly reduced DBP (WMD: -7.49 mmHg; 95% CI: -9.64, -5.34; <em>P</em> < 0.001) and SBP (WMD: -5.61 mmHg; 95% CI: -8.77, -2.44; <em>P</em> = 0.001). Moreover, consuming chia seeds was linked to a notable decrease in WC (WMD: -1.46 cm; 95% CI: -2.68, -0.25; <em>P</em> = 0.01), but it had no significant effect on, BMI (WMD: -0.31 kg/m<sup>2</sup>; 95% CI: - 0.96, 0.34; <em>P</em> = 0.34) and weight (WMD: 0.09 kg; 95% CI: -0.76, 0.93; <em>P</em> = 0.84).</div></div><div><h3>Implications</h3><div>Chia consumption can significantly reduce SBP, DBP, and WC in adults, but no significant impact was showed on BMI and weight. To verify these results, more studies involving a greater number of participants are required.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"47 2","pages":"Pages 168-175"},"PeriodicalIF":3.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142821900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.clinthera.2024.11.017
Xin Yu , Yi Zhang , Zhuoling An , Xin Feng , Hui Yang
Purpose
Calcineurin inhibitors (CNIs) are currently the first-line drugs for preventing and treating post-transplant rejection in organ transplant recipients. However, these drugs, especially tacrolimus, have the potential to induce thrombotic microangiopathy (TMA), a rare but potentially fatal complication that can develop following transplantation. This condition has garnered considerable attention within the medical community. Consequently, the study conducted an observational retrospective pharmacovigilance study to investigate the risk signal of thrombotic microangiopathy associated with CNIs.
Methods
A retrospective pharmacovigilance study was conducted to investigate the relationship between CNIs and TMA using data from the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. A disproportionality analysis was performed to evaluate risk signals.
Findings
A total of 1019 cases of CNIs-associated TMA were identified, with 785 cases attributed to tacrolimus and 234 cases to cyclosporine A. Overall, the incidence of CNIs related TMA was higher compared to the entire database (ROR = 29.76 [27.84–31.82], IC = 4.64 [4.55–4.74]). A stronger signal was observed for tacrolimus-associated TMA compared to cyclosporine A (ROR = 3.72 [3.20–4.23], IC = 0.63 [0.50–0.77]). Additionally, residing in the Americas may be a protective factor against mortality in tacrolimus-related TMA, while for cyclosporine A-related TMA, patients from Asia and female patients have a significantly higher risk of death.
Implications
Clinician awareness of CNIs-associated TMA needs to be heightened, particularly with tacrolimus. Special attention should be given to patients’ geographic regions and gender differences.
目的：钙调磷酸酶抑制剂（calcalineurin inhibitors, CNIs）是目前预防和治疗器官移植后排斥反应的一线药物。然而，这些药物，尤其是他克莫司，有可能诱发血栓性微血管病变（TMA），这是一种罕见但潜在致命的并发症，可在移植后发生。这种情况在医学界引起了相当大的关注。因此，该研究进行了一项观察性回顾性药物警戒研究，以调查与cni相关的血栓性微血管病变的风险信号。方法：采用美国食品药品监督管理局（FDA）不良事件报告系统（FAERS）数据库的数据，进行回顾性药物警戒研究，探讨CNIs与TMA之间的关系。进行歧化分析以评估风险信号。结果：共发现1019例CNIs相关TMA，其中785例归因于他克莫司，234例归因于环孢素A。总体而言，与整个数据库相比，CNIs相关TMA的发生率较高（ROR = 29.76 [27.84-31.82], IC = 4.64[4.55-4.74]）。与环孢素A相比，他克莫司相关的TMA信号更强（ROR = 3.72 [3.20-4.23], IC = 0.63[0.50-0.77]）。此外，居住在美洲可能是预防他克莫司相关TMA死亡率的保护因素，而对于环孢素a相关TMA，来自亚洲的患者和女性患者的死亡风险要高得多。意义：临床医生需要提高对cnis相关TMA的认识，特别是他克莫司。应特别注意患者的地理区域和性别差异。
{"title":"Thrombotic Microangiopathy Associated with Calcineurin Inhibitors: A Real-World Analysis of Postmarketing Surveillance Data","authors":"Xin Yu , Yi Zhang , Zhuoling An , Xin Feng , Hui Yang","doi":"10.1016/j.clinthera.2024.11.017","DOIUrl":"10.1016/j.clinthera.2024.11.017","url":null,"abstract":"<div><h3>Purpose</h3><div>Calcineurin inhibitors (CNIs) are currently the first-line drugs for preventing and treating post-transplant rejection in organ transplant recipients. However, these drugs, especially tacrolimus, have the potential to induce thrombotic microangiopathy (TMA), a rare but potentially fatal complication that can develop following transplantation. This condition has garnered considerable attention within the medical community. Consequently, the study conducted an observational retrospective pharmacovigilance study to investigate the risk signal of thrombotic microangiopathy associated with CNIs.</div></div><div><h3>Methods</h3><div>A retrospective pharmacovigilance study was conducted to investigate the relationship between CNIs and TMA using data from the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. A disproportionality analysis was performed to evaluate risk signals.</div></div><div><h3>Findings</h3><div>A total of 1019 cases of CNIs-associated TMA were identified, with 785 cases attributed to tacrolimus and 234 cases to cyclosporine A. Overall, the incidence of CNIs related TMA was higher compared to the entire database (ROR = 29.76 [27.84–31.82], IC = 4.64 [4.55–4.74]). A stronger signal was observed for tacrolimus-associated TMA compared to cyclosporine A (ROR = 3.72 [3.20–4.23], IC = 0.63 [0.50–0.77]). Additionally, residing in the Americas may be a protective factor against mortality in tacrolimus-related TMA, while for cyclosporine A-related TMA, patients from Asia and female patients have a significantly higher risk of death.</div></div><div><h3>Implications</h3><div>Clinician awareness of CNIs-associated TMA needs to be heightened, particularly with tacrolimus. Special attention should be given to patients’ geographic regions and gender differences.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"47 2","pages":"Pages 117-122"},"PeriodicalIF":3.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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