Psychometric validation and interpretation of the Nocturia Impact Diary in a clinical trial setting

Purpose Psychometric evaluation of the Nocturia Impact (NI) Diary was conducted to support its use as a trial endpoint. Methods As part of a randomized, controlled Phase 2 clinical trial investigating a novel drug candidate for nocturnal polyuria, adult nocturia patients completed the NI Diary and a voiding diary for three nights preceding their clinic visit at Baseline and Weeks 1, 4, 8, and 12 (end of treatment). Exit interviews were conducted to obtain patient impressions of the NI Diary. Results A total of N = 302 participants were included. Confirmatory factor analysis (CFA) indicated that the 11-item measure is unidimensional with values of CFI, TLI, and RMSEA meeting relevant thresholds. Good internal consistency (Cronbach’s α 0.941) and test–retest reliability (intra-class correlation coefficients 0.730–0.880). Convergent validity with two reference measures was demonstrated with strong correlations of 0.573–0.730 were shown. Significant differences (P = 0.0018, standardized effect size = 0.372) between groups defined by number of night-time voids supported known-groups validity. Exit interviews in 66 patients indicated all participants experienced improvement in at least 1 NI Diary item and that a 1-point improvement on the item response scale and 1-void reduction per night (associated with an average best cut point on ROC analysis of − 11.6) constituted meaningful improvement. Anchor and distribution-based analyses identified a meaningful change threshold of − 15 to − 18 points on the NI Diary. Conclusion The NI Diary is a reliable and valid patient-reported psychometric instrument which is fit-for-purpose to evaluate the impact of nocturia on patient quality of life in the clinical trial setting. Trial registration number and registration date NCT03201419; June 28, 2017.

Real World Experience on the Use of Ibrutinib Monotherapy in Waldenström Macroglobulinemia

BACKGROUND Ibrutinib is approved as a second line treatment option for Waldenström Macroglobulinemia (WM) patients in the United Kingdom and for patients unsuitable for chemo-immunotherapy. In a clinical trial setting, Ibrutinib monotherapy produced a major response rate (MRR) of 79.4% and a predicted five-year overall survival (OS) rate of 87%1. Valuable insights can be gained on the response and tolerability outcomes of Ibrutinib monotherapy in WM outside of the clinical trial setting. This study aimed to evaluate these outcomes in a large specialist centre which receives referrals from across the UK. METHODS A retrospective analysis was performed on consecutive patients with WM who commenced Ibrutinib between December 2014 and February 2021; all included patients were treated for at least 3 months. Data were collated from the WMUK Rory Morrison Registry. The primary outcomes were depth of response, event free survival (EFS, defined as time from commencement to permanent ibrutinib discontinuation due to toxicity, disease progression or death), duration of response (time from best response to progressive disease, PD), progression free survival (PFS) and overall survival (OS). Response was determined in accordance with the Sixth International Workshop on WM (IWWM) response criteria 2. Baseline characteristics and toxicity data were also collated. RESULTS Of the 84 patients who had commenced ibrutinib, sufficient data was available for 62 patients; median age was 69 years (range 44 - 85) and 40 (64.5%) were male. Among the 50 patients for whom International Prognostic Scoring System for WM (IPSSWM) data were available, the IPSSWM risk score at the time of ibrutinib initiation was low (n=8, 16%), intermediate (n=25, 50%) and high (n=17, 34%). The median number of prior therapy lines was 2 (range 1 - 7). The median time from diagnosis to commencement of ibrutinib was 70 months (Range 2 - 243). The median follow-up was 29 months (Range 3 - 71). Objective response rate (≥MR) was 79% (n=49) and MRR was 62.9% (n=39). Best response achieved was CR in 12.9%, VGPR in 24.2%, PR in 25.8%, MR in 16.1% and SD in 11.2%; 9.7% of patients experienced PD. The median time to best response was 5 months (Figure 1A) and the median EFS was 37 months (Range 3 - 71). Of the 49 patients who achieved an objective response, the median PFS was not reached and the two-year predicted PFS rate was 73.5%. At the time of analysis, 15 patients (24.2%) had discontinued ibrutinib due to disease progression, 5 (8.1%) due to adverse effects and 4 (6.5%) due to death. The median OS was not reached, and the predicted two-year OS rate was 87.8% (Figure 1B). The most common adverse effects were diarrhoea (14.5%), atrial fibrillation (AF, 9.7%) and rash (9.7%). Six of the seven patients who developed treatment-emergent AF continued ibrutinib with concurrent anticoagulants and either rate or rhythm control. Ibrutinib was permanently discontinued due to heart failure/AF (n=1), intracranial haemorrhage whilst taking ibrutinib and warfarin concurrently for brittle antiphospholipid syndrome and WM (n=1), significant liver function derangement (n=2) and intractable diarrhoea (n=1). Ibrutinib dose was reduced to 280 mg daily (n=13) and 140 mg daily (n=4) due to adverse reactions. CONCLUSION In a real-world setting, ibrutinib produces clinically meaningful objective responses in patients with relapsed WM; these response rates are comparable to those achieved in a clinical trial setting. Ibrutinib can produce durable disease control with long remission intervals. The toxicity profile is acceptable. REFERENCES 1. Treon, S., Meid, K., Gustine, J., Yang, G., Xu, L., & Liu, X. et al. (2021). Long-Term Follow-Up of Ibrutinib Monotherapy in Symptomatic, Previously Treated Patients With Waldenström Macroglobulinemia. Journal Of Clinical Oncology, 39(6), 565-575. doi: 10.1200/jco.20.00555 2. Owen, S., Kyle, R., Stone, M., Rawstron, A., Leblond, V., Merlini, G. et al. (2013). Response assessment in Waldenström Macroglobulinemia: updated from the VIth International Workshop. British Journal of Haematology, 60, 171-176. doi: 10.1111/bjh.12102 Figure 1 Figure 1. Disclosures D'Sa: Sanofi: Honoraria; BeiGene: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding.

Real-World Outcomes of Advanced Soft Tissue Sarcoma Patients Treated with Pazopanib

Background: Pazopanib is an oral multitarget tyrosine kinase inhibitor that is currently approved for the treatment of select subtypes of advanced Soft Tissue Sarcoma (STS) in patients who have progressed on prior anthracyclinebased chemotherapy regimens. In this study, we examine data from multiple centers to assess the efficacy of pazopanib in practice outside of a clinical trial setting. Methods: A retrospective chart analysis was conducted for pre-treated, advanced soft tissue sarcoma patients who began treatment with pazopanib in Alberta, Canada and Cairo, Egypt (2012-2018). Results: In total, 39 predominantly male (56.4%) patients received pazopanib. The median age was 51, 67% of whom had an ECOG of one or less. The predominant sarcoma subtype was leiomyosarcoma (30.8%), and all patients had received at least one prior line of systemic therapy. Thirtytwo of the 39 patients (82%) were initially given the full dose of 800mg with a median time on treatment of 116 days. Seven of the 39 (18%) patients required a dose reduction while on treatment. A majority (94.9%) of patients ultimately discontinued pazopanib treatment for reasons including death (21.6%), disease progression (62.2%), and toxicity (16.4%). The median progression-free and overall survival for these patients was 4.1 months (95%CI, 3.6-4.5) and 8.4 months (95% CI, 4.3-12.5), respectively. Conclusion: Pazopanib is an efficient and generally well-tolerated oral systemic therapy for the treatment of advanced, pre-treated, non-adipocytic soft tissue sarcoma. These results show the efficacy of pazoponib outside of a clinical trial setting.

Data Security in Clinical Trials Using Blockchain Technology

Blockchain technology in a clinical trial setting is a valuable asset due to decentralization, immutability, transparency, and traceability features. For this chapter, a literature review was conducted to map the current utilization of blockchain systems in clinical trials, particularly data security managing systems and their characteristics, such as applicability, interests of use, limitations, and issues. The advantages of data security are producing a more transparent and tamper-proof clinical trial by providing accurate, validated data, therefore producing a more reliable and credible clinical trial. On the other hand, data integrity is a critical issue since data obtained from trials are not instantly made public to all participants. Work needs to be done to establish the significant implications in security data when applying blockchain technology in a real-world clinical trial setting and generalized conditions of use to establish its security.

How to run a placebo study

This chapter is addressed to those who want to run a study aimed at identifying the underlying mechanisms of placebo effects. To study a placebo effect requires specific designs that cannot be performed in the classic clinical trial setting. Complex experimental designs are particularly necessary when one wants to investigate the neurobiological mechanisms, for example by means of agonist and antagonist drugs. Complex pharmacological designs have used up to twelve experimental arms (groups) in order to answer specific questions. To study the role of learning in placebo effects, for example conditioning, one needs to control the associations between conditioned and unconditioned stimuli both in the experimental and in the clinical setting. In addition, several approaches are possible for hiding a therapy from the subject’s view, so that he is totally unaware that a treatment is being performed, thus allowing the investigation of placebo effects without the administration of placebos.

The Prognostic Importance of the 6-Minute Walk Test in AL Amyloidosis

Background The six-minute walk test (6MWT) is an easy-to-implement objective measure of functional capacity. This standardised reproducible measure of individual function may have value in systemic AL amyloidosis to provide an additional objective measure of fitness for chemotherapy, impact of chemotherapy and, within the clinical trial setting, both as a potential clinical endpoint and exclusion criteria. We aim to validate its prognostic value in AL amyloidosis. Methods All patients from a prospective observational study of newly diagnosed AL amyloidosis, (ALchemy) over a 5-year period, were studied. Six-minute walk testing was performed at baseline and 6, 12, 18, 24, 36 and 48-month follow up. Both the median 6MWT and percentage predicted for age, sex, height and weight were analysed. Results In total, 799 evaluable patients were included of whom 564 (70.6%) had cardiac involvement. Baseline 6MWT distance was 418.5 metres (m) / 80.5% predicted, and diminished with increasing cardiac Mayo stage (p<0.0001). A baseline 6MWT ≥300m was independent of Mayo staging in predicting survival (Mayo II Hazard ratio [HR] 2.21 [1.35-3.64], p=0.002; Mayo IIIa HR 3.92 [2.42-6.34], p<0.0001; Mayo IIIb HR 6.08 [3.63-10.12], p<0.0001; 6MWT ≥300m HR 2.97 [2.38-3.72], p<0.0001). Baseline 6MWT correlated strongly with other prognostic factors including Eastern Cooperative Oncology Group (ECOG) performance status (p<0.0001) and New York Heart Association (NYHA) Classification of Heart Failure (p=0.008). Patients were followed up for a median of 32 (1-90) months following diagnosis. Median overall survival (OS) was 70.0 (56.8-83.2) months. The median OS of patients achieving ≥300m on baseline 6MWT was not reached whilst those achieving <300m had a median OS of 25.0 (18.1-31.9) months. Patients unable to attempt the test had a median OS of 5.0 (2.8-7.2) months (p<0.0001). Patients achieving ≥300m at any time point had a significantly better OS (at 6, 12, 24 and 36 months p<0.0001 whilst at 48 months p=0.03). Patients unable to attempt a 6MWT at any point in time has a median OS of 10 (6.4-13.6) months from that point. In patients with Mayo IIIb disease, the 6MWT remained prognostic (≥300m: 61 [4.2-117.8] months vs. <300m: 4.0 [1.3-6.9] months vs. unable to walk: 1.0 [0.3-1.7] months, p<0.0001). The 6MWT fell significantly by 6 months (391.0m/73.5%, p=0.0002) then rose again by 12 months (median 415.0m/78.0%, p=0.02). There was no significant change in 6MWT thereafter. When stratified by haematological response and censoring deaths before 12 months, only patients in a complete response (CR) improved at 12 months (431.0m/83.0% vs. 437.0m/85%, p=0.001) whilst those with a lesser haematological response got worse (Very good partial response [VGPR]: 403.5m/75.0% to 395.5m/76.5%, p=0.02; Partial Response [PR]: 413.0m/79.0% to 362.5m/74.0%, p=0.0007; Nil response [NR]: 437.0m/83.0% to 355.0m/70%, p=0.0002). A 33m improvement in 6MWT, a value reported to be clinically meaningful in cardiopulmonary disorders, was independent of haematological response in predicting survival (CR [reference], VGPR: HR 2.02 [1.08-3.80], p=0.03; PR: HR 3.51 [1.83-6.73], p<0.0001; NR: HR 5.61 [2.88-10.92], p<0.0001; 6MWT improvement ≥33m: HR 1.61 [1.01-2.59], p=0.047). Patients in whom 6MWT improved by ≥33m at 12 months survived longer although median OS was not reached in either category (p=0.01). In patients who achieved a baseline 6MWT of <300m but improved by ≥33m at 12 months, median OS was superior to those who improved by <33m (not reached vs. 35.0 [25.7-44.3] months, p=0.006). Among patients with Mayo stage IIIb disease and censoring all deaths within 12 months, those who improved by ≥33m at 12 months lived longer (OS NR vs. 70.0 [51.4-88.6] months, p<0.0001). Conclusion The 6MWT is prognostic in AL amyloidosis at multiple time points and a baseline distance of ≥300m is independent of current Mayo stage criteria in predicting survival. Inability to undertake a 6MWT at baseline is an extremely poor prognostic indicator. At 12 months, improvement in 6MWT of ≥33m predicts survival independent of haematological response. The 6MWT is a useful prognostic indicator in systemic AL amyloidosis and could be used as an inclusion/exclusion criterion in the clinical trial setting. Disclosures Wechalekar: Celgene: Honoraria; Takeda: Honoraria, Other: Travel; Janssen: Honoraria, Other: Advisory; Caelum: Other: Advisory.