Norfolk QOL-DN Research Articles

Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy

Transthyretin gene silencing is an emerging treatment strategy for hereditary transthyretin (ATTRv) amyloidosis. To evaluate eplontersen, an investigational ligand-conjugated antisense oligonucleotide, in ATTRv polyneuropathy. NEURO-TTRansform was an open-label, single-group, phase 3 trial conducted at 40 sites across 15 countries (December 2019-April 2023) in 168 adults with Coutinho stage 1 or 2 ATTRv polyneuropathy, Neuropathy Impairment Score 10-130, and a documented TTR variant. Patients treated with placebo from NEURO-TTR (NCT01737398; March 2013-November 2017), an inotersen trial with similar eligibility criteria and end points, served as a historical placebo ("placebo") group. Subcutaneous eplontersen (45 mg every 4 weeks; n = 144); a small reference group received subcutaneous inotersen (300 mg weekly; n = 24); subcutaneous placebo weekly (in NEURO-TTR; n = 60). Primary efficacy end points at week 65/66 were changes from baseline in serum transthyretin concentration, modified Neuropathy Impairment Score +7 (mNIS+7) composite score (scoring range, -22.3 to 346.3; higher scores indicate poorer function), and Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) total score (scoring range, -4 to 136; higher scores indicate poorer quality of life). Analyses of efficacy end points were based on a mixed-effects model with repeated measures adjusted by propensity score weights. Among 144 eplontersen-treated patients (mean age, 53.0 years; 69% male), 136 (94.4%) completed week-66 follow-up; among 60 placebo patients (mean age, 59.5 years; 68% male), 52 (86.7%) completed week-66 follow-up. At week 65, adjusted mean percentage reduction in serum transthyretin was -81.7% with eplontersen and -11.2% with placebo (difference, -70.4% [95% CI, -75.2% to -65.7%]; P < .001). Adjusted mean change from baseline to week 66 was lower (better) with eplontersen vs placebo for mNIS+7 composite score (0.3 vs 25.1; difference, -24.8 [95% CI, -31.0 to -18.6; P < .001) and for Norfolk QoL-DN (-5.5 vs 14.2; difference, -19.7 [95% CI, -25.6 to -13.8]; P < .001). Adverse events by week 66 that led to study drug discontinuation occurred in 6 patients (4%) in the eplontersen group vs 2 (3%) in the placebo group. Through week 66, there were 2 deaths in the eplontersen group consistent with known disease-related sequelae (cardiac arrhythmia; intracerebral hemorrhage); there were no deaths in the placebo group. In patients with ATTRv polyneuropathy, the eplontersen treatment group demonstrated changes consistent with significantly lowered serum transthyretin concentration, less neuropathy impairment, and better quality of life compared with a historical placebo. ClinicalTrials.gov Identifier: NCT04136184; EU Clinical Trials Register: EudraCT 2019-001698-10.

Treatment response and neurofilament light chain levels with long-term patisiran in hereditary transthyretin-mediated amyloidosis with polyneuropathy: 24-month results of an open-label extension study

Background Longitudinal changes in neurofilament light chain (NfL) levels were evaluated alongside prespecified clinical assessments 24 months into the patisiran Global open-label extension (OLE) study in patients with ATTRv amyloidosis with polyneuropathy. Methods All patients enrolled in the Global OLE, from phase III APOLLO and phase II OLE parent studies, received patisiran. Assessments included measures of polyneuropathy (modified Neuropathy Impairment Score+7 (mNIS+7)), quality of life (QOL; Norfolk QOL-Diabetic Neuropathy questionnaire (Norfolk QOL-DN)), and plasma NfL. Results Patients receiving patisiran in the parent study (APOLLO-patisiran, n = 137; phase II OLE-patisiran, n = 25) demonstrated sustained improvements in mNIS+7 (mean change from parent study baseline (95% confidence interval): APOLLO-patisiran −4.8 (−8.9, −0.6); phase II OLE-patisiran −5.8 (−10.5, −1.2)) and Norfolk QOL-DN (APOLLO-patisiran −2.4 (−7.2, 2.3)), and maintained reduced NfL levels at Global OLE 24 months. After initiating patisiran in the Global OLE, APOLLO-placebo patients (n = 49) demonstrated stabilized mNIS+7, improved Norfolk QOL-DN, and significantly reduced NfL levels. Patisiran continued to demonstrate an acceptable safety profile. Earlier patisiran initiation was associated with a lower exposure-adjusted mortality rate. Conclusions Long-term patisiran treatment led to sustained improvements in neuropathy and QOL, with NfL demonstrating potential as a biomarker for disease progression and treatment response in ATTRv amyloidosis with polyneuropathy.

Impact of Vutrisiran on Quality of Life and Physical Function in Patients with Hereditary Transthyretin-Mediated Amyloidosis with Polyneuropathy.

Hereditary transthyretin (ATTRv; v for variant) amyloidosis, also known as hATTR amyloidosis, is a progressive and fatal disease associated with rapid deterioration of physical function and patients' quality of life (QOL). Vutrisiran, a subcutaneously administered RNA interference (RNAi) therapeutic that reduces hepatic production of transthyretin, was assessed in patients with ATTRv amyloidosis with polyneuropathy in the pivotal HELIOS-A study. The phase 3 open-label HELIOS-A study investigated the efficacy and safety of vutrisiran in patients with ATTRv amyloidosis with polyneuropathy, compared with an external placebo group from the APOLLO study of the RNAi therapeutic patisiran. Measures of QOL and physical function were assessed. At month 18, vutrisiran improved Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) total score (least squares mean difference [LSMD] in change from baseline [CFB]: -21.0; p=1.84×10-10) and Norfolk QOL-DN domain scores, compared with external placebo. This benefit relative to external placebo was evident across all baseline polyneuropathy disability (PND) scores and most pronounced in patients with baseline PND scores I-II. Compared with external placebo, vutrisiran also demonstrated benefit in EuroQoL-Visual Analog Scale (EQ-VAS) score (LSMD in CFB: 13.7; nominal p=2.21×10-7), 10-m walk test (LSMD in CFB: 0.239m/s; p=1.21×10-7), Rasch-built Overall Disability Score (LSMD in CFB: 8.4; p=3.54×10-15), and modified body mass index (mBMI) (LSMD in CFB: 140.7; p=4.16×10-15) at month 18. Overall, Norfolk QOL-DN, EQ-VAS, and mBMI improved from pretreatment baseline with vutrisiran, whereas all measures worsened from baseline in the external placebo group. At month 18, Karnofsky Performance Status was stable/improved from baseline in 58.2/13.1% with vutrisiran versus 34.7/8.1% with external placebo. Vutrisiran treatment provided significant clinical benefits in multiple measures of QOL and physical function in patients with ATTRv amyloidosis with polyneuropathy. Benefits were most pronounced in patients with earlier-stage disease, highlighting the importance of early diagnosis and treatment. ClinicalTrials.gov: NCT03759379.

Indirect treatment comparison (ITC) of the efficacy of vutrisiran and tafamidis for hereditary transthyretin-mediated amyloidosis with polyneuropathy

ABSTRACT Background Vutrisiran and tafamidis are approved therapies for treating hereditary transthyretin-mediated (ATTRv/hATTR) amyloidosis with polyneuropathy, a rapidly progressive and fatal disease. To assist healthcare decision-makers, an indirect treatment comparison (ITC) was undertaken to explore the comparative efficacy of vutrisiran and tafamidis. Research design and methods Individual patient data (vutrisiran vs. placebo) and published results (tafamidis vs. placebo) from phase 3 randomized controlled trials were used in a Bucher analysis to assess differences in treatment effects between vutrisiran and tafamidis on: Neuropathy Impairment Score-Lower Limbs (NIS-LL), Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) score, NIS-LL Response, and modified Body Mass Index (mBMI). Results Greater treatment effects were observed at 18 months with vutrisiran vs. tafamidis for all endpoints, with statistically significant improvements in polyneuropathy (relative mean change in NIS-LL: −5.3 [95% confidence interval (CI): −9.4, −1.2; p = 0.011]), health-related quality of life (HRQOL, relative mean change in Norfolk QOL-DN: −18.3 [95% CI: −28.6, −8.0; p < 0.001]), and nutritional status (relative mean change in mBMI: 63.9 [95% CI: 10.1, 117.7; p = 0.020]). Conclusions This analysis suggests vutrisiran has greater efficacy on multiple measures of polyneuropathy impairment and HRQOL compared to tafamidis in patients with ATTRv amyloidosis with polyneuropathy.

Effect of Patisiran on Polyneuropathy and Cardiomyopathy in Patients with hATTR Amyloidosis with V122I/T60A Variants: A Phase 4 Observational Study (S14.005)

Effect of Patisiran on Polyneuropathy and Cardiomyopathy in Patients with hATTR Amyloidosis with V122I/T60A Variants: A Phase 4 Observational Study (S14.005)

Impact of baseline polyneuropathy severity on patisiran treatment outcomes in the APOLLO trial

Objective Assess how baseline polyneuropathy severity impacts response to patisiran regarding neurologic impairment and quality of life (QOL) in patients with hereditary transthyretin-mediated amyloidosis (ATTRv amyloidosis). Methods This post hoc analysis grouped patients from the Phase 3 APOLLO study (n = 225) by baseline Neuropathy Impairment Score (NIS) into quartiles: 6–<31; 31–<57; 57–<85.5; 85.5–141.6. Neurologic impairment (modified NIS+7 [mNIS+7], NIS total score), disability (Rasch-built Overall Disability Scale [R-ODS]), gait speed (10-meter walk test [10-MWT]), grip strength, and QOL (Norfolk Quality of Life-Diabetic Neuropathy [Norfolk QOL-DN] questionnaire) were assessed. Results Across all baseline NIS quartiles, patisiran improved several clinical markers of disease compared with placebo at 18 months. Patients in lower NIS quartiles, treated with patisiran earlier in the disease course, maintained better scores in mNIS+7, NIS total score, R-ODS, 10-MWT, grip strength, and Norfolk QOL-DN versus those in higher NIS quartiles, while placebo-treated patients experienced worsening of all functional measures after 18 months across all quartiles. Conclusions Patisiran treatment improved neurologic function and QOL across a wide range of baseline polyneuropathy severities versus placebo. Timing of treatment initiation in patients with ATTRv amyloidosis remains critical for the preservation of function. (ClinicalTrials.gov number, NCT01960348)

Pupillometric findings in ATTRv patients and carriers: results from a single-centre experience

Introduction Hereditary transthyretin amyloidosis (ATTRv) is a treatable multisystemic disease with great phenotypic heterogeneity. Among extra-neurological features, pupillary abnormalities have been reported, either related to amyloid deposition in the eye or to a progressive autonomic neuropathy. Objective To evaluate the role of automated pupillometry, a non-invasive and rapid test able to provide objective and reproducible data on pupil size and reactivity, as a marker of disease severity in late-onset ATTRv patients. Patients and methods We performed automated pupillometry on a cohort of ATTRv patients and pre-symptomatic TTR mutation carriers and compared results to healthy controls. An exhaustive clinical and instrumental evaluation was performed on all enrolled subjects. Results A statistically significant difference in most pupillometry parameters was found in ATTRv patients as compared to both carriers and healthy controls. Moreover, in ATTRv patients, we found a significant correlation between many pupillometry findings and disease duration, as well as widely accepted clinical scales and investigations (NIS, Sudoscan from feet, and Norfolk QoL-DN questionnaire). Conclusions We suggest pupillometry may play a role as a reliable and non-invasive biomarker to evaluate ATTRv disease severity and monitor its progression.

Long-term efficacy and safety of inotersen for hereditary transthyretin amyloidosis: NEURO-TTR open-label extension 3-year update

BackgroundHereditary transthyretin amyloidosis (hATTR/ATTRv) results from the deposition of misfolded transthyretin (TTR) throughout the body, including peripheral nerves. Inotersen, an antisense oligonucleotide inhibitor of hepatic TTR production, demonstrated a favorable efficacy and safety profile in patients with the polyneuropathy associated with hATTR in the NEURO-TTR (NCT01737398) study. We report longer-term efficacy and safety data for inotersen, with a median treatment exposure of 3 years.MethodsPatients who satisfactorily completed NEURO-TTR were enrolled in its open-label extension (OLE) study. Efficacy assessments included the modified Neuropathy Impairment Score + 7 (mNIS + 7), Norfolk Quality of Life–Diabetic Neuropathy (Norfolk QoL-DN) questionnaire total score, and the Short Form 36 (SF-36v2) Health Survey Physical Component Summary score. Safety and tolerability were also assessed. Efficacy is reported for patients living in Europe and North America (this cohort completed the study approximately 9 months before the remaining group of patients outside these regions); safety is reported for the full safety dataset, comprising patients living in Europe, North America, and Latin America/Australasia. This study is registered with ClinicalTrials.gov, identifier NCT02175004.ResultsIn the Europe and North America cohort of the NEURO-TTR study, 113/141 patients (80.1%) completed the study, and 109 patients participated in the OLE study. A total of 70 patients continued to receive inotersen (inotersen–inotersen) and 39 switched from placebo to inotersen (placebo–inotersen). The placebo–inotersen group demonstrated sustained improvement in neurological disease progression as measured by mNIS + 7, compared with predicted worsening based on projection of the NEURO-TTR placebo data (estimated natural history). The inotersen–inotersen group demonstrated sustained benefit, as measured by mNIS + 7, Norfolk QoL-DN, and SF-36v2, compared with estimated natural history as well as compared with the placebo–inotersen group. With a maximum exposure of 6.2 years, inotersen was not associated with any additional safety concerns or increased toxicity in the OLE study. Platelet and renal monitoring were effective in reducing the risk of severe adverse events in the OLE study.ConclusionInotersen treatment for > 3 years slowed progression of the polyneuropathy associated with hATTR, and no new safety signals were observed.

Factors associated with increased health‐related quality‐of‐life benefits in hereditary transthyretin amyloidosis polyneuropathy patients treated with inotersen

Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a genetic condition associated with significant morbidity and mortality. In this study we aimed to identify patient subgroups exhibiting the greatest health-related quality of life (HRQL) benefit from inotersen treatment. We examined data from the inotersen phase 2/3 randomized, controlled trial for ATTRv-PN, NEURO-TTR (NCT01737398, 66 weeks). LASSO regression models predicted changes in Norfolk QoL-DN total score (TQoL, range -4 to 136; higher scores indicate poorer HRQL) from baseline in the inotersen and placebo arm, respectively. Individualized efficacy scores (ES) were calculated as differences between predicted change scores had patients received inotersen vs placebo. Patients were ranked by ES to define the greatest-benefit subpopulation (top 50%). Characteristics of the top 50% and bottom 50% of patients were compared. The overall mean ± standard deviation TQoL change was -0.20 ± 19.13 for inotersen (indicating no change) and 10.77 ± 21.13 for placebo (indicating deterioration). Within the highest-benefit patients, mean TQoL change was -11.03 ± 17.06 (improvement) for inotersen and 11.24 ± 22.97 (deterioration) for placebo (P < .001). Compared with the overall population, patients in the greatest-benefit subpopulation were younger, more likely to have polyneuropathy disability (PND) scores 1 or 2, less likely to have received prior tafamidis or diflunisal treatment, and more likely to have Val30Met mutations and higher (worse) baseline TQoL. Patients who were younger and/or at earlier polyneuropathy stages experienced greater HRQL benefits from inotersen over 66 weeks. These findings underscore the need for early diagnosis and treatment initiation, especially among more severely affected patients in early stages of ATTRv-PN.

Characteristics of patients with autonomic dysfunction in the Transthyretin Amyloidosis Outcomes Survey (THAOS)

Background Autonomic dysfunction is common in transthyretin amyloidosis (ATTR amyloidosis), but its frequency, characteristics, and quality-of-life (QoL) impact are not well understood. Methods The Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing, global, longitudinal survey of patients with ATTR amyloidosis, including patients with inherited (ATTRv) and wild-type (ATTRwt) disease and asymptomatic patients with TTR mutations (ClinicalTrials.gov: NCT00628745). In a descriptive analysis, characteristics and Norfolk QoL-DN total (TQoL) scores at enrolment were compared in patients with vs without autonomic dysfunction (analysis cut-off: 1 August 2020). Results Autonomic dysfunction occurred in 1181/2922 (40.4%) symptomatic patients, and more commonly in ATTRv (1107/1181 [93.7%]) than ATTRwt (74/1181 [6.3%]) amyloidosis. Time (mean [SD]) from ATTR amyloidosis symptom onset to first autonomic dysfunction symptom was shorter in ATTRv (3.4 [5.7] years) than ATTRwt disease (9.7 [10.4]). In ATTRv disease, patients with vs without autonomic dysfunction had worse QoL (TQoL, 47.3 [33.2] vs 16.1 [18.1]); in ATTRwt disease, those with vs without autonomic dysfunction had similar QoL (23.0 [18.2] vs 19.9 [20.5]). Conclusions Autonomic dysfunction was more common and presented earlier in symptomatic ATTRv than ATTRwt amyloidosis and adversely affected QoL in ATTRv disease. These THAOS findings may aid clinicians in diagnosing and treating patients with ATTR amyloidosis. Trial registration: ClinicalTrials.gov: NCT00628745

Neurofilament light chain as adisease severity biomarker in ATTRv: data from a single-centre experience.

Hereditary transthyretin amyloidosis (ATTRv) is a treatable multisystem disorder with prevalent peripheral nervous system impairment. Besides neurophysiological measures, there are few markers to monitor disease progression. Neurofilament light chain (NfL) has recently been considered a sensitive biomarker for neuroaxonal damage in this setting. To evaluate NfL levels in a cohort of ATTRv patients and pre-symptomatic carriers and correlate the serum concentrations with other markers of disease severity. We analysed NfL serum from 17 ATTRv patients or carriers and 26 controls. An exhaustive clinical and instrumental evaluation was performed in all patients. NfL levels were significantly higher in ATTRv cases when compared with controls. A significant correlation was found between NfL values and NIS scale, Sudoscan values from feet, interventricular septum thickness, and Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) questionnaire. We confirm that NfL is a reliable and promising biomarker to evaluate the ATTRv severity and monitor its progression.

Effect of Monochromatic Infrared Energy on Quality of Life and Intraepidermal Nerve Fiber Density in Painful Diabetic Neuropathy: A Randomized, Sham Control Study.

Monochromatic infrared energy (MIRE) has evoked mixed results for symptomatic relief of painful diabetic peripheral neuropathy (DPN). However, intraepidermal nerve-fiber density (IENFD) the gold standard for small-fiber neuropathy has not been evaluated. We assessed the IENFD, pain symptoms and quality of life (QoL) with MIRE therapy compared to placebo in painful DPN. Participants with type 2 diabetes and painful DPN were randomized to receive MIRE or sham therapy dosed thrice a week for 12 weeks. Quantitative assessment of IENFD was performed from 3 mm skin punch-biopsy specimens at baseline and after 12 weeks. We also assessed the QoL with Norfolk QOL, symptom severity with visual analogue scale (VAS), and neuropathy assessment with Michigan neuropathy severity instrument and neuropathy disability score. Thirty-eight participants were enrolled and 30 completed the study protocol. The mean age of participants in MIRE cohort was 59.1 ± 9.2 years, duration of diabetes 12.9 ± 3.1 years, and symptom duration of 3.9 ± 3.7 months. The mean IENFD was 0.90 ± 0.73/mm2 (P < 0.01) and 1.71 ± 1.11/mm2 in the MIRE cohort and 0.60 ± 0.89/mm2 and 2.17 ± 0.98/mm2 (P < 0.01) in sham cohort at baseline and after 3 months. The median decline in VAS was 5.1 (4.0-7.6) and 3.0 (0.4-5.6) points (intergroup difference, P = 0.01); and an increase in Norfolk QoL-DN by 15 (11-18) and 4 (4-14.2) points (intergroup difference, P = 0.021) in MIRE and sham cohort, respectively after 3 months. MIRE therapy does not increase IENFD over short-term usage. However, MIRE therapy provides symptomatic benefit and improves QoL in patients with painful DPN.

Early Data on Long-term Impact of Inotersen on Quality-of-Life in Patients with Hereditary Transthyretin Amyloidosis Polyneuropathy: Open-Label Extension of NEURO-TTR

IntroductionPatients with hereditary transthyretin amyloidosis associated with polyneuropathy (ATTRv-PN) experience deterioration in health-related quality of life (HRQOL) as the disease progresses. Findings from the randomized placebo-controlled phase III NEURO-TTR study showed treatment benefit of inotersen, an antisense oligonucleotide, for preserving or improving HRQOL after 65 weeks of treatment. The current analysis examines longitudinal trends in specific aspects of HRQOL, including polyneuropathy symptoms, daily activities, and physical, role, and social functioning in patients with ATTRv-PN receiving long-term treatment in a follow-up open-label extension (OLE) study.MethodsOne-hundred thirty-five patients with ATTRv-PN were enrolled in an ongoing 5-year OLE study following completion of NEURO-TTR. Eighty-five patients received continuous weekly treatment with inotersen in both studies (inotersen-inotersen group), while 50 patients switched from placebo to inotersen at OLE study baseline (placebo-inotersen group). Descriptive analyses of changes in domain scores and item responses through week 104 of the OLE study were conducted for measures of neuropathy-related and generic HRQOL: Norfolk QOL-Diabetic Neuropathy (DN) questionnaire and SF-36v2® Health Survey (SF-36v2), respectively.ResultsFor both inotersen-inotersen and placebo-inotersen groups, all Norfolk QOL-DN and most SF-36v2 domain scores remained stable from OLE baseline through week 104. Differences in HRQOL between the two groups at OLE baseline were sustained through week 104. Analysis of item responses from NEURO-TTR baseline to OLE study week 104 (170 weeks) for the inotersen-inotersen group found no notable increases in the proportion of patients reporting substantial impairments across a wide variety of symptoms, daily activities, and functioning.ConclusionLong-term treatment with inotersen preserved HRQOL for patients with ATTRv-PN for periods of up to 3 years. The gap in HRQOL between those who had previously received inotersen or placebo in NEURO-TTR did not close by week 104 of the OLE phase, indicating the importance of early treatment for maintaining HRQOL in these patients.Trial RegistrationClinicalTrials.gov Identifiers NCT01737398 for NEURO-TTR study; NCT02175004 for OLE studyInfographic

Responder analysis for neuropathic impairment and quality-of-life assessment in patients with hereditary transthyretin amyloidosis with polyneuropathy in the NEURO-TTR study

ObjectiveHereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a rare disease characterized by rapid neuropathic progression. In pivotal studies of gene-silencing treatments, the modified Neuropathy Impairment Score + 7 tests (mNIS + 7) and Norfolk-Quality of Life (QOL)-Diabetic Neuropathy (DN) questionnaire assessed treatment impact on neuropathic progression. Establishing responder definition (RD) thresholds for these measures would enable evaluation of clinically meaningful treatment benefit.MethodsmNIS + 7 and Norfolk-QOL-DN were administered at baseline and week 65 to 165 adults with ATTRv-PN receiving inotersen (n = 106) or placebo (n = 59) in the NEURO-TTR study. Anchor-based approaches for estimating RD thresholds were used for Norfolk QOL-DN, while distribution-based approaches were used for both measures. Responders were patients with a score change < RD, indicating improvement or stabilization (i.e., no clinically meaningful progression). Odds ratios (ORs) and Fisher’s exact tests compared proportions of responders by treatment.ResultsThe mean RD estimates were 12.2 points and 8.8 points for mNIS + 7 and Norfolk QOL-DN, respectively. The proportions of patients whose change in score indicated improvement or stabilization were statistically significantly larger for inotersen than placebo for all estimated RD thresholds for mNIS + 7 (64–86% responders for inotersen vs. 27–46% for placebo, ORs = 3.8–7.2, ps < 0.001) and Norfolk QOL-DN (66–81% vs. 35–56%, ORs = 2.4–3.6, ps < 0.05).DiscussionEstablishing RD thresholds for these instruments enables evaluation of clinically relevant and individual-level treatment benefit on neuropathic progression. Across RDs estimated using multiple methods, a higher proportion of patients receiving inotersen than placebo showed improved or stabilized neuropathic progression at week 65.Trial registrationClinicalTrials.gov Identifier: NCT01737398; Date of registration: November 29, 2012.

P011. Impact of Patisiran on Activities of Daily Living and Functional Status in hATTR Amyloidosis

<h3>Background</h3> Hereditary transthyretin-mediated (hATTR) amyloidosis, a rare, multi-systemic, life-threatening disease, causes neurologic and cardiac dysfunction, leading to impaired functional status and declining ability to perform activities of daily living (ADLs). <h3>Objectives</h3> To analyze the impact of patisiran on ADLs and functional status in the Phase 3 APOLLO study. <h3>Methods</h3> APOLLO was a randomized, placebo-controlled study of patisiran in patients with hATTR amyloidosis with polyneuropathy (NCT01960348). ADL/functional status assessments included: Rasch-built Overall Disability Scale (R-ODS), Karnofsky Performance Status (KPS), the ADL subdomain of Norfolk QOL-DN (Norfolk ADL). Post-hoc analyses quantified patients with no change/improvement in these assessments at 18 months. <h3>Results</h3> APOLLO enrolled 225 patients worldwide with a mean age of 60.5 years, 74% male, and 43% with V30M transthyretin mutation. At baseline, patisiran and placebo groups had similar R-ODS, KPS, and Norfolk ADL scores. After 18 months, a higher proportion of patisiran-treated patients experienced no change/improvement in functional status and ADLs relative to placebo: R-ODS 49.3% vs 13.0% (odds ratio [OR] 6.5, 95% confidence interval [CI] 2.8 to 15.4), KPS 64.9% vs 42.9%, (OR 2.5, 95% CI 1.3 to 4.8), Norfolk ADL 56.2% vs 20.4% (OR 5.0, 95% CI 2.4 to 10.5). <h3>Conclusions</h3> In APOLLO, the largest randomized clinical study of patients with hATTR amyloidosis with polyneuropathy to date, patisiran preserved ability to perform ADLs and functional status for the majority of patients and demonstrated greater odds of stabilizing or improving these assessments compared to placebo.

Reduced microvascular reactivity in patients with diabetic neuropathy.

Neurogenic regulation is involved in the development of microcirculation response to local heating. We suggest that microvascular reactivity can be used to estimate the severity of diabetic polyneuropathy (DPN). To evaluate the prospects for using the parameters of skin microvascular reactivity to determine the severity of DPN. 26 patients with diabetes mellitus were included in the study (patients with retinopathy (n = 15), and without retinopathy (n = 11)). The severity of DPN was assessed using Michigan Neuropathy Screening Instrument (MNSI) and Norfolk QOL-DN (NQOLDN). Skin microcirculation was measured by laser Doppler flowmetry with local heating test. There were revealed moderate negative correlations between microvascular reactivity and the severity of DPN (for MNSI (Rs = -0.430), for NQOLDN (Rs = -0.396)). In patients with retinopathy, correlations were stronger than in the general group (for MNSI (Rs = -0.770) and NQOLDN (Rs = -0.636)). No such correlations were found in patients without retinopathy. Correlation of the microvascular reactivity and DPN was revealed in patients with registered structural disorders in microvessels (retinopathy). The lack of such correlation in patients without retinopathy may be explained by the intact compensatory mechanisms of microvessels without severe disorders.

Patisiran in hATTR Amyloidosis: Six-Month Latency Period before Efficacy.

Hereditary amyloidosis associated with mutations in the transthyretin gene (hATTR) is a progressive devastating disease, with a fatal outcome occurring within 10years after onset. In recent years, TTR gene silencing therapy appeared as a promising therapeutic strategy, showing evidence that disease progression can be slowed and perhaps reversed. We report here 18 subjects affected by hATTR amyloidosis treated with patisiran, a small interfering RNA acting as TTR silencer, and evaluated with a PND score, the NIS and NIS-LL scale, and a Norfolk QOL-DN questionnaire at baseline and then every 6 months. A global clinical stabilizationwas observed for the majority of the patients, with mild-moderate improvements in some cases, even in advanced disease stage (PND score > 2). Analysis of NIS, NIS-LL and Norfolk QOL-DN results, and PND score variation suggest the possible presence of a 6-month latency period prior to benefit of treatment.

Factors influencing the quality of life over a 4-year period of time in Romanian patients with diabetes mellitus.

To evaluate the changes in quality of life (QOL), diabetic neuropathy (DN) and amputations over 4years in patients with diabetes. In 2012, 25,000 Romanian-translated Norfolk QOL-DN self-administered questionnaires were distributed during a cross-sectional study. Between March-December 2016, all patients identified from the 2012 cohort and enrolled in this follow-up study completed the Norfolk QOL-DN questionnaire; amputations suffered since 2012 were recorded. The influence of age and duration of diabetes (DD) on delta QOL scores (defined as the differences between 2012 and 2016 scores) and of sex, age, diabetes type, DD and declared DN on amputations was explored using multivariate linear and logistic regression, respectively. The mean (standard deviation) age of the 1865 participants was 60.6 (10.3) years. Mean total QOL-DN score increased from 2012 to 2016 by 4.39% (P=.079). Both DD (b=0.39, 95% confidence interval [CI] 0.21-0.57, P<.001) and age (b=0.25, 95% CI 0.13-0.36, P<.001) were significantly correlated with total QOL-DN score. Delta total QOL was higher in patients whose statement about having DN changed since 2012. Over 4years, 36 patients suffered amputations. Male sex (OR=3.11, 95% CI 1.46-6.62, P=.003), physical functioning/large-fibre neuropathy subscale score (OR=1.04, 95% CI 1.001-1.09, P=.047), autonomic neuropathy subscale score (OR=0.78, 95% CI 0.64-0.94, P=.011) and small-fibre neuropathy subscale score (OR=1.21, 95% CI 1.05-1.40, P=.007) were significant predictors of amputations. Delta total QOL-DN score was 10 times higher in patients who suffered amputation(s) compared with their amputation-free counterparts. QOL deteriorates with age and DD. Norfolk QOL-DN subscale scores can predict amputations.

A Comparison of Neuropathy Quality of Life Tools: Norfolk QOL-DN, PN-QOL-97, and NeuroQOL-28

Aims To explore the effectiveness of the Norfolk QOL-DN (QOL-DN), PN-QOL-97, and NeuroQOL-28 as tools for early detection of diabetic peripheral neuropathy in overweight, obese, and inactive (OOI), prediabetes (PD), and type 2 diabetes (T2D) individuals. Methods Thirty-four adults were divided by A1C [(10 OOI, 13 PD, and 11 T2D] and the sural nerves were tested bilaterally via NC-Stat DPN Check, conducting a sural nerve conduction study (NCS). Participants were individually timed, filling out questionnaires (QOL-DN, NeuroQOL-28, and PN-QOL-97) at a self-selected pace. Data were analyzed and compared to NCS findings to determine the best instrument for early neuropathy detection, usability in screening settings, and application for individuals with OOI, PD, and T2D. Results Abnormal NCS results were obtained from 27 individuals, of which 25 were bilateral and symmetrical. Confirmed DSPN criteria were met for 24, and 1 case met criteria for subclinical neuropathy. Normal NCS findings, reported symptoms, and reduced bilateral sensation were found in 7 cases. The QOL-DN and NeuroQOL-28 significantly predict neuropathy criteria in OOI, PD, and T2D subjects. Analyses revealed the QOL-DN as the quickest for completion (M=5.17; SD=1.83), followed by the NeuroQOL-28 (M=5.58; SD=3.56), and the PN-QOL-97 (M=13.23; SD=3.606). Conclusions The QOL-DN and NeuroQOL-28 are valid early screening measures for DPN detection. Time completion studies revealed that the QOL-DN and NeuroQOL-28 may be used as excellent short screening measures, completed in approximately 6 minutes or less, with reasonable scoring for both. The NeuroQOL-28 is a better fit for immediate feedback, time constraints, or limited staff. Future investigations should evaluate these tools for detection in DPN-prone individuals and in subclinical populations screenings.

Specified Influence of Painful Diabetic Neuropathy on Quality of Life in Egyptian Patients with Type 2 Diabetes Mellitus

Background: There is a lack of data in discrimination of different aspects of quality of life impairment in Egyptian patients with painful diabetic neuropathy (PDN). Objective: To assess the influence of PDN on different aspects of life quality in patients with type 2 diabetes mellitus (T2D). Patients and methods: A cross-sectional study that included 125 patients with T2D (100 with PDN and 25 without) during the period from December 2018 to May 2019. All patients were subjected to history, examination with modified Neuropathy Disability Score (NDS), neuropathy symptom score (NSS), visual analogue pain score (VAS), nerve conduction study for (peroneal, sural and ulnar nerves) bilaterally and Norfolk Quality of Life QuestionnaireDiabetic Neuropathy (Norfolk QOL-DN) and lab. Other neuropathy causes were excluded. Results: PDN patients have longer duration of T2D. Norfolk QOL-DN showed a significant deterioration of the activity of daily life (ADL) and general health status in PDN patients. We found a significant positive correlation between the NSS, VAS, NDS, superficial pain sensation, and the duration of T2D with the effects on ADL and health status in the case group. In addition, there was a significant positive correlation between insulin therapy, HbA1c, electrical sensation, NSS, VAS, NDS and the duration of T2D with axonal neuropathy. The NDS was the only independent predictor of ADL and health status impairment. Axonal neuropathy was independently determined by NDS, electrical sensation and insulin therapy. Conclusion: PDN impaired the activity of daily life and health status of patients with T2D. The NDS independently could predict axonal neuropathy, ADL and health status impairment.