Transjugular Transcatheter Tricuspid Valve Replacement: Early Compassionate Use Outcomes.

BACKGROUND: Data on procedural and early outcomes after transjugular transcatheter tricuspid valve replacement (TTVR) are limited. OBJECTIVES: This study sought to evaluate first-in-man procedural and clinical outcomes after transjugular TTVR with a special focus on patients who received large device sizes in whom TTVR outcomes have been questioned. METHODS: The retrospective registry included patients who underwent TTVR using the LuX-Valve Plus system (Jenscare Biotechnology Co Ltd) for symptomatic tricuspid regurgitation (TR) from January 2022 until February 2024 at 15 international centers in a compassionate use setting. The endpoints were procedural TR reduction, in-hospital death, adverse events, and 1-month survival. We further stratified results according to the size of the implanted device (<55 vs ≥55 mm). RESULTS: The registry included a total of 76 patients at a median age of 78 years (Q1-Q3: 72-83 years, 47.4% women). TR was reduced to ≤2+ and ≤1+ in 94.7% and 90.8% of patients (75.0% of patients received TTVR devices ≥55 mm) with well-sustained results at 1-month follow-up (TR ≤2+ in 95.0% and ≤1+ 86.8%). Residual TR was paravalvular in all cases. In-hospital death occurred in 4 patients (5.3%). Four patients (5.3%) underwent cardiac surgery during index hospitalization. Major in-hospital bleeding events occurred in 5 patients (6.6%). New in-hospital pacemaker implantation was required in 3.9% of patients in the overall cohort (5.7% in "pacemaker-naive" individuals). No cases of valve thrombosis, stroke, myocardial infarction, or pulmonary embolism were observed. At 1-month follow-up, survival was 94.4%, and NYHA functional class significantly improved. One further patient received a pacemaker, 1 further bleeding event occurred, and 2 patients underwent reintervention or surgery within the first 30 days after TTVR. No differences in procedural outcomes or adverse events were observed after stratification for valve size. CONCLUSIONS: Transjugular TTVR appears to be a safe and effective treatment option for patients with severe TR with comparable outcomes in very large tricuspid anatomies.

The Early Access and the Potential Cost Savings by the Compassionate Use of Onco-haematological Drugs: Results from the Italian Study Compass-O.

BACKGROUND: Compassionate drug use (CDU) provides early access to not yet authorised medicines and is funded by pharmaceutical companies. The observational retrospective study Compass-O monitored the CDU of onco-haematological drugs, managed by seven Italian units for cytotoxic drug preparations (Unità Farmaci Antiblastici [UFA]), between 1 January, 2016 and 31 December, 2021. OBJECTIVE: We aimed to evaluate the CDU of onco-haematological drugs managed by seven Italian UFA, between 2016 and 2021. METHODS: The seven UFA provided anonymised data concerning CDU approved in the study period. The early access and potential cost savings for the National Health System (Servizio Sanitario Nazionale [SSN]) were analysed for CDU concerning drug-therapeutic indication combinations with complete data and reimbursed by SSN up to December 2023 (date of study execution), according to the executive decision of the Italian Medicines Agency (Agenzia Italiana del Farmaco [AIFA]). Both analyses distinguished solid/liquid tumours and categorised the combinations as innovative (fully/conditionally) or non-innovative based on AIFA assessments. RESULTS: Compass-O collected 783 CDU authorisations, with 572 (73.1%) analysable in terms of early access and cost savings. On average, early access amounted to 514 days and the total cost savings was €376,115,801. Compassionate drug use approvals involved mainly solid tumours (93.7% vs 6.3% for liquid tumours), and the combination of trastuzumab emtansine-breast cancer was the most dispensed (n = 73; early access = 426 days; potential cost savings: €610,388). Out of 572 CDU approvals, 200 (35%) were innovative drug-therapeutic indication combinations, with 598 days of early access and a total potential saving of €113,124,069. CONCLUSIONS: The study Compass-O showed a significant economic burden of CDU and a relevant need for early access, particularly for innovative drugs. However, there is currently no structured monitoring of CDU in Italy, suggesting the need for a national observatory, of which Compass-O can be the pilot phase.

Longitudinal experiences of Canadians receiving compassionate access to psilocybin-assisted psychotherapy.

Recent clinical trials have found that the serotonergic psychedelic psilocybin effectively alleviates anxiodepressive symptoms in patients with life-threatening illnesses when given in a supportive environment. These outcomes prompted Canada to establish legal pathways for therapeutic access to psilocybin, coupled with psychological support. Despite over one-hundred Canadians receiving compassionate access since 2020, there has been little examination of these 'real-world' patients. We conducted a prospective longitudinal survey which focused on Canadians who were granted Section 56 exemptions for legal psilocybin-assisted psychotherapy. Surveys assessing various symptom dimensions were conducted at baseline, two weeks following the session (endpoint), and optionally one day post-session. Participant characteristics were examined using descriptive statistics, and paired sample t-tests were used to quantify changes from baseline to the two-week post-treatment endpoint. Eight participants with Section 56 exemptions (four females, Mage = 52.3 years), all with cancer diagnoses, fully completed baseline and endpoint surveys. Significant improvements in anxiety and depression symptoms, pain, fear of COVID-19, quality of life, and spiritual well-being were observed. Attitudes towards death, medical assistance in dying, and desire for hastened death remained unchanged. While most participants found the psilocybin sessions highly meaningful, if challenging, one reported a substantial decrease in well-being due to the experience. These preliminary data are amongst the first to suggest that psilocybin-assisted psychotherapy can produce psychiatric benefits in real-world patients akin to those observed in clinical trials. Limited enrollment and individual reports of negative experiences indicate the need for formal real-world evaluation programs to surveil the ongoing expansion of legal access to psychedelics.

Compassionate drug uses in Italy. Analysis at single-center level.

AIMS: Using a database from two pharmaceutical companies that managed several compassionate use programs in the last few years in Italy, we have previously analyzed the data by the number of patients and centers in each region and province, showing that the use of compassionate drugs is largely diffused in the country, in a manner directly related to the size of population of each region. In the present study we used the same database to expand the analysis to single-center level, aiming to test the hypothesis whether, despite a good diffusion of compassionate drug uses in each region, the majority of them concentrates within a relatively low number of centers. METHODS: Data from different programs were grouped per center, and the centers were ordered per the number of compassionate uses dispensed, and per region. Two cutoff levels, at 75% and 90%, were drawn to look at the number of centers accounting for such percentages of compassionate uses in each region. RESULTS: Out of 343 centers throughout Italy, 93 and 156 centers (i.e., 27.11% and 45.48% of the total) account for about 75% and 90% of all compassionate drugs dispensed in Italy. In 6 regions out of 20 (Valle d'Aosta, Liguria, Umbria, Lazio, Molise and Campania) the centers accounting for 75% of all compassionate drugs dispensed are located in a single town. Forty and 20 out of the 93 centers dispensing 75% of all compassionate drugs are academic hospitals and research hospitals (Istituti di Ricovero e Cura a Carattere Scientifico, IRCCS), respectively. CONCLUSIONS: In this study we have demonstrated that, in spite of widespread diffusion of compassionate drug uses in all Italian regions, their management is restricted to a relatively low number of dispensing centers in each region.

The Impact of Umbilical Cord Mesenchymal Stem Cells on Motor Function in Children with Cerebral Palsy: Results of a Real-world, Compassionate use Study.

The aim of this study was to analyze the impact of human umbilical cord-derived MSCs (hUC-MSCs) on motor function in children with cerebral palsy (CP). The study enrolled 152 children with CP who received up to two courses of five hUC-MSCs injections. Children's motor functions were assessed with the Gross Motor Function Measure (GMFM), 6-Minute Walk Test (6-MWT), Timed Up and Go test (Up&Go test), and Lovett's test, and mental abilities were assessed with the Clinical Global Impression (CGI) scale. Data collected at visit 1 (baseline) and visit 5 (after four injections) were analyzed retrospectively. After four hUC-MSCs administrations, all evaluated parameters improved. The change in GMFM score, by a median of 1.9 points (IQR: 0.0-8.0), correlated with age. This change was observed in all GFMCS groups and was noticed in all assessed GMFM areas. A median increase of 75 m (IQR: 20.0-115.0) was noted on the 6-MWT, and this correlated with GMFM score change. Time on the Up&Go test was reduced by a median of 2 s (IQR: -3 to - 1) and the change correlated with age, GMFM score at baseline, and the difference observed on the 6-MWT. Results of Lovett's test indicated slight changes in muscle strength. According to the CGI, 75.5% (96/151) of children were seriously (level VI) or significantly ill (level V) at the 1st visit, with any improvement observed in 63.6% (96/151) of patients at the 5th visit, 23.8% (36/151) with improvement (level II) or great improvement (level I). In conclusion, the application of hUC-MSCs generally enhanced functional performance, but individual responses varied. The therapy also benefited children with high level of disability but not to the same extent as the initially less disabled children. Although younger patients responded better to the treatment, older children can also benefit. Trial Registration 152/2018/KB/VII and 119/2021/KB/VIII. Retrospective registration in ClinicalTrials: ongoing.

Administration of 4% tetrasodium EDTA lock solution and central venous catheter complications in high-risk pediatric patients with intestinal failure: A retrospective cohort study.

BACKGROUND: Selection of central venous catheter (CVC) lock solution impacts catheter mechanical complications and central line-associated bloodstream infections (CLABSIs) in pediatric patients with intestinal failure. Disadvantages of the current clinical standards, heparin and ethanol lock therapy (ELT), led to the discovery of new lock solutions. High-risk pediatric patients with intestinal failure who lost access to ELT during a recent shortage were offered enrollment in a compassionate use trial with 4% tetrasodium EDTA (T-EDTA), a lock solution with antimicrobial, antibiofilm, and antithrombotic properties. METHODS: We performed a descriptive cohort study including 14 high-risk pediatric patients with intestinal failure receiving 4% T-EDTA as a daily catheter lock solution. CVC complications were documented (repairs, occlusions, replacements, and CLABSIs). Complication rates on 4% T-EDTA were compared with baseline rates, during which patients were receiving either heparin or ELT (designated as heparin/ELT). RESULTS: Patients initiated 4% T-EDTA at the time they were enrolled in the compassionate use protocol. Use of 4% T-EDTA resulted in a 50% reduction in CVC complications, compared with baseline rates on heparin/ELT (incidence rate ratio: 0.50; 95% CI, 0.25-1.004; P = 0.051). CONCLUSION: In a compassionate use protocol for high-risk pediatric patients with intestinal failure, the use of 4% T-EDTA reduced composite catheter complications, including those leading to emergency department visits, hospital admissions, additional procedures, and mortality. This outcome suggests 4% T-EDTA has benefits over currently available lock solutions.

Outcomes and clinical characteristics of the compassionate use of plitidepsin in COVID-19 patients with solid tumours, haematological malignancies or anti-CD20 antibody treatment.

OBJECTIVE: To study the effect of plitidepsin antiviral treatment in immunocompromised COVID-19 patients with underlying haematological malignancies or solid tumours, particularly those who have undergone anti-CD20 therapies. DESIGN: We conducted a retrospective observational study, involving 54 adults treated with plitidepsin on compassionate use as an antiviral drug. Our analysis compared outcomes between patients with solid tumours and those with haematological malignancies, and a cohort of cases treated or not with anti-CD20 monoclonal antibodies. RESULTS: Patients with a history of anti-CD20 therapies showed a prolonged time-to-negative RT-PCR for SARS-CoV-2 infection compared to non-treated patients (33 d (28;75) vs 15 (11;25); p = .002). Similar results were observed in patients with solid tumours in comparison to those with haematological malignancies (13 (10;16) vs 26 (17;50); p < .001). No serious adverse events were documented. CONCLUSIONS: Patients with haematological malignancies appear to be at a heightened risk for delayed SARS-CoV-2 clearance and subsequent clinical complications. These findings support plitidepsin as a well-tolerated treatment in this high-risk group. A phase II clinical trial (NCT05705167) is ongoing to evaluate plitidepsin as an antiviral drug in this population.KEY POINTSHaematological patients face an increased risk for severe COVID-19.Anti-CD20 therapies could increase fatal outcomes in COVID-19 patients.Persistent viral replication is increased in immunocompromised patients.Plitidepsin does not lead to new serious adverse events in immunocompromised patients.

Outcomes of pirtobrutinib for relapsed/refractory mantle cell lymphoma in compassionate use program in Europe.

BACKGROUND: Mantle cell lymphoma (MCL) is a type of B-cell lymphoma that is currently incurable. Pirtobrutinib shows promising response rates in heavily pretreated MCL patients according to the approval study, but the real-world data are scarce. METHODS: In this study, we retrospectively analyzed the efficacy and safety profile of pirtobrutinib in 10 relapsed/refractory MCL patients from compassionate use program (CUP). RESULTS: On average, the patients underwent three lines of systemic therapy prior to pirtobrutinib and were predominantly BTKi exposed (9/10). The best overall response rate (BORR) was 67%. In a median follow-up of 8.6 months, the mean duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were not reached. No new safety signals were documented. CONCLUSIONS: In summary, pirtobrutinib represented a safe and effective treatment option in a small real-world population.

Protocol for phage matching, treatment, and monitoring for compassionate bacteriophage use in non-resolving infections.

Phage therapy has re-emerged as a promising treatment for non-resolving infections. Given the lack of approved phage treatments, there is a need to establish a compassionate use pipeline. Here, we present a protocol for phage matching, treatment, and monitoring for compassionate bacteriophage use in non-resolving infections. We describe steps for consultation and request implementation, evaluating and comparing different aspects of phage activity, and phage production. We then detail procedures for multidisciplinary meetings, ethics approvals, phage therapy, and follow-up. For complete details on the use and execution of this protocol, please refer to Onallah et al.1,2.

Expert opinion on mexiletine treatment in adult patients with myotonic dystrophy.

In France, mexiletine - a class I antiarrhythmic drug - can be prescribed for the symptomatic treatment of myotonia of the skeletal muscles in adult patients with myotonic dystrophy under a compassionate use programme. Mexiletine is used according to its summary of product characteristics, which describes its use for myotonia treatment in adult patients with non-dystrophic myotonia, a different neuromuscular condition without cardiac involvement. A cardiac assessment is required prior to initiation and throughout treatment due to potential proarrhythmic effects. The presence of conduction system disease, the most common cardiac manifestation of myotonic dystrophy, mandates repeated cardiac evaluations in patients with this condition, and becomes even more important when they are given mexiletine. A group of experts, including three neurologists and five cardiologists from French neuromuscular reference centres, were involved in a task force to develop a treatment algorithm to guide mexiletine use in myotonic dystrophy. The recommendations are based on data from a literature review of the safety of mexiletine-treated patients with myotonic dystrophy, the compassionate use protocol for mexiletine and the personal clinical experience of the experts. The main conclusion of the expert group is that, although existing safety data in mexiletine-treated patients with myotonic dystrophy are reassuring, cardiac assessments should be reinforced in such patients compared with mexiletine-treated patients with non-dystrophic myotonia. This expert opinion to guide mexiletine treatment in patients with myotonic dystrophy should help to reduce the risk of severe adverse events and facilitate interactions between specialists involved in the routine care of patients with myotonic dystrophy.

Evaluation of a pharmacist-led workflow for the FDA Expanded Access Program.

PURPOSE: This project aimed to characterize the resources necessary for pharmacists to support the required steps for obtaining and handling investigational drugs outside of a study protocol in the individual patient and intermediate-size population Expanded Access Program (EAP) processes. The second aim was to characterize the types of EAP requests received. SUMMARY: This retrospective, single-center, observational study was performed by reviewing EAP requests initiated at Duke University Hospital (DUH) between August 1, 2017, and February 11, 2023. The annualized cost of unreimbursed EAP study services was projected to be approximately $196,500 at DUH for 2023. Of the 168 EAP requests submitted after the institutional policy requiring pharmacy and therapeutics (P&T) committee approval was established, 162 (96.4%) were approved by the P&T committee. CONCLUSION: Given the lack of published information on a pharmacist-led workflow related to EAP services, this study sought to share DUH's process for managing EAP requests. As there is no mechanism for reimbursement of EAP services, they can be difficult to manage given the labor resources required. Further work is needed to recoup unreimbursed investigational drug service labor costs to ensure compassionate use programs can be implemented in a manner that is financially sustainable for a health system.

Global Risdiplam Compassionate Use Program for Patients with Type 1 or 2 Spinal Muscular Atrophy.

PURPOSE: Spinal muscular atrophy (SMA) is a genetic neuromuscular disease causing progressive muscle weakness and reducing life expectancy. Risdiplam (Evrysdi; Genentech/F. Hoffmann-La Roche Ltd, Basel, Switzerland) is a drug approved for use in the treatment of patients with SMA. The ongoing global risdiplam Compassionate Use Program (CUP), initiated in November 2019, is the largest CUP in SMA, currently providing access to risdiplam for >2000 patients with type 1 or 2 SMA in 59 countries. Here, the challenges and learnings from the risdiplam CUP are presented. METHODS: Enrolled patients (aged ≥2 months) had type 1 or 2 SMA and no alternative treatment options (ie, they were not medically eligible for approved SMA treatments, were unable to continue their SMA treatment due to medical reasons, were at risk for lack/loss of SMA treatment efficacy, or did not qualify for/had no access to SMA treatment within a clinical trial). Requests were made by the treating physicians via an end-to-end system. FINDINGS: The risdiplam CUP highlighted the importance of collaborating with patient advocacy groups early to learn about patients' perspectives on unmet medical needs, understanding the sometimes-unique nature of local regulations and requirements, and adapting physician- and patient-eligibility criteria. Key learnings were obtained from enrolling patients from low- to middle-income countries and from countries without dedicated Compassionate Use regulations, and from operating the CUP during the coronavirus disease 2019 pandemic. IMPLICATIONS: The risdiplam CUP experience was successful in many ways and may help to design and implement future CUPs in rare diseases, as well as patients living in countries or in circumstances in which access to innovative treatments is a challenge.

Sotorasib in KRAS G12C-mutated non-small cell lung cancer: A multicenter real-world experience from the compassionate use program in Germany.

BACKGROUND: Sotorasib is a first-in-class KRAS p.G12C-inhibitor that has entered clinical trials in pretreated patients with non-small cell lung cancer (NSCLC) in 2018. First response rates were promising in the CodeBreaK trials. It remains unclear whether response to sotorasib and outcomes differ in a real-world setting when including patients underrepresented in clinical trials. METHODS: Patients with KRAS p.G12C-mutated advanced or metastatic NSCLC received sotorasib within the German multicenter sotorasib compassionate use program between 2020 to 2022. Data on efficacy, tolerability, and survival were analyzed in the full cohort and in subgroups of special interest such as co-occurring mutations and across PD-L1 expression levels. RESULTS: We analyzed 163 patients who received sotorasib after a median of two treatment lines (range, 0 to 7). Every fourth patient had a poor performance status and 38% had brain metastases (BM). The objective response rate was 38.7%. The median overall survival was 9.8 months (95% CI, 6.5 to not reached). Median real-world (rw) progression-free survival was 4.8 months (9% CI, 3.9 to 5.9). Dose reductions and permanent discontinuation were necessary in 35 (21.5%) and 7 (4.3%) patients, respectively. Efficacy seems to be influenced by PD-L1 expression and a co-occurring KEAP1 mutation. KEAP1 was associated with an inferior survival. Other factors such as BM, STK11, and TP53 mutations had no impact on response and survival. CONCLUSION: First results from a real-world population confirm promising efficacy of sotorasib for the treatment of advanced KRAS p.G12C-mutated NSCLC. Patients with co-occurring KEAP1 mutations seem to derive less benefit.

Theranostic Innovation by Humane N-of-One Cancer Care in Real-World Patients.

Patients with relapsed or refractory metastatic cancer unresponsive to standard therapies have motivated nuclear physicians to develop innovative radioligands, precisely targeted to tumor molecular receptors, for effective treatment of specific advanced malignancies. Individual practitioners in departments of nuclear medicine across the world have performed first-in-human studies on compassionate patient usage N-of-One protocols. These physician-sponsored studies then evolved into early-phase clinical trials and obtained real-world data to demonstrate real-world evidence of effectiveness in prolonging survival and enhancing quality of life of many so-called "End-Stage" cancer patients. Virtually all the therapeutic radiopharmaceuticals in current clinical oncology have been discovered and developed into effective specific treatments of targetable cancers by individual doctors in the course of their hospital practice. Pharma industry was not involved until many years later when performance of mandated Phase 3 randomized controlled trials became necessary to achieve regulatory agency approval. This article traces the history of several novel theranostic agents developed from compassionate N-of-One studies by hospital physicians over the past 36 years. It acknowledges the collegiality and collaboration of individual nuclear medicine specialists, worldwide, in pioneering effective humane therapy of particular advanced cancers unresponsive to conventional treatments.

Ruxolitinib in patients with graft versus host disease (GvHD): findings from a compassionate use program.

The ruxolitinib compassionate use (CU) program offered ruxolitinib to patients ≥2 years of age with confirmed steroid-resistant acute or chronic graft-versus-host disease (aGvHD and cGvHD, respectively). Data from 1180 patients (n = 775, 370 and 35 with cGvHD, aGvHD, and non-specified GvHD, respectively) were analyzed. Most patients had severe cGvHD (56%) or stage III/IV aGvHD (70%) disease and had previously received corticosteroids ( > 80%); ruxolitinib was requested primarily as a second-/third-line option. Patients <12 and ≥12 years old most often received the recommended ruxolitinib doses (5 mg twice daily [BID] and 10 mg BID, respectively); however, 23% and 30% of ≥12 year olds with cGvHD and aGvHD, respectively, received the lower dose of 5 mg BID. Notably, corticosteroid usage decreased with ruxolitinib treatment; at the initial ruxolitinib request, 81% and 91% of patients with cGvHD and aGvHD, respectively, were receiving corticosteroids whereas at resupply, 62% and 64%, respectively, were receiving corticosteroids. Eighty two percent of evaluable patients with cGvHD had a complete or partial response to treatment and 56% of evaluable patients with aGvHD had a best response of grade 0/I. These findings demonstrate the rapid and positive effects of ruxolitinib in patients with GvHD in a real-world setting.