Chronic Illness Therapy-Fatigue Research Articles

Mirikizumab Sustained Impact on Fatigue in Patients with Moderately to Severely Active Crohn's Disease in the Phase 2 AMAG Study.

Fatigue is a burdensome,under-recognized, multidimensional symptom experienced by patients with Crohn's disease (CD). We evaluated the impact of mirikizumab on fatigue and the association between changes in select patient-reported outcomes and clinical measures with changes in fatigue from baseline to week 104 (W104). Patients (N = 191) were randomized (2:1:1:2) to receive placebo (PBO), 200mg, 600mg, or 1000mg of mirikizumab, administered intravenously (IV) every 4 weeks at W0, W4, and W8. Patients who achieved ≥1 point improvement in Simple Endoscopic Score for Crohn's Disease (SES-CD) and received mirikizumab at W12 (rerandomized maintenance cohort) were rerandomized to continue induction IV treatment assignment (IV-C) or received 300mg of mirikizumab subcutaneously (SC) until W52. Nonrandomized maintenance cohort had endoscopic nonimprovers (1000mg) and PBO patients (PBO/1000mg) who received 1000mg of mirikizumab until W52. Subjects from the maintenance period with clinical benefit received 300mg SC Q4W from W52 to W104. The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaire was used to assess fatigue, and the FACIT-F associations were assessed using Pearson correlation coefficient. At W12, mirikizumab groups reported improved FACIT-F scores compared with PBO, and improvement was maintained through W52 and W104. Changes in FACIT-F at W52 and W104 had strong correlations with changes at the same time point in quality of life (QoL) scores but lacked correlations with changes in inflammatory biomarkers. Mirikizumab treatment significantly improved fatigue in patients with moderately to severely active CD, which was sustained to W104. The improvement in fatigue was correlated with improvement in clinical measures and was strongly correlated with improvement in QoL.

Safety and Efficacy of Upadacitinib in Patients with Rheumatoid Arthritis Refractory to Biologic DMARDs: Results Through Week 216 from the SELECT-CHOICE Study.

Thesafety and efficacy of upadacitinib 15mg (UPA15) through week 216 was evaluated in patients with rheumatoid arthritis (RA) from the long-term extension (LTE) of the phase 3 SELECT-CHOICE study. Patients with RA refractory to biologic disease-modifying antirheumatic drugs (bDMARDs) were randomized to UPA15 or abatacept (ABA) for 24weeks. During the open-label LTE, patients on ABA switched to UPA15 at week 24, and those on UPA15 continued treatment. Thesafety and efficacy of continuous UPA15, and ABA to UPA15, are summarized through week 216. The LTE was comprised of 91.4% (n = 277/303) of patients that initially received UPA15, and 89.6% (n =277/309) that initially received ABA. Of patients on UPA15 in the LTE (n =547), 28.3% (n =155/547) discontinued the study drug by week 216. Relative to other adverse events of special interest, and largely consistent with previous findings at week 24, higher rates of serious infection, COVID-19, herpes zoster, and elevated creatine phosphokinase were reported, while rates of malignancy excluding nonmelanoma skin cancer (NMSC), NMSC, major adverse cardiovascular event (MACE), and venous thromboembolism (VTE) were low. Long-term safety data with UPA through week 216 aligned with previous observations and no new safety risks were identified, including in patients who switched from ABA to UPA15. Proportions of patients achieving 28-joint disease activity score based on C-reactive protein (DAS28[CRP]) < 2.6/ ≤ 3.2, clinical disease activity index (CDAI) and simple disease activity index (SDAI) low disease activity/remission, ≥ 20%/50%/70% improvement in theAmerican College of Rheumatology (ACR20/50/70) response criteria, and Boolean remission were maintained or improved with UPA15 through week 216. Improvements in theHealth Assessment Questionnaire-Disability Index (HAQ-DI), patient's assessment of pain, and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were also maintained or improved with UPA15 through week 216. Across all efficacy endpoints, similar results were observed in patients who switched from ABA to UPA15 versus continuous UPA15. Patients with an inadequate response to ≥ 1 prior tumor necrosis factor (TNF) inhibitor (UPA15: n =263/303, 86.8%; ABA to UPA15: n =273/309, 88.3%) showed similar responses to the total population. The long-term safety profile of UPA was consistent with previous findings and the broader RA clinical program. Compared to the primary analyses at week 24, efficacy responses were maintained or further improved with UPA15 through week 216 in patients with RA. Trial registration, ClinicalTrials.gov identifier: NCT03086343.

Cognitive and psychiatric symptom trajectories 2–3 years after hospital admission for COVID-19: a longitudinal, prospective cohort study in the UK

COVID-19 is known to be associated with increased risks of cognitive and psychiatric outcomes after the acute phase of disease. We aimed to assess whether these symptoms can emerge or persist more than 1 year after hospitalisation for COVID-19, to identify which early aspects of COVID-19 illness predict longer-term symptoms, and to establish how these symptoms relate to occupational functioning. The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a prospective, longitudinal cohort study of adults (aged ≥18 years) who were hospitalised with a clinical diagnosis of COVID-19 at participating National Health Service hospitals across the UK. In the C-Fog study, a subset of PHOSP-COVID participants who consented to be recontacted for other research were invited to complete a computerised cognitive assessment and clinical scales between 2 years and 3 years after hospital admission. Participants completed eight cognitive tasks, covering eight cognitive domains, from the Cognitron battery, in addition to the 9-item Patient Health Questionnaire for depression, the Generalised Anxiety Disorder 7-item scale, the Functional Assessment of Chronic Illness Therapy Fatigue Scale, and the 20-item Cognitive Change Index (CCI-20) questionnaire to assess subjective cognitive decline. We evaluated how the absolute risks of symptoms evolved between follow-ups at 6 months, 12 months, and 2-3 years, and whether symptoms at 2-3 years were predicted by earlier aspects of COVID-19 illness. Participants completed an occupation change questionnaire to establish whether their occupation or working status had changed and, if so, why. We assessed which symptoms at 2-3 years were associated with occupation change. People with lived experience were involved in the study. 2469 PHOSP-COVID participants were invited to participate in the C-Fog study, and 475 participants (191 [40·2%] females and 284 [59·8%] males; mean age 58·26 [SD 11·13] years) who were discharged from one of 83 hospitals provided data at the 2-3-year follow-up. Participants had worse cognitive scores than would be expected on the basis of their sociodemographic characteristics across all cognitive domains tested (average score 0·71 SD below the mean [IQR 0·16-1·04]; p<0·0001). Most participants reported at least mild depression (263 [74·5%] of 353), anxiety (189 [53·5%] of 353), fatigue (220 [62·3%] of 353), or subjective cognitive decline (184 [52·1%] of 353), and more than a fifth reported severe depression (79 [22·4%] of 353), fatigue (87 [24·6%] of 353), or subjective cognitive decline (88 [24·9%] of 353). Depression, anxiety, and fatigue were worse at 2-3 years than at 6 months or 12 months, with evidence of both worsening of existing symptoms and emergence of new symptoms. Symptoms at 2-3 years were not predicted by the severity of acute COVID-19 illness, but were strongly predicted by the degree of recovery at 6 months (explaining 35·0-48·8% of the variance in anxiety, depression, fatigue, and subjective cognitive decline); by a biocognitive profile linking acutely raised D-dimer relative to C-reactive protein with subjective cognitive deficits at 6 months (explaining 7·0-17·2% of the variance in anxiety, depression, fatigue, and subjective cognitive decline); and by anxiety, depression, fatigue, and subjective cognitive deficit at 6 months. Objective cognitive deficits at 2-3 years were not predicted by any of the factors tested, except for cognitive deficits at 6 months, explaining 10·6% of their variance. 95 of 353 participants (26·9% [95% CI 22·6-31·8]) reported occupational change, with poor health being the most common reason for this change. Occupation change was strongly and specifically associated with objective cognitive deficits (odds ratio [OR] 1·51 [95% CI 1·04-2·22] for every SD decrease in overall cognitive score) and subjective cognitive decline (OR 1·54 [1·21-1·98] for every point increase in CCI-20). Psychiatric and cognitive symptoms appear to increase over the first 2-3 years post-hospitalisation due to both worsening of symptoms already present at 6 months and emergence of new symptoms. New symptoms occur mostly in people with other symptoms already present at 6 months. Early identification and management of symptoms might therefore be an effective strategy to prevent later onset of a complex syndrome. Occupation change is common and associated mainly with objective and subjective cognitive deficits. Interventions to promote cognitive recovery or to prevent cognitive decline are therefore needed to limit the functional and economic impacts of COVID-19. National Institute for Health and Care Research Oxford Health Biomedical Research Centre, Wolfson Foundation, MQ Mental Health Research, MRC-UK Research and Innovation, and National Institute for Health and Care Research.

Impact of upadacitinib induction and maintenance therapy on health-related quality of life, fatigue, and work productivity in patients with moderately-to-severely active Crohn's disease.

Quality of life in patients with active Crohn's disease may be significantly reduced. We evaluated the effects of upadacitinib induction and maintenance therapy on fatigue, quality of life, and work productivity in the phase 3 trials U-EXCEL, U-EXCEED, and U-ENDURE. Clinical responders to upadacitinib 45mg in U-EXCEL and U-EXCEED induction trials were re-randomized 1:1:1 to upadacitinib 30mg, 15mg, or placebo for 52 weeks of maintenance in U-ENDURE. Clinically meaningful improvements in Inflammatory Bowel Disease Questionnaire (IBDQ) response, IBDQ remission, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), and Work Productivity and Activity Impairment were evaluated. Percentages of patients achieving clinically meaningful improvements were assessed at induction Weeks 4 and 12 and maintenance Week 52. Analysis included 1021 and 502 patients assessed at induction and maintenance, respectively. In U-EXCEL, greater improvements (all p≤0.001) in IBDQ response (71.0% vs 50.2%), IBDQ remission (44.2% vs 23.7%), and FACIT-Fatigue (42.0% vs 27.0%) were observed in upadacitinib-treated patients versus placebo at Week 4. Improvements in IBDQ response, IBDQ remission, and FACIT-Fatigue were similar or greater at Week 12. Clinically meaningful improvement in overall work impairment (52.1% vs 38.1%, p≤0.05) was demonstrated at Week 12. Similar results were observed in U-EXCEED. Improvements were sustained through 52 weeks of upadacitinib maintenance treatment. In patients with active Crohn's disease, upadacitinib treatment relative to placebo significantly improved fatigue, quality of life, and work productivity as early as Week 4. These effects were sustained through 52 weeks of maintenance.

Efficacy of treatment with traditional Chinese patent medicine (Fufang E'jiao Syrup) for cancer-related fatigue in patients with advanced cancer: A randomized, double-blinded, placebo-controlled, multicenter trial.

12053 Background: There is ongoing interest in finding effective drugs for cancer-related fatigue (CRF) in advanced cancer patients, although studies have had mixed results. Fufang E'jiao Syrup (FFEJS), a traditional Chinese patent medicine, has shown promise in alleviating CRF. This trial aims to investigate whether FFEJS could reduce fatigue and improve quality of life in advanced cancer patients. Methods: This prospective, multicenter, double-blinded, placebo-controlled trial was implemented at 29 hospitals in China, enrolling 611 advanced non-small cell lung cancer, colorectal cancer, and gastric cancer patients with Visual Analogue Scale for Fatigue ≥ 4 points. The study was conducted between September 23, 2019 and April 7, 2022, with a final follow-up on May 25, 2022. Participants were randomized to receive FFEJS (20 ml, 3 times per day) or a matching placebo orally for six weeks. The safety assessments were extended until the fourth week after the trial ended. The primary outcome was the change in total mean score (range: 0 [no fatigue] to 10 [extreme fatigue] points) on the Revised Piper Fatigue Scale-Chinese Version (RPFS-CV) from baseline to week 6. Secondary outcomes include quality of life (Functional Assessment of Chronic Illness Therapy-Fatigue, FACIT-F) and adverse events. FFEJS were compared with the placebo group using a linear mixed model. Results: Among 611 patients randomized (FFEJS: 303 and placebo: 308; 210 non-small cell lung cancer [34.4%], 201 colorectal cancer [32.9%], 200 gastric cancer [32.7%]; mean [SD] age, 62.8 [9.3] years; 413 [68.3%] man; mean [SD] baseline RPFS-CV total mean score, 4.86 [1.30] points), 503 (82.3%) completed the primary end point. By the end of week 6, the FFEJS group achieved normal fatigue levels (RPFS-CV &lt; 4) compared to the placebo group (FFEJS: 3.78 vs Placebo: 4.39, adjusted mean difference 0.59 points [95% CI, 0.45 to 0.76 points]; P &lt; .001). The adjusted mean difference for a favorable shift to a higher FACIT-F total score at week 6 comparing FFEJS with placebo was 2.77 points (97.36 vs 94.23 points; [95% CI, 0.56-4.96 points]; P = .02). There was no difference in adverse events occurrence between FFEJS and the placebo groups (110 [20%] vs 122 [18%], P = .38). Conclusions: In this randomized clinical trial among advanced cancer patients with CRF, FFEJS reducedfatigue severity and improved quality of life compared to placebo. Research is needed to assess the mechanism, clinical effect, and long-term safety of FFEJS for CRF in advanced cancer patients. Clinical trial information: NCT04147312 .

Assessment of fatigue in adult patients with sickle cell disease: Useof the functional assessment of chronic illness therapy-Fatigue (FACIT-fatigue) questionnaire.

Few studies have used validated scales to assess the intensity and determinants of fatigue, a major symptom of sickle cell disease (SCD). We aimed to assess the level of basal fatigue in adult patients with SCD, using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) questionnaire. We prospectively included 102 stable adult outpatients with SCD over 2 months, who answered the FACIT-Fatigue (ranging from 0 (worst imaginable fatigue) to 52 (no fatigue)) and reported on the intensity of fatigue and its impact on quality of life. The cut-off for significant fatigue was <34. The median [IQR] FACIT-Fatigue score was 29 [22-37], indicating moderate-to-severe fatigue. In a multivariate analysis, the FACIT-Fatigue score was significantly associated with female sex, high body mass index, high level of stress, poor sleep quality, and number of previous episodes of acute chest syndrome, but not with the genotype or the haemoglobin level. Most adult patients with SCD experience significant and sometimes intense fatigue; this is probably due to several factors, including disease activity. Fatigue should be evaluated systematically during consultations and in patient education programmes and as an end-point in therapeutic trials.

Efficacy and safety of guselkumab in patients with active psoriatic arthritis who had inadequate efficacy and/or intolerance to one prior tumor necrosis factor inhibitor: study protocol for SOLSTICE, a phase 3B, multicenter, randomized, double-blind, placebo-controlled study

BackgroundTumor necrosis factor inhibitors (TNFi) are frequently chosen as the first biologic for patients with psoriatic arthritis (PsA). Given that many patients with PsA are TNFi inadequate responders (TNF-IR; either inadequate efficacy or intolerance), treatments utilizing alternative mechanisms of action are needed. In phase 3 studies, the fully human interleukin (IL)-23p19 subunit-inhibitor, guselkumab, was efficacious in patients with active PsA, including TNFi-IR. Efficacy was generally consistent between TNFi-naïve and TNFi-experienced cohorts; however, in the latter, higher response rates have been observed with the Q4W dosing regimen relative to the Q8W dosing regimen for some endpoints, suggesting the need to evaluate whether more frequent dosing may provide an incremental clinical benefit for TNFi-IR patients.MethodsThe phase 3b SOLSTICE study will assess guselkumab efficacy and safety in TNFi-IR PsA patients. Eligibility criteria include a PsA diagnosis for ≥ 6 months; active disease (≥ 3 swollen, ≥ 3 tender joints, C-reactive protein ≥ 0.3 mg/dL); and inadequate efficacy with, and/or intolerance to, one prior TNFi. Participants will be randomized 1:1:1 to guselkumab Q4W or Q8W or placebo→guselkumab Q4W (at Week 24). The primary endpoint is the proportion of patients achieving ≥ 20% improvement in the American College of Rheumatology criteria (ACR20) at Week 24. Major secondary endpoints include ACR50, ACR70; an Investigator’s Global Assessment (IGA) of psoriasis score of 0/1 plus ≥ 2-grade reduction and ≥ 90% improvement in Psoriasis Area and Severity Index (both among patients with ≥ 3% body surface area affected by psoriasis and baseline IGA ≥ 2); minimal/very low disease activity; and changes from baseline in Health Assessment Questionnaire-Disability Index, the 36-item Short-Form Health Survey Physical Component Summary, and Functional Assessment of Chronic Illness Therapy-Fatigue scores. The target sample size (N = 450) is estimated to provide > 90% power in detecting differences between each guselkumab group and the placebo group for the primary endpoint assuming a 2-sided α = 0.05. Cochran-Mantel–Haenszel testing and analyses of covariance will be used to compare efficacy for binary and continuous endpoints, respectively.DiscussionFindings from the phase 3b SOLSTICE study, the design of which was informed by results from previously conducted phase 3 studies, is expected to provide important efficacy and safety information on guselkumab therapy in TNFi-IR patients with PsA.Trial registrationThis trial was registered at ClinicalTrials.gov, NCT04936308, on 23 June 2021.

Methylphenidate Versus Placebo for Treating Fatigue in Patients With Advanced Cancer: Randomized, Double-Blind, Multicenter, Placebo-Controlled Trial.

To compare effects and side effects of 6 weeks of individually dose-titrated methylphenidate or placebo on fatigue in palliative care patients with advanced cancer. This is a randomized, double-blind, placebo-controlled, multicenter trial. Eligible patients had advanced incurable cancer and fatigue >3/10. Principal exclusions were hypertension; psychiatric, cardiovascular, cerebrovascular, renal, liver, or blood disorders; substance dependency; and epilepsy. Patients were randomly assigned 1:1 methylphenidate or placebo starting at 5 mg twice daily. Dose of methylphenidate/placebo was titrated once per week, over 6 weeks, up to a maximum of 20 mg three times daily. Trial ended at 10 weeks. Primary outcome was the difference in Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) scores between groups at 6 ± 2 weeks. Secondary outcomes included adverse effects, quality of life, and mood. One hundred sixty-two patients (73 men; mean, 65.8; standard deviation [SD], 10.3 years) were randomly assigned, and three were excluded from analysis. Seventy-seven were allocated placebo (baseline FACIT-F = 22 [SD, 10]); 82 were allocated methylphenidate (FACIT-F = 20 [SD, 9]). After 6 ± 2 weeks, FACIT-F scores were 1.97 points (95% CI, -0.95 to 4.90; P = .186) higher (better) on methylphenidate than placebo. Across 10 weeks of the study, FACIT-F was nominally higher in the methylphenidate group versus placebo (Diff, 2.20 [95% CI, 0.39 to 4.01]), but this did not reach the minimally clinically important difference (5-points). At 6 weeks, there were no differences between groups in quality-of-life or symptom domains except for depression scores (nominally reduced in the methylphenidate group: Diff, -1.35 [95% CI, -2.41 to -0.30]). There were no differences in mortality or serious adverse events. After 6 ± 2 weeks of treatment, methylphenidate was not superior to placebo for treating fatigue in advanced cancer. Methylphenidate was safe and well-tolerated.

Enthesitis and Dactylitis Resolution with Risankizumab for Active Psoriatic Arthritis: Integrated Analysis of the Randomized KEEPsAKE 1 and 2 Trials.

The presence (vs absence) of enthesitis/dactylitis is associated with greater psoriatic arthritis (PsA) activity and reduced health-related quality of life. Risankizumab, an interleukin 23 antagonist, demonstrated superior treatment efficacy over placebo in patients with PsA, including enthesitis/dactylitis. Herein, we report the efficacy of risankizumab on complete resolution of enthesitis and/or dactylitis and improvements in patient-reported outcomes in patients with PsA. This integrated post hoc analysis of data from KEEPsAKE 1 and KEEPsAKE 2 included patients with baseline enthesitis (Leeds Enthesitis Index > 0) and/or dactylitis (Leeds Dactylitis Index > 0). Efficacy outcomes at weeks 24 and 52 included proportion of patients achieving enthesitis and/or dactylitis resolution and minimal clinically important differences (MCID) in pain, Health Assessment Questionnaire-Disability Index, and Functional Assessment of Chronic Illness Therapy-Fatigue. Of 1407 patients, approximately 63%, 28%, and 20% had baseline enthesitis, dactylitis, and both enthesitis/dactylitis, respectively. At week 24, higher response rates were observed for risankizumab vs placebo for resolution of enthesitis, dactylitis, and both enthesitis/dactylitis (differences of 13.9%, 16.9%, and 13.3%, respectively; p < 0.05). By week 52, risankizumab treatment resulted in complete resolution of enthesitis, dactylitis, and both enthesitis and dactylitis in 55.0%, 76.1%, and 52.3% of patients; similar resolution rates occurred among patients who switched from placebo to risankizumab. Among risankizumab-treated patients who achieved resolution of enthesitis and/or dactylitis, MCIDs were also attained in patient-reported pain, disability, and fatigue at week 24 (all p < 0.05; except fatigue in patients with resolution of both enthesitis/dactylitis); responses were sustained through week 52. Higher proportions of risankizumab-treated (vs placebo-treated) patients achieved enthesitis and/or dactylitis resolution and meaningful improvements in patient-reported outcomes at week 24 and generally sustained responses at week 52. Thus, risankizumab may result in sustained alleviation of PsA-related pathognomonic musculoskeletal lesions of enthesitis/dactylitis. NCT03675308, and NCT03671148.

Development of a Primary Biliary Cholangitis-specific Version of Chronic Liver Disease Questionnaire: CLDQ-PBC.

Primary biliary cholangitis (PBC) is a chronic liver disease leading to cirrhosis and impairment of patient-reported outcomes (PROs). We aimed to develop a PBC-specific version of the Chronic Liver Disease Questionnaire (CLDQ) instrument to assess health-related quality of life of patients with PBC. From our Liver Database, we included patients with PBC who had CLDQ, clinico-laboratory data, and completed Short Form-36 (SF-36) and The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). The 29 items of CLDQ were subjected to item reduction, exploratory factor analysis, and fed into a standard instrument validation pipeline. Data were available for 108 PBC patients: 57±11 years, 7% male, 58% cirrhosis, 24% decompensated cirrhosis (Child's B and C). Of 29 CLDQ items, none met the exclusion criteria. Exploratory factor analysis (95% of variance) returned 7 factors. Based on evaluation of factor loadings and face validity, those factors yielded 7 domains (Diet, Emotion, Fatigue, Itch, Symptoms, Sleep, Worry). Good to excellent internal consistency (Cronbach's alpha 0.85-0.93) was observed for 5/7 domains. For the remaining two domains (Diet, Itch), additional items obtained from patients, experts and review of the literature were included. For 5 domains, known-groups validity tests discriminated between PBC patients with and without cirrhosis, advanced cirrhosis, depression (p<0.05 for 3-5 domains). The CLDQ-PBC domains were correlated with relevant domains of SF-36, CLDQ-PBC Fatigue correlated with Fatigue Scale of FACIT-F (rho=+0.85) and CLDQ-PBC Worry domain negatively correlated with alkaline phosphatase (rho=-0.38, p=0.0082). The CLDQ-PBC has been developed based on the original CLDQ. The new instrument has evidence for internal consistency and validity, and is being fully validated using an external cohort.

Assessment of the Impact of RNase in Patients With Severe Fatigue Related to Post-Acute Sequelae of SARS-CoV-2 Infection (PASC): A Randomized Phase 2 Trial of RSLV-132.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and RNA debris persist in viral reservoirs for weeks to months following infection, potentially triggering interferon production and chronic inflammation. RSLV-132 is a biologic drug composed of catalytically active human RNase1 fused to human IgG1 Fc and is designed to remain in circulation and digest extracellular RNA. We hypothesized that removal of SARS-CoV-2 viral RNA from latent reservoirs may improve inflammation, neuroinflammation, and fatigue associated with post-acute sequelae of SARS-CoV-2 infection (PASC). This was a phase 2, double-blind, placebo-controlled randomized clinical trial in participants with a 24-week history of PASC and severe fatigue. The primary endpoint of the trial assessed the impact of 6 intravenous doses of RSLV-132 on the mean change from baseline at day 71 in the Patient-Reported Outcomes Measurement Information System Fatigue Short Form 7a (PROMIS Fatigue SF 7a). A statistically significant difference on day 71 was not observed with respect to the primary or secondary endpoints. This was likely due to a placebo response that increased during the trial. Statistically significant improvement in fatigue as measured by the PROMIS Fatigue SF 7a, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), and Physicians Global Assessment (PGA) instruments were observed earlier in the trial, with women demonstrating greater responses to RSLV-132 than men. While fatigue was not statistically significantly improved at Day 71, earlier timepoints revealed statistically significant improvement in fatigue and physician global assessment. The data suggest eliminating latent viral RNA by increasing serum RNase activity may improve fatigue in PASC patients. Women may respond better to this approach than men. Future studies will aim to confirm these findings.

The effects of vitamin D supplementation on disease activity and fatigue in Libyan rheumatoid arthritis patients.

This study aimed to investigate the effect of vitamin D supplementation therapy on disease activity and fatigue in rheumatoid arthritis (RA) patients. A prospective randomized clinical trial was conducted at rheumatology clinics in Tripoli Central Hospital, Libya. The eligible patients received disease-modifying antirheumatic drugs (DMARDs) and were divided into two groups: group A received 50,000 IU of vitamin D once a week; while group B received conventional DMARDs without vitamin D supplementation. The groups were monitored for 12 weeks. The study included 68 RA patients, with the majority being female (75%). There were no significant differences in parameters such as age, sex, duration of illness, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), calcium, and vitamin D levels, as well as DAS28 (Disease Activity Score with 28-joint count) and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) levels between these two groups at baseline. After 12 weeks, group A showed a significant improvement in mean vitamin D levels and FACIT-F scores compared to group B. The increase in vitamin D levels in group A (24.21 ±4.81 nmol/l) was higher than that in group B (5.76 ±3.36 nmol/l). Furthermore, the FACIT-F score in group A was in the normal range (mean: 39.36 ±6.15), whereas group B still exhibited "abnormal" FACIT-F < 27.75 ±4.41. Correlation analysis indicated a positive correlation between FACIT-F and vitamin D levels, suggesting that higher vitamin D levels were associated with improved fatigue. Additionally, a weak inverse correlation was observed between DAS28 and vitamin D levels though the difference was not statistically significant (p > 0.05). Finally, the correlation between DAS28 and FACIT-F was positive (R = 0.557, p = 0.000). The results of the recent study indicated that vitamin D3 (50,000 IU of cholecalciferol) supplementation had a positive impact in RA patients compared to conventional DMARDs drugs, as was clear from the significant FACIT-F.

Changes in fatigue symptoms following an exercise-based rehabilitation programme for patients with long COVID.

There is evidence to support COVID-19 rehabilitation programmes improving persistent COVID-19 symptoms; however, there is concern that therapies that include an exercise component may increase fatigue and post-exertional symptom exacerbation (PESE). The objectives of the present study were to determine the effect of a 6-week COVID-19 rehabilitation programme on fatigue and PESE in individuals with ongoing COVID-19 symptoms. After a routine medical assessment, individuals with persistent COVID-19 symptoms were enrolled on a 6-week COVID-19 specific rehabilitation programme. The programme included symptom-titrated exercise, education and self-management advice. Fatigue was assessed pre- and post-programme using the Functional Assessment Chronic Illness Therapy Fatigue questionnaire (FACIT). Exercise capacity (Incremental and Endurance Shuttle Walking Test (ISWT and ESWT)) and PESE (DePaul Symptom Questionnaire (DSQ)) were also assessed pre- and post-programme. Composite scores were calculated for the frequency and severity domains of the DSQ. 148 patients (median (IQR) age 59 (49-72) years, 82 (55%) female, 81 (54%) hospitalised) completed the COVID-19 rehabilitation programme. FACIT score was reduced pre- to post-programme by a mean (CI) change of -5 (-7- -4); p<0.01. Exercise capacity increased by 82 (65-99) m for the ISWT and 398 (333-462) s for the ESWT (n=148). PESE was assessed in 44 patients. The DSQ frequency and severity composite score improved by 20 (13-28) and 19 (13-26) points, respectively (p<0.01, n=44). These data demonstrate the potential benefits of a COVID-19 rehabilitation programme in improving fatigue, exercise capacity and symptom exacerbation in those with persistent COVID-19 symptoms.

Digital Therapeutic (Mika) Targeting Distress in Patients With Cancer: Results From a Nationwide Waitlist Randomized Controlled Trial.

Distress is highly prevalent among patients with cancer, but supportive care needs often go unmet. Digital therapeutics hold the potential to overcome barriers in cancer care and improve health outcomes. This study conducted a randomized controlled trial to investigate the efficacy of Mika, an app-based digital therapeutic designed to reduce distress across the cancer trajectory. This nationwide waitlist randomized controlled trial in Germany enrolled patients with cancer across all tumor entities diagnosed within the last 5 years. Participants were randomized into the intervention (Mika plus usual care) and control (usual care alone) groups. The participants completed web-based assessments at baseline and at 2, 6, and 12 weeks. The primary outcome was the change in distress from baseline to week 12, as measured by the National Comprehensive Cancer Network Distress Thermometer. Secondary outcomes included depression, anxiety (Hospital Anxiety and Depression Scale), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue), and quality of life (Clinical Global Impression-Improvement Scale). Intention-to-treat and per-protocol analyses were performed. Analyses of covariance were used to test for outcome changes over time between the groups, controlling for baseline. A total of 218 patients (intervention: n=99 and control: n=119) were included in the intention-to-treat analysis. Compared with the control group, the intervention group reported greater reductions in distress (P=.03; ηp²=0.02), depression (P<.001; ηp²=0.07), anxiety (P=.03; ηp²=0.02), and fatigue (P=.04; ηp²=0.02). Per-protocol analyses revealed more pronounced treatment effects, with the exception of fatigue. No group difference was found for quality of life. Mika effectively diminished distress in patients with cancer. As a digital therapeutic solution, Mika offers accessible, tailored psychosocial and self-management support to address the unmet needs in cancer care. German Clinical Trials Register (DRKS) DRKS00026038; https://drks.de/search/en/trial/DRKS00026038.

5-EPIFAT trial protocol: a multi-center, randomized, placebo-controlled trial of the efficacy of pharmacotherapy for fatigue using methylphenidate, bupropion, ginseng, and amantadine in advanced cancer patients on active treatment

BackgroundCancer-related fatigue (CRF) is still undertreated in most patients, as evidence for pharmacological treatments is limited and conflicting. Also, the efficacy of the pharmacological agents relative to each other is still unclear. Therefore, medications that may potentially contribute to improving CRF will be investigated in this head-to-head trial. Our main objective is to compare the efficacy of methylphenidate vs. bupropion vs. ginseng vs. amantadine vs. placebo in patients with advanced cancer.MethodsThe 5-EPIFAT study is a 5-arm, randomized, multi-blind, placebo-controlled, multicenter trial that will use a parallel-group design with an equal allocation ratio comparing the efficacy and safety of four medications (Methylphenidate vs. Bupropion vs. Ginseng vs. Amantadine) versus placebo for management of CRF. We will recruit 255 adult patients with advanced cancer who experience fatigue intensity ≥ 4 based on a 0–10 scale. The study period includes a 4-week intervention and a 4-week follow-up with repeated measurements over time. The primary outcome is the cancer-related fatigue level over time, which will be measured by the functional assessment of chronic illness therapy-fatigue (FACIT-F) scale. To evaluate safety, the secondary outcome is the symptomatic adverse events, which will be assessed using the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events in cancer clinical trials (PRO-CTCAE). Also, a subgroup analysis based on a decision tree-based machine learning algorithm will be employed for the clinical prediction of different agents in homogeneous subgroups.DiscussionThe findings of the 5-EPIFAT trial could be helpful to guide clinical decision-making, personalization treatment approach, design of future trials, as well as the development of CRF management guidelines.Trial registrationIRCT.ir IRCT20150302021307N6. Registered on 13 May 2023.

Patient-reported Quality of Life and Survival Outcomes in Prostate Cancer: Analysis of the ECOG-ACRIN E3805 Chemohormonal Androgen Ablation Randomized Trial (CHAARTED)

BackgroundChemohormonal therapy with androgen deprivation therapy and docetaxel (ADT + D) improves overall survival (OS) and quality of life (QOL) at 12 mo versus androgen deprivation therapy (ADT) alone in men with metastatic hormone-sensitive prostate cancer (mHSPC). However, the prognostic role of QOL is unknown in this population. ObjectiveTo study the relationship between QOL, disease characteristics, and OS in men with mHSPC. Design, setting, and participantsIn this exploratory post hoc analysis, 790 patients with mHSPC completed the QOL instruments Functional Assessment of Cancer Therapy—Prostate (FACT-P), Functional Assessment of Chronic Illness Therapy—Fatigue (FACIT-F), and Brief Pain Inventory (BPI). Outcome measurements and statistical analysisLog-rank test and Cox proportional hazard models tested the association between QOL and OS by clinical and disease characteristics. Results and limitationsBaseline higher FACT-P trended toward improved survival after accounting for clinical variables (hazard ratio [HR] 0.80 [0.62, 1.04], p = 0.09), while higher 3-mo FACT-P was independently associated with better survival (HR 0.76 [0.58, 1.0], p = 0.05). Patients with the poorest QOL (bottom quartile) at baseline and 3 mo had longer survival if they received ADT + D rather than ADT alone (median OS 45.2 vs 34.4 mo, HR 0.75 [0.53, 1.05], p = 0.09, and 48.3 vs 29.3 mo, HR 0.69 [0.48, 0.99], p = 0.05 respectively). In contrast, patients with the best QOL (top quartile) at baseline and 3 mo had comparable survival irrespective of whether or not docetaxel was added (median OS 72.1 vs 51.7 mo, HR 0.92 [0.63, 1.36], p = 0.69, and 69.9 vs 68.9 mo, HR 1.11 [0.73, 1.67], p = 0.63, respectively). Survival was linked with baseline FACIT-F (HR 0.76 [0.57, 1.0], p = 0.05), but not BPI (HR 0.98 [0.75, 1.28], p = 0.90). ConclusionsThree-month QOL had a stronger independent association with survival. The most symptomatic patients had longer survival with the addition of docetaxel; conversely, the least symptomatic patients did not appear to benefit. Consideration of QOL may enhance decision-making and patient selection when choosing chemohormonal treatment in mHSPC. Patient summaryQuality of life independently forecasted the survival of men with metastatic hormone-sensitive prostate cancer in the CHAARTED study. Close tracking of quality of life could help patients and clinicians make decisions about the appropriate treatment in this setting.

Efficacy and safety of tofacitinib for chronic plaque psoriasis and psoriatic arthritis: a systematic review and meta-analysis of randomized controlled trials.

To summarize and analyze the results of published randomized controlled trials of tofacitinib for the treatment of chronic plaque psoriasis and psoriatic arthritis(PsA) and discuss its efficacy and safety. An exhaustive systematic search encompassing PubMed, Cochrane, Embase, and Web of Science databases was conducted up to July 2023. Studies eligible for inclusion were analyzed, organized using Review Manager version 5.4.1 (Cochrane Collaboration, Oxford, UK) and STATA 15.0 version (Stata Corp, College Station, TX, USA) software. A total of six articles, covering 1393 patients (844 treated with tofacitinib and 549 with placebo), were included. The foundational characteristics of tofacitinib and placebo group showed similarity, except for age and Dermatology Life Quality Index (DLQI) score, especially in the context of chronic plaque psoriasis. It is noteworthy that we discovered tofacitinib exhibited a significant impact on Psoriasis Area and Severity Index 75 (PASI75) response, Physician's Global Assessment (PGA) response, and adverse events (AEs) in cases of chronic plaque psoriasis. Similarly, tofacitinib demonstrated substantial influence on American College of Rheumatology 20/50 (ACR20/50) response, PASI75 response, as well as alterations in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score, Health Assessment Questionnaire-Disability Index (HAQ-DI) Score, Dactylitis Severity Score (DSS), and Leeds Enthesitis Index (LEI) Score in the context of psoriatic arthritis (PsA). Nevertheless, there was no statistically significant impact of tofacitinib on serious adverse events (SAEs) in chronic plaque psoriasis, as well as on both adverse events (AEs) and SAEs in psoriatic arthritis (PsA). A comprehensive analysis revealed that tofacitinib has a positive effect on addressing skin and joint symptoms, as well as improving the quality of life for patients with chronic plaque psoriasis and psoriatic arthritis (PsA). However, the safety of the drug's long-term usage even requires further validation. Key Points • In 6 analyses involving a total of 1393 patients, tofacitinib exhibits positive effect on the treatment of both chronic plaque psoriasis and psoriatic arthritis (PsA). • Although dose-based subgroup analyses have demonstrated effectiveness. Some studies indicate that the 5-mg dose (twice daily) may not show an effect due to the failure of non-inferiority trials comparing tofacitinib with placebo. Therefore, caution is required when interpreting its effectiveness. On the other hand, the 10-mg dose (BID) has been associated with an increase in adverse events and serious adverse events,and is recommended to be used with caution in patients with cardiovascular or uveitis risk factors. • Tofacitinib has efficacy in comorbid psychiatric disorders (depression, anxiety, or Alzheimer's disease) and inflammatory bowel disease (ulcerative colitis), but patients with comorbid renal insufficiency, hepatic dysfunction, osteoporosis, cardiovascular disease, or uveitis may need to be moderated or avoided with tofacitinib.

Fatigue Item Response among Hemoglobin-Normalized Patients with Paroxysmal Nocturnal Hemoglobinuria: PEGASUS Trial Results at 16 and 48 Weeks.

Background. A common symptom of paroxysmal nocturnal hemoglobinuria (PNH) is fatigue, which in some patients can be severe. Eculizumab (Ecu) has proven efficacy in controlling intravascular hemolysis, but commonly results in persistent anemia and fatigue. Pegcetacoplan's (Peg) efficacy was documented in the PEGASUS phase III clinical trial, showing improved hemoglobin (Hb) and patient-reported fatigue. This post-hoc analysis sought to describe this fatigue improvement related to Hb normalization using the Functional Assessment of Chronic Illness Therapy-Fatigue subscale (FACIT-F)'s individual questions to speak more directly to patients' experience and clinicians' day-to-day practice. Methods. The PEGASUS trial compared Peg with Ecu in patients who remained anemic on Ecu over 16 weeks (n = 41 and 39, for Peg and Ecu, respectively), after which all patients received Peg open label for 32 weeks ("Peg" vs. "Ecu-to-Peg" at Week 48). Hb normalization was defined as ≥12-16 g/dL for females and ≥13.6-18 g/dL for males. The FACIT-F assessed fatigue. Using the complete-case data set, Cohen's d summarized the effect sizes of the mean FACIT-F item change for both study arms from the baseline to week 16 (n = 36 and 37, for Peg and Ecu, respectively) and from the baseline to week 48 (n = 30 and 29, for Peg and Ecu-to-Peg, respectively), and for Hb-normalized patients in each study arm from the baseline to week 16 (n = 14 and 0, for Peg and Ecu, respectively) and from the baseline to week 48 (n = 10 and 12, for Peg and Ecu-to-Peg, respectively). Results. The FACIT-F scores for both arms were worse at the baseline compared to later in the trial. Peg patients reported improvements on all fatigue items at Week 16, but Ecu patients reported improvement in only one item. At Week 48, the improvement in fatigue was maintained in Peg patients, and Ecu-to-Peg patients' fatigue improved on all FACIT-F items. Hb normalization was achieved in 14 Peg patients but no Ecu patients at Week 16, and in 10 Peg and 12 Ecu-to-Peg patients, respectively, at week 48. The FACIT-F single items showing the largest change overall, and particularly in Hb-normalized patients across the study arms, were related to symptoms and social limitations. Conclusions. Peg patients reported lasting improvements in fatigue. Patients who were anemic on Ecu reported sustained improvements in fatigue with Peg treatment. Patients who had Hb normalization generally had large, clinically important improvements in fatigue items.

Association between enthesitis/dactylitis resolution and patient-reported outcomes in guselkumab-treated patients with psoriatic arthritis

ObjectivesTo evaluate the association between enthesitis resolution (ER) and dactylitis resolution (DR) and meaningful improvements in patient-reported outcomes (PROs) among biologic-naïve patients with PsA receiving guselkumab in the DISCOVER-2 study.MethodsEnthesitis and dactylitis, characteristic lesions of PsA, were evaluated by independent assessors using the Leeds Enthesitis Index (range, 0–6) and Dactylitis Severity Score (range, 0–60). Proportions of patients with ER or DR (score = 0) among those with score > 0 at baseline were determined at weeks 24, 52, and 100. PROs included: fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-Fatigue]), pain (0–100 visual analog scale), physical function (Health Assessment Questionnaire-Disability Index [HAQ-DI]), and health-related quality of life (36-item Short-Form Health Survey physical/mental component summary [SF-36 PCS/MCS]). Meaningful responses were defined as: improvements of ≥ 4 for FACIT-Fatigue, ≥ 0.35 for HAQ-DI, and ≥ 5 for SF-36 PCS/MCS and absolute scores of ≤ 15 for minimal pain and ≤ 0.5 for normalized HAQ-DI. Associations between ER/DR status and PRO response status were tested using a Chi-square test.ResultsGuselkumab-treated patients with ER were more likely than those without ER to achieve minimal pain (p < 0.001), normalized HAQ-DI (p < 0.001), and PCS response (p < 0.05) at weeks 24, 52, and 100. Patients with DR were more likely than those without DR to achieve FACIT-Fatigue response at week 24 and week 52 (both p ≤ 0.01) and minimal pain at week 24 and normalized HAQ-DI at week 52 (both p ≤ 0.03).ConclusionIn biologic-naïve patients with active PsA treated with guselkumab, achieving ER or DR was associated with durable improvements in selected PROs, including those of high importance to patients.Trial registrationClinicalTrials.gov (https://clinicaltrials.gov) NCT03158285; Registered: May 16, 2017.Key Points• At week 100, 65% and 76% of guselkumab-treated patients achieved enthesitis and dactylitis resolution (ER/DR).• Achieving ER was associated with achieving DR and vice versa through the end of study.• Achieving ER or DR was associated with durable and meaningful improvements in selected patient-reported outcomes.

A Prospective Randomised Trial to Determine the Effect of a Reduced Versus Standard Dose of Enzalutamide on Side Effects in Frail Patients with Prostate Cancer

Background and objectiveEnzalutamide is a potent antiandrogen inhibitor, effectively used for the treatment of different stages of prostate cancer. Side effects occur frequently at the registered dose, whilst a lower dose might be equally effective. Therefore, the aim of this study is to determine the effect of a reduced dose of enzalutamide on side effects in frail patients with prostate cancer. MethodsThis multicentre randomised trial compared the standard enzalutamide dose of 160 mg once daily (OD) with a reduced dose of 120 mg OD in frail patients with prostate cancer. Fatigue, cognitive side effects, and depressive symptoms were measured by the Functional Assessment of Chronic Illness Therapy—Fatigue (FACIT-Fatigue) questionnaire, Functional Assessment of Cancer Therapy—Cognitive Function (FACT-Cog) questionnaire, and Geriatric Depression Scale—15 (GDS-15). Linear mixed-effect models were used to study differences in side effects over time between both groups. Key findings and limitationsIn total, 52 patients were included in the analysis (25 reduced dose and 27 standard dose). Patients treated with the reduced dose had significantly lower fatigue after 24 wk than those with the standard dose (difference FACIT-Fatigue 6.2; 95% confidence interval 1.4–11.0; p = 0.01). Patients treated with the reduced dose showed stable fatigue, cognitive side effects, and depressive symptoms over time, whilst patients with the standard dose showed significantly worse side effects after 24 wk than at baseline. Conclusions and clinical implicationsA reduced dose of enzalutamide results in less fatigue, cognitive side effects, and depressive symptoms in frail patients with prostate cancer than the standard dose, without any indication of interference with efficacy endpoints. Patient summaryIn this report, we looked at the side effects of enzalutamide at two dose levels. We found that, in frail patients, three tablets a day result in less fatigue than four tablets a day. Patients treated with four tablets a day showed an increase in fatigue, cognitive side effects, and depression. We conclude that a lower dose of three tablets can be used to alleviate side effects without indications for less efficacy.