Noncomparative Trial Research Articles

Neoadjuvant immunotherapy with or without chemotherapy in locally advanced oral squamous cell carcinoma: Randomized, two-arm, phase 2 trial.

Patients with locally advanced oral squamous cell carcinoma (OSCC) have poor outcomes with standard care. Neoadjuvant therapy is shown to be effective for these patients. In the randomized, two-arm, phase 2, non-comparative trial, we investigate the efficacy and safety of the neoadjuvant programmed cell death 1 (PD-1) inhibitor camrelizumab with or without docetaxel-cisplatin-5-fluorouracil (TPF) chemotherapy in patients with resectable locally advanced OSCC. Patients with stage III-IVA OSCC receive neoadjuvant therapy with three cycles of camrelizumab (arm Cam) with or without two cycles of TPF chemotherapy (arm Cam+TPF), followed by surgery and adjuvant therapy. Major pathological response (MPR) is achieved in both arm Cam (5/34, 14.7%) and arm Cam+TPF (26/34, 76.4%). With a median follow-up of 32months, the 2-year event-free survival (EFS) rate of arm Cam and Cam+TPF is 52.9% and 91.2%, respectively. This work demonstrates feasibility and safety for immunochemotherapy in the neoadjuvant setting for OSCC. This study was registered at ClinicalTrials.gov (NCT04649476).

Combination of Baricitinib and Phototherapy in Adults With Active Vitiligo

Vitiligo is a chronic autoimmune disorder leading to skin depigmentation and reduced quality of life (QOL). Patients with extensive and very active disease are the most difficult to treat. To assess the efficacy and adverse events of baricitinib combined with narrowband UV-B in adults with severe, active, nonsegmental vitiligo. This academic, multicenter, double-blind, noncomparative randomized clinical trial was conducted at 4 dermatology departments between July 2021 and April 2023 and included adult patients with extensive and active nonsegmental vitiligo. The study was designed to evaluate the effect of baricitinib plus narrowband UV-B based solely on the results from this experimental group. The placebo group was used as a calibration group. Data were analyzed from August to November 2023. Participants were randomized 3:1 to baricitinib, 4 mg per day, or placebo for 36 weeks alone for the first 12 weeks and then in combination with narrowband UV-B twice a week from weeks 12 to 36. The primary outcome was mean percentage change in total Vitiligo Area Scoring Index (VASI) score from baseline to week 36 (baricitinib group). The prespecified aim of the study was to show that the reduction in the baricitinib plus narrowband UV-B was significantly greater than 42.9%, a repigmented surface threshold previously observed in patients treated with narrowband UV-B alone. Adverse events and secondary outcomes of change in disease activity and QOL were assessed. Post hoc analyses were additionally performed. Of 49 included patients, 35 (71%) were female, and the median (IQR) age was 49.9 (38.4-59.8) years. A total of 37 patients were randomized to the baricitinib group and 12 to the placebo group. The mean change in total VASI at week 36 was -44.8% (95% CI, -58.4% to -31.3%) for the baricitinib group and -9.2% (95% CI, -27.7% to 24.7%) for the placebo group. This was not significantly greater than the sufficient repigmented surface threshold of 42.9%. Post hoc analyses showed a significant difference at week 36 for total VASI score in the baricitinib plus narrowband UV-B group compared with placebo plus narrowband UV-B (-44.8% vs -9.2%, respectively; P = .02). There was a greater improvement in disease activity and QOL in the baricitinib group vs placebo group and no significant difference in the number of adverse events. This proof-of-concept randomized clinical trial confirmed the efficacy of baricitinib combined with narrowband UV-B in the treatment of patients with extensive and active vitiligo. ClinicalTrials.gov Identifier: NCT04822584.

Machine learning prediction model of the treatment response in schizophrenia reveals the importance of metabolic and subjective characteristics.

Predicting early treatment response in schizophrenia is pivotal for selecting the best therapeutic approach. Utilizing machine learning (ML) technique, we aimed to formulate a model predicting antipsychotic treatment outcomes. Data were obtained from 299 patients with schizophrenia from three multicenter, open-label, non-comparative clinical trials. For prediction of treatment response at weeks 4, 8, and 24, psychopathology (both objective and subjective symptoms), sociodemographic and clinical factors, functional outcomes, attitude toward medication, and metabolic characteristics were evaluated. Various ML techniques were applied. The highest area under the curve (AUC) at weeks 4, 8 and 24 was 0.711, 0.664 and 0.678 with extreme gradient boosting, respectively. Notably, our findings indicate that BMI and attitude toward medication play a pivotal role in predicting treatment responses at all-time points. Other salient features for weeks 4 and 8 included psychosocial functioning, negative symptoms, subjective symptoms like psychoticism and hostility, and the level of prolactin. For week 24, positive symptoms, depression, education level and duration of illness were also important. This study introduced a precise clinical model for predicting schizophrenia treatment outcomes using multiple readily accessible predictors. The findings underscore the significance of metabolic parameters and subjective traits.

Efficacy and Safety of Short Intravenous Hydration for Preventing Nephrotoxicity From High-Dose Cisplatin: A Randomized, Open-Label, Phase II Trial.

The use of short hydration (SH) to prevent cisplatin-induced nephrotoxicity lacks substantive prospective evaluation. The aim of this study was to evaluate the safety and efficacy of SH, including those with head and neck cancer (HNC) who are at higher risks of mucositis that causes diminished oral intake. This phase II randomized noncomparative trial included patients with cancer who were scheduled to receive high-dose cisplatin (≥60 mg/m2) in combination with another chemotherapy or concurrently with radiotherapy. Patients were randomly assigned to receive either the SH or conventional hydration (CH) protocol. The primary end point was the proportion of patients with increased serum creatinine (SCr) after undergoing SH. Secondary end points included the severity of SCr elevation, adverse events, cisplatin modification as a result of nephrotoxicity, duration of hospital stay, quality of life (QoL), and cost. Among 100 enrolled patients, 64 and 36 patients underwent the SH and CH protocols, respectively. The median duration of chemotherapy infusion and intravenous hydration were 5.79 and 27.58 hours with SH and CH, respectively. A total of 32.8% and 33.3% of the SH and CH groups, respectively, experienced SCr elevation. Grade 2 SCr elevations were rarely observed in both groups (1.6% in SH, 2.8% in CH). Rate of cisplatin modification was similar between the two groups. Out of 82 patients with HNC, the rate of SCr elevation was comparable for both hydration protocols. The QoL scores were meaningfully higher in the SH group during the second cycle of cisplatin, although the overall direct medical costs were similar. The SH protocol is feasible and safe, with a remarkably reduced duration of administration. Thus, SH can be an alternative to CH in the prevention of cisplatin-related nephrotoxicity.

PD202 Reimbursement Success For Pharmaceutical Products With Noncomparative Data: Are Health Technology Assessment Bodies Well Suited To Embrace Innovations?

IntroductionRandomized controlled trials are ideal for securing marketing authorization (MA) for pharmaceuticals. However, ethical and feasibility constraints have led to the use of noncomparative trials by regulatory bodies to balance evidence uncertainty and patient access, especially for medicines addressing rare diseases or unmet healthcare needs. This research focused on pharmaceuticals approved with noncomparative data and how these translate into reimbursement outcomes.MethodsIndications approved by the European Medicines Agency (EMA) between January 2018 and October 2023 based on noncomparative data were identified. Generics and biosimilars were excluded. Approvals based on non-comparative trial data were identified from European public assessment reports and from “Procedural steps taken and scientific information after authorization” documents. The latter were also used to identify changes in MAs after submission of new data. Missing trial information was extracted from ClinicalTrials.gov. Health technology assessment (HTA) outcomes from the EU4Health programme and the UK were extracted from agency websites.ResultsThe EMA approved 46 indications based on noncomparative data: 18 of the 46 (39%) received full MA, 23 (50%) received conditional MA (CMA), and five (11%) had a CMA converted to full MA with additional data. The results for HTAs conducted in various countries were as follows:•England: 29 of 46 (63%) indications assessed, (23/29 [79%] recommended);•Scotland: 28 of 46 (61%) indications assessed, (20/28 [71%] recommended);•France: 33 of 46 (72%) indications assessed, (7/33 [21%] received Amélioration du Service Médical Rendu level I to III);•Germany: 37 of 46 (80%) indications assessed, (2/37 [5%] achieved additional benefit);•Italy: 37 of 46 (80%) products assessed, (33/37 [89%] reimbursed); and•Spain: 34 of 46 (74%) products assessed, (23/34 [68%] reimbursed). ConclusionsIndications approved by the EMA with noncomparative data achieved mixed HTA outcomes in the EU4Health programme and the UK. More negative outcomes were seen in markets with clinical-benefit payer archetypes (France and Germany). All conversions from CMA to full MA occurred within the last 24 months.

Intermittent or Continuous Panitumumab Plus Fluorouracil, Leucovorin, and Irinotecan for First-Line Treatment of RAS and BRAF Wild-Type Metastatic Colorectal Cancer: The IMPROVE Trial.

To investigate whether intermittent treatment after an induction phase of first-line schedule of fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus panitumumab (PAN) prevents or delays the onset of resistance and improves safety and compliance with treatment in patients with unresectable RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC). IMPROVE (ClinicalTrials.gov identifier: NCT04425239) was an open-label, multicenter, randomized phase II noncomparative trial. Patients with unresectable RAS/BRAF wt mCRC were randomly assigned (1:1) to receive FOLFIRI plus PAN continuously until progression (arm A) or intermittently, with treatment-free intervals (arm B) until progression on treatment, toxicity, or death. The primary end point was progression-free survival on treatment (PFSot) at 12 months. Assuming a null hypothesis of median PFSot time ≤7 months and target PFSot ≥10 months, 65 patients per arm were needed to achieve 80% power and 10% type I error, according to the binomial test. Between May 2018 and June 2021, 69 patients were randomly assigned to arm A and 68 to arm B. The median number of treatment cycles was 13 in arm A and 16 in arm B. At a median follow-up of 43.2 months (IQR, 35.0-50.5), median PFSot was 11.2 and 17.5 months with 12-month PFSot rates of 45.7% and 58.5%, for arms A and B, respectively. The overall response rates were 68.1% and 61.2%, and median overall survival rates were 36.3 and 35.1 months in arms A and B, respectively. The overall rate of grade >2 skin PAN-related adverse events was 30.3% in arm A and 17.9% in arm B. Intermittent FOLFIRI plus PAN after the induction phase was feasible, and the primary end point was met with reduced toxicity while allowing patients more time off treatment.

Safety outcomes and immunological correlates in a prospective clinical trial of immune checkpoint therapy plus debulking surgery for patients with metastatic renal cell carcinoma.

Surgical removal of primary tumors was shown to reverse tumor-mediated immune suppression in pre-clinical models with metastatic disease. However, how cytoreductive surgery in the metastatic setting modulates the immune responses in patients, especially in the context of immune checkpoint therapy (ICT)-containing treatments is not understood. Here, we report the first prospective, non-comparative clinical trial to evaluate the feasibility, clinical benefits, and immunologic changes of combining three different ICT-containing strategies with cytoreductive surgery or biopsy for patients with metastatic clear cell renal cell carcinoma (mccRCC). Based upon baseline evaluation and surgical eligibility after 6 weeks of ICT treatment, 43 patients on this trial proceeded with cytoreductive surgery, while 36 patients who had medical comorbidities preventing surgery or did not have a lesion amenable for surgical resection underwent post-ICT biopsy as specified in the clinical trial protocol, and 25 patients who discontinued study participation due to progressive disease or toxicities or withdrawal of consent did not receive either procedure (total N=104). Our data demonstrated that, in the subgroup of patients receiving the combination of ICT with cytoreductive surgery or biopsy, no additional ICT- or procedure-related toxicities were observed as compared to historical data. The median OS (overall survival) was 54.7 months for patients who received ICT-containing regimens plus cytoreductive surgery (n=43). Immune-monitoring studies with co-detection by indexing (CODEX) identified distinct tumor spatial conformation of cellular subsets as a novel and improved predictor of response to ICT. Importantly, single-cell RNA-sequencing (sc-RNA-seq) data demonstrated that surgical removal of the tumor increased antigen-presenting dendritic cell population with a concurrent reduction in KDM6B-expressing immune-suppressive myeloid cells in the peripheral blood. Together, this study highlighted the feasibility of combining ICT with cytoreductive surgery in a metastatic setting and demonstrated the potential enhancement of immune responses following ICT plus cytoreductive surgery in patients with metastatic disease.

Yoga as an Adjunct Treatment to Manage Pain, Anxiety, Depression, and Stress During Hospital Stays: A Systematic Review.

People frequently report pain, anxiety, depression, and stress during hospital stays. Yoga has been shown to decrease these experiences in various settings. However, it is unclear whether yoga can be implemented during a hospital stay and has positive effects on pain and psychological well-being. The present systematic review aimed to examine the feasibility and impact of yoga interventions on pain, anxiety, depression, and stress when performed by patients during a hospital stay. Using PRISMA guidelines, three databases, and a registry, we conducted a search between August 2021 and December 2022. Both randomized and nonrandomized studies were included. Two authors independently assessed articles and risk of bias. Thirteen studies were included in this review, comprising individuals with a wide age range and various conditions. Three randomized controlled trials, one nonrandomized comparative trial, and nine noncomparative trials were included. Of the five studies reporting on pain (primary outcome), four found a statistically significant reduction. Of the eight studies reporting on anxiety, six found a statistically significant decrease and two reported a nonsignificant decrease in anxiety level. All four studies investigating depression reported a statistically significant decrease. All three studies reporting on stress found a decrease in stress, although only one at a statistically significant level. Five studies reported on the feasibility of performing yoga in a hospital setting, without any negative effects or increase in symptoms. Limited studies have integrated yoga during a hospital stay to address pain and psychological symptoms. Nevertheless, the current evidence suggests that yoga interventions during hospitalization are feasible, and yoga has promising benefits with potential clinically significant reduction in symptoms. Results should be viewed with caution given the lack of randomized trials, low methodological quality, and small sample sizes in the included studies. Further studies are needed to build on this evidence.

Effectiveness of pulpotomy in managing carious exposure in mature permanent teeth: A systematic review and meta-analysis

ObjectivesThis quantitative systematic review evaluated whether pulpotomy performed with hydraulic calcium silicate cements may be used as an alternative to root canal treatment (RCT) in mature permanent teeth with carious pulp exposure. Data sourcesA comprehensive search was conducted in PubMed, Web of Science, Scopus, and the Cochrane Library. No language restrictions were applied. The search included randomised controlled trials that compared pulpotomy to root canal treatment for managing carious exposure in mature permanent teeth. Study selectionStudies were selected based on predetermined inclusion criteria: randomised controlled trials involving mature permanent teeth with carious pulp exposure, using hydraulic calcium silicate cements for pulpotomy. Non-comparative studies, case reports, and trials involving primary or immature permanent teeth were excluded. DataData were extracted on success rates, clinical outcomes, follow-up periods, pain profiles, and potential complications. A meta-analysis was performed, revealing no statistically significant differences in success rates between pulpotomy and RCT. Both interventions demonstrated success rates exceeding 90 % at one-year and two-year follow-up periods. Pain profiles consistently showed lower post-operative pain intensity in the pulpotomy group compared to the RCT group during the first week. Potential complications, such as non-responsive pulp and difficulties in determining pulp vitality, were reported more frequently in the pulpotomy group. ConclusionsPulpotomy with bioactive hydraulic calcium silicate cements shows comparable success rates to RCT in managing carious pulp exposure in mature permanent teeth. The results suggest pulpotomy as a viable, less invasive alternative to RCT, particularly in cases where preservation of pulp vitality is paramount. Clinical significanceThis systematic review highlights pulpotomy as a less invasive and cost-effective alternative to root canal treatment in mature permanent teeth. With comparable success rates and lower post-operative pain, pulpotomy offers a promising approach to managing carious exposure and preserving tooth vitality.

Fixation for Osteochondral Lesions of the Talus with Open Lift, Drill, Fill and Fix (LDFF) Results in Excellent Two-Year Clinical Outcomes

Category: Ankle Introduction/Purpose: Outcomes after fixation of osteochondral lesions of the talus (OLTs) are currently underreported in literature. Clinical and radiological outcomes after the open fixation procedure ‘lift-drill-fill-fix’ (LDFF) for OLT with an osteochondral fragment are unknown. The advantages of fixation over other surgical techniques is the preservation of the native hyaline cartilage, immediate stabilization of the fragment and restoration of the talar dome congruency, as well as facilitating subchondral bone healing. Methods: This study describes the results of open LDFF treatment in a prospective, multicentre, nonrandomized, noncomparative clinical trial of 42 ankles in 40 patients with a 2-year follow-up period. The primary outcome measure in this study was the numeric rating scale (NRS) of pain during walking. Secondary outcome measures included the NRS of pain during rest, running and stairclimbing, the foot and ankle outcome sore (FAOS), and the mental component scale (MCS) and physical component scale (PCS) of the short form 36 (SF-36), and the radiological union rate as well as the level of the subchondral bone layer as measured on 1-year postoperative CT. Results: A total of 40 ankles which underwent fixation of an OLT with a fragment were prospectively included with 2-years follow-up. The primary outcome, pain during walking, significantly improved with 3.5 (95% CI 2.4-4.6) points on the NRS (p=< 0.001). Significant improvement was also seen for the NRS of pain during rest (p=< 0.001), pain during running (p=< 0.001) and pain during stair climbing (p=< 0.001). Additionally, all subscales of the FAOS, and the MCS and PCS significantly improved as well. Postoperative CT-scans showed union in 88% of the lesions 1-year after the procedure, a flush subchondral bone layer in 88%, and a depressed subchondral bone layer in 12%. Conclusion: Open fixation by means of LDFF for OLT results in a significant improvement of clinical outcomes up-to mid-term follow-up. Radiological follow-up shows a union rate and a flush subchondral bone layer in 88% of lesions. These results indicate that open fixation should always be considered when an osteochondral fragment is present as it leads to an excellent improvement in PROMs.

A meta-epidemiological analysis of post-hoc comparisons and primary endpoint interpretability among randomized noncomparative trials in clinical medicine

ObjectivesRandomized noncomparative trials (RNCTs) promise reduced accrual requirements vs randomized controlled comparative trials because RNCTs do not enroll a control group and instead compare outcomes to historical controls or prespecified estimates. We hypothesized that RNCTs often suffer from two methodological concerns: (1) lack of interpretability due to group-specific inferences in nonrandomly selected samples and (2) misinterpretation due to unlicensed between-group comparisons lacking prespecification. The purpose of this study was to characterize RNCTs and the incidence of these two methodological concerns. Study Design and SettingWe queried PubMed and Web of Science on September 14, 2023, to conduct a meta-epidemiological analysis of published RNCTs in any field of medicine. Trial characteristics and the incidence of methodological concerns were manually recorded. ResultsWe identified 70 RNCTs published from 2002 to 2023. RNCTs have been increasingly published over time (slope = 0.28, 95% CI 0.17–0.39, P < .001). Sixty trials (60/70, 86%) had a lack of interpretability for the primary endpoint due to group-specific inferences. Unlicensed between-group comparisons were present in 36 trials (36/70, 51%), including in the primary conclusion of 31 trials (31/70, 44%), and were accompanied by significance testing in 20 trials (20/70, 29%). Only five (5/70, 7%) trials were found to have neither of these flaws. ConclusionAlthough RNCTs are increasingly published over time, the primary analysis of nearly all published RNCTs in the medical literature was unsupported by their fundamental underlying methodological assumptions. RNCTs promise group-specific inference, which they are unable to deliver, and undermine the primary advantage of randomization, which is comparative inference. The ongoing use of the RNCT design in lieu of a traditional randomized controlled comparative trial should therefore be reconsidered.

Modeling the Determinants of Subjective Well-Being in Schizophrenia.

The ultimate goal of successful schizophrenia treatment is not just to alleviate psychotic symptoms, but also to reduce distress and achieve subjective well-being (SWB). We aimed to identify the determinants of SWB and their interrelationships in schizophrenia. Data were obtained from 637 patients with schizophrenia enrolled in multicenter, open-label, non-comparative clinical trials. The SWB under the Neuroleptic Treatment Scale (SWN) was utilized; a cut-off score of 80 indicated a high level of SWB at baseline and 6 months. Various machine learning (ML) algorithms were employed to identify the determinants of SWB. Furthermore, network analysis and structural equation modeling (SEM) were conducted to explore detailed relationship patterns. The random forest (RF) model had the highest area under the curve (AUC) of 0.794 at baseline. Obsessive-compulsive symptoms (OCS) had the most significant impact on high levels of SWB, followed by somatization, cognitive deficits, and depression. The network analysis demonstrated robust connections among the SWB, OCS, and somatization. SEM analysis revealed that OCS exerted the strongest direct effect on SWB, and also an indirect effect via the mediation of depression. Furthermore, the contribution of OCS at baseline to SWB was maintained 6 months later. OCS, somatization, cognition, and depression, rather than psychotic symptoms, exerted significant impacts on SWB in schizophrenia. Notably, OCS exhibited the most significant contribution not only to the current state of well-being but also to follow-up SWB, implying that OCS was predictive of SWB. The findings demonstrated that OCS management is critical for the treatment of schizophrenia.

Accelerated Approval for Cancer Drugs in the United States and the Clinical Evidence Required for Conversion to Regular Approval

PurposeOncology products often leverage accelerated approval program to seek earlier launches in the United States. Little is known about how the Food and Drug Administration (FDA) has been balancing evidence and access, and the factors that may characterize post-accelerated approval requirements. The present study aimed to obtain insights on how accelerated approval is determined by investigating the balance between pre-accelerated approval and supplemental clinical evidence required for future regular approval.MethodsThe product properties, pre-accelerated approval evidence, rationale, post-accelerated approval requirements, and prior regulatory designations for oncology accelerated approvals were summarized based on public databases. Regression analyses were performed to investigate factors that may have been associated with the post-accelerated approval requirements.ResultsHundred fifty-seven accelerated approvals were granted between 1992 and 2021. An increase in the number of pre-accelerated approval trials by one trial resulted in a 20% decrease in supplemental trials. The endpoint for the post-accelerated approval trial tended to be more robust when products were indicated for common cancers, while less robust when products had been used to treat fewer subjects, when products were indicated for respiratory and skin cancers, or when less malignant cancers were targeted.ConclusionsAccelerated approvals for oncology products were often based on the response rate of a noncomparative trial. However, considerable variation was observed in the post-accelerated approval requirements. Factors such as the quality and quantity of pre-accelerated approval evidence, regulatory designations, and operational feasibility may have been considered when determining the accelerated approvals and post-accelerated approval requirements.

The Importance of Clinical Context and Consistency in Methodology When Using Matching-Adjusted Indirect Comparisons (MAICs) to Compare Outcomes.

Hemophilia A is rare, which makes large, randomized, controlled, statistically driven, head-to-head comparison trials difficult. Matching-adjusted indirect comparisons (MAICs) are validated statistical tools designed to help make the results of non-comparative trials more comparable. The purpose of this commentary is to provide an insight into the MAIC method, in order to assist the hemophilia community with interpretation of MAIC data. It includes a comparison of the findings from previously published MAICs comparing recombinant factor replacement options and their methodologies. As MAICs are being used more often to compare treatment options for patients with hemophilia A, it is paramount that robust and consistent methodologies for cross-trial comparisons are used and that all efficacy analysis findings are linked to factor utilization.

Rifaximin and Metronidazole Fixed Dose Combination: New Treatment Option in the Management of Diarrhea

Background: Endemic infectious diarrhea is a widespread problem around the world, caused by a combination of viruses, bacteria, and parasites. While commonly used fluoroquinolone antibiotics are effective for specific types of acute diarrhea, they carry potential side effects. Aim: To assess the effectiveness and tolerability of a fixed-dose combination of rifaximin and metronidazole as an alternative treatment approach for the management of acute diarrhea. Study Design: A multicentre, open-label, non-comparative and non-randomized trial was conducted in 370 patients suffering from acute diarrhea due to various factors. Methodology: Patients were given a tablet containing fixed-dose combination of 200 mg of rifaximin and 400 mg of metronidazole twice daily for 5 days. The primary outcomes evaluated were changes in the number of loose/watery stools, the presence of fever, nausea, vomiting, abdominal pain and gas/flatulence from baseline to day 5. A global assessment using a 3-point scale (Excellent/Good/Poor) was done by the investigators for efficacy and tolerability evaluation. Adverse drug reactions were monitored throughout the study period. Results: After 5-day therapy, the average number of watery stools per day decreased significantly from 7.853 ± 3.773 to 0.766 ± 0.949 (P &lt; .001). None of the patients experienced fever and vomiting, while few patients experienced nausea (0.31%), abdominal pain (0.31%), and gas/flatulence (0.93%) at the end of the study. According to the evaluation by the investigators, all patients reported good to excellent efficacy and tolerability. Conclusions: The combination therapy of rifaximin and metronidazole is clinically effective and safe to treat acute diarrhea caused by different factors and can serve as a new treatment option for managing acute diarrhea.

An open-labeled randomized non-comparative clinical trial on the efficacy of fairfoot ointment in Vipadika

In Ayurveda, cracked or fissured feet are often associated with an imbalance in the Vata dosha. An excess of Vata in the body can lead to various skin issues, including dry and cracked skin, not only on the feet but on other parts of the body. Fairfoot ointment, a proprietary product, is an antifungal and antiseptic combination of Jathyadi Grutham, Jeevanthyadi Yamakam and Karanja Thailam, intended for external application of cracked feet and other skin conditions like chapped lips, anal fissures etc. An open-labeled randomized non-comparative clinical trial study was conducted on 30 patients presenting with cracked feet, fissures, dry scaly skin, pain, and itching to prove the efficacy in Vipadika. The associated symptoms of pigmentation and skin elasticity were also evaluated as part of this trial. A visual analog scale (VAS) was used to quantify pain. On a Likert scale of 1 to 5, dryness, wrinkles, scaling, itching, and skin laxity were scored. At each point of examination, the amount of cracking and pigmentation were counted. The study involved four evaluations of the participants. Following pairwise analysis using the SPSS 16.0 program, data were examined using Repeated Measure ANOVA. The results of the study showed a considerable reduction in the symptoms of dryness, cracking, pain, and itching. Additionally, there was a statistically significant decline in the symptoms of skin laxity, wrinkles, sealing, and pigmentation. No adverse events were observed during the course of the experiment, suggesting that the medication is safe. Clinical findings indicate that Fairfoot ointment could be used for the improvement and treatment of patients with Vipadika.

A phase II, non-comparative randomised trial of two treatments involving liposomal amphotericin B and miltefosine for post-kala-azar dermal leishmaniasis in India and Bangladesh.

In Southeast Asia, treatment is recommended for all patients with post-kala-azar dermal leishmaniasis (PKDL). Adherence to the first-line regimen, twelve weeks of miltefosine (MF), is low and ocular toxicity has been observed with this exposure period. We assessed the safety and efficacy of two shorter-course treatments: liposomal amphotericin B (LAmB) alone and combined with MF. An open-label, phase II, randomized, parallel-arm, non-comparative trial was conducted in patients with parasitologically confirmed PKDL, 6 to ≤60 years. Patients were assigned to 20 mg/kg LAmB (total dose, in five injections over 15 days) alone or combined with allometric MF (3 weeks). The primary endpoint was definitive cure at 12 months, defined as complete resolution of papular and nodular lesions and >80% re-pigmentation of macular lesions. Definitive cure at 24 months was a secondary efficacy endpoint. 118/126 patients completed the trial. Definitive cure at 12 months was observed in 29% (18/63) patients receiving LAmB and 30% (19/63) receiving LAmB/MF (mITT), increasing to 58% and 66%, respectively, at 24 months. Most lesions had resolved/improved at 12 and 24 months for patients receiving LAmB (90%, 83%) and LAmB/MF (85%, 88%) by qualitative assessment. One death, unrelated to study drugs, was reported; no study drug-related serious adverse events were observed. The most frequent adverse drug reactions were MF-related vomiting and nausea, and LAmB-related hypokalaemia and infusion reactions. Most adverse events were mild; no ocular adverse events occurred. Both regimens are suitably safe and efficacious alternatives to long-course MF for PKDL in South Asia. CTRI/2017/04/008421.

Quality of life outcomes in patients with resectable dedifferentiated liposarcoma treated with neoadjuvant immunotherapy.

e23552 Background: Currently there is a lack of robust data on health-related quality of life outcomes for patients with retroperitoneal sarcoma. The purpose of this study was to look at trends in health-related quality of life outcomes for patients and determine what symptoms impacted patients the most. Patients with surgically resectable dedifferentiated liposarcoma who were participating in a randomized, phase II, non-comparative trial of combination nivolumab (nivo) and ipilimumab (ipi/nivo) were selected to participate in this study. Methods: Five patients were randomized to participate in structured qualitative interviews. Three patients were randomized to the nivo/ipi arm and 2 to the nivo arm. The interviews were conducted at 6 separate time points, both during receipt of neoadjuvant therapy and after tumor resection. Questions were structured around ten themes which included treatment side effects, abdominal complications, appetite, energy levels, quality of life effects, and financial complications. Patient responses were transcribed, coded, and themes in symptoms during treatment were identified. Results: Different themes in symptoms emerged during each time-period of treatment. During the pretreatment period patients were more likely to report abdominal complaints that they attributed to their primary tumor. During neoadjuvant immunotherapy (week 3) patients reported more skin complaints, including the development of rashes and pruritis. These tended to improve by their preoperative visit. Patients reported typical postoperative symptoms at their 6-week post operative visit including increases in pain medications, muscle pain, and some abdominal soreness. By one year patients reported no significant symptoms and demonstrated resolution of all prior symptoms. Overall patients reported few energy and sleep related symptoms throughout their treatment course. Conclusions: For patients with resectable dedifferentiated liposarcoma receiving immune checkpoint blockade, health-related quality of life symptoms were present throughout their treatment course. Common themes that emerged demonstrated a lack of severe symptoms experienced by patients in either arm and resolution of symptoms by one year post treatment. Our interview results can help clinicians focus on symptoms that are impactful to patients in future clinical trials.

Efficacy and safety of onasemnogene abeparvovec for the treatment of patients with spinal muscular atrophy type 1: A systematic review with meta-analysis.

Onasemnogene abeparvovec has been approved for the treatment of spinal muscular atrophy 5q type 1 in several countries, which calls for an independent assessment of the evidence regarding efficacy and safety. Conduct a meta-analysis to assess the efficacy and safety of onasemnogene abeparvovec in patients diagnosed with SMA type 1, based on the available evidence. This article results from searches conducted on databases up to November 2022. Outcomes of interest were global survival and event-free survival, improvement in motor function and treatment-related adverse events. Risk of bias assessment and certainty of evidence were performed for each outcome. Proportional meta-analysis models were performed when applicable. Four reports of three open-label, non-comparative clinical trials covering 67 patients were included. Meta-analyses of data available in a 12-month follow-up estimate a global survival of 97.56% (95%CI: 92.55 to 99.86, I2 = 0%, n = 67), an event-free survival of 96.5% (95%CI: 90.76 to 99.54, I2 = 32%, n = 66) and a CHOP-INTEND score ≥ 40 points proportion of 87.28% (95%CI: 69.81 to 97.83, I2 = 69%, n = 67). Proportion of 52.64% (95%CI: 27.11 to 77.45, I2 = 78%, n = 67) of treatment-related adverse events was estimated. The results indicate a potential change in the natural history of type 1 SMA, but the methodological limitations of the studies make the real extent of the technology's long-term benefits uncertain.

First-Line LV5FU2 with or without Aflibercept in Patients with Non-Resectable Metastatic Colorectal Cancer: A Randomized Phase II Trial (PRODIGE 25-FFCD-FOLFA).

Fluropyrimidine monotherapy is an option for some patients with inoperable metastatic colorectal cancer. Unlike bevacizumab, the addition of aflibercept, an antibody acting as an anti-angiogenic agent, has never been evaluated in this context. The aim of the study was to determine whether aflibercept could increase the efficacy of fluoropyrimidine monotherapy without increasing toxicity. This multicenter phase II non-comparative trial evaluated the addition of aflibercept to infusional 5-fluorouracil/folinic acid (LV5FU2 regimen) as first-line treatment in patients unfit to receive doublet cytotoxic chemotherapy. The primary endpoint was 6-month progression-free survival (PFS). The clinical hypotheses expected a PFS rate at 6 months of over 40% (60% expected). A total of 117 patients, with a median age of 81 years, were included: 59 in arm A (LV5FU2-aflibercept) and 58 in arm B (LV5FU2 alone). Six-month PFS was 54.7% in both arms (90% CI 42.5-66.5 in both). Median overall survival was 21.8 months (arm A) and 25.1 months (arm B). Overall toxicity was more common in arm A: grade ≥ 3 toxicity in 82% versus 58.2%. Given the 6-month PFS, the study can be considered positive. However, the toxicity of aflibercept in this population was high, and continuation of the trial into phase III is not envisaged.