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Inhaled colistimethate sodium in patients with bronchiectasis and Pseudomonas aeruginosa infection: results of PROMIS-I and PROMIS-II, two randomised, double-blind, placebo-controlled phase 3 trials assessing safety and efficacy over 12 months.
Haworth, CS, Shteinberg, M, Winthrop, K, Barker, A, Blasi, F, Dimakou, K, Morgan, LC, O'Donnell, AE, Ringshausen, FC, Sibila, O, et al
The Lancet. Respiratory medicine. 2024;(10):787-798
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BACKGROUND Chronic lung infection with Pseudomonas aeruginosa is associated with increased exacerbations and mortality in people with bronchiectasis. The PROMIS-I and PROMIS-II trials investigated the efficacy and safety of 12-months of inhaled colistimethate sodium delivered via the I-neb. METHODS Two randomised, double-blind, placebo-controlled trials of twice per day colistimethate sodium versus placebo were conducted in patients with bronchiectasis with P aeruginosa and a history of at least two exacerbations requiring oral antibiotics or one requiring intravenous antibiotics in the previous year in hospitals in Argentina, Australia, Belgium, Canada, France, Germany, Greece, Israel, Italy, Netherlands, New Zealand, Poland, Portugal, Spain, Switzerland, the UK, and the USA. Randomisation was conducted through an interactive web response system and stratified by site and long term use of macrolides. Masking was achieved by providing colistimethate sodium and placebo in identical vials. After random assignment, study visits were scheduled for 1, 3, 6, 9, and 12 months (the end of the treatment period); and telephone calls were scheduled for 7 days after random assignment and 2 weeks after the end of treatment. The primary endpoint was the mean annual exacerbation rate. These trials are registered with EudraCT: number 2015-002743-33 (for PROMIS-I) and 2016-004558-13 (for PROMIS-II), and are now completed. FINDINGS 377 patients were randomly assigned in PROMIS-I (177 to colistimethate sodium and 200 to placebo; in the modified intention-to-treat population, 176 were in the colistimethate sodium group and 197 were in the placebo group) between June 6, 2017, and April 8, 2020. The annual exacerbation rate was 0·58 in the colistimethate sodium group versus 0·95 in the placebo group (rate ratio 0·61; 95% CI 0·46-0·82; p=0·0010). 287 patients were randomly assigned in PROMIS-II (152 were assigned to colistimethate sodium and 135 were assigned to placebo, in the modified intention-to-treat population), between Feb 12, 2018, and Oct 22, 2021. PROMIS-II was then prematurely terminated due to the effect of the COVID-19 pandemic. No significant difference was observed in the annual exacerbation rate between the colistimethate sodium and placebo groups (0·89 vs 0·89; rate ratio 1·00; 95% CI 0·75-1·35; p=0·98). No major safety issues were identified. The overall frequency of adverse events was 142 (81%) patients in the colistimethate sodium group versus 159 (81%) patients in the placebo group in PROMIS-I, and 123 (81%) patients versus 104 (77%) patients in PROMIS-II. There were no deaths related to study treatment. INTERPRETATION The data from PROMIS-I suggest a clinically important benefit of colistimethate sodium delivered via the I-neb adaptive aerosol delivery system in patients with bronchiectasis and P aeruginosa infection. These results were not replicated in PROMIS-II, which was affected by the COVID-19 pandemic and prematurely terminated. FUNDING Zambon.
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The association of inflammatory markers with frailty and in-hospital mortality in older COVID-19 patients.
Tran Van Hoi, E, Appelman, B, Mooijaart, S, Dalm, VASH, Polinder Bos, HA, van Heemst, D, van Raaij, BFM, Noordam, R, Kuranova, A, Hoogerwerf, JJ, et al
Experimental gerontology. 2024;:112534
Abstract
INTRODUCTION During the COVID19 pandemic, older patients hospitalized for COVID-19 exhibited an increased mortality risk compared to younger patients. While ageing is associated with compromised immune responses and frailty, their contributions and interplay remain understudied. This study investigated the association between inflammatory markers and mortality and potential modification by frailty among older patients hospitalized for COVID-19. METHODS Data were from three multicenter Dutch cohorts (COVID-OLD, CliniCo, Covid-Predict). Patients were 70 years or older, hospitalized for COVID-19and categorized into three frailty groups: fit (Clinical frailty score (CFS) 1-3), pre-frail (CFS 4-5), and frail (CFS 6-9). Immunological markers (lymphocyte count, neutrophil count, C-reactive protein, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic inflammation index (SII)) were measured at baseline. Associations with in hospital mortality were examined using logistic regression. RESULTS A total of 1697 patients were included from COVID-OLD, 656 from Covid-Predict, and 574 from CliniCo. The median age was 79, 77, and 78 years for each cohort. Hospital mortality rates were 33 %, 27 % and 39 % in the three cohorts, respectively. A lower CRP was associated with a higher frailty score in all three cohorts (all p < 0.01). Lymphocyte count, neutrophil count, NLR, PLR, or SII, were similar across frailty groups. Higher CRP levels were associated with increased in-hospital mortality risk across all frailty groups, across all cohorts (OR (95 % CI), 2.88 (2.20-3.78), 3.15 (1.95-5.16), and 3.28 (1.87-5.92)), and frailty did not modify the association between inflammatory markers and in-hospital mortality (all p-interaction>0.05). CONCLUSION While frailty is a significant factor in determining overall outcomes in older patients, our study suggests that the elevated risk of mortality in older patients with frailty compared to fit patients is likely not explained by difference in inflammatory responses.
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Telephone lifestyle intervention to prevent diabetes in women with recent gestational diabetes mellitus attending the national health system: the LINDA-Brasil clinical trial.
Schmidt, MI, Bracco, PA, Nunes, MA, Cherubini, KA, Castilhos, CD, Spagiari, JZ, Galliano, LM, Ladwig, R, Del Vecchio, FB, Del Vecchio, AHM, et al
BMJ open. 2024;(10):e082572
Abstract
OBJECTIVES To evaluate a postpartum telephone-based lifestyle intervention to prevent diabetes in high-risk women with recent gestational diabetes mellitus (GDM). DESIGN Multicentre parallel randomised clinical trial. SETTING Specialised antenatal clinics in the Brazilian National System. METHODS Lifestyle Intervention for Diabetes Prevention After Pregnancy compared (1:1) postpartum telephone support for lifestyle changes with conventional care in women with recent GDM at substantial risk for diabetes. Randomisation started on 28 March 2015 and ended on 13 March 2020, with the onset of the COVID-19 pandemic. We used Cox regression to estimate HRs for diabetes and analysis of covariance adjusted for follow-up time to assess weight change. OUTCOMES The primary outcome was incident diabetes ascertained with blinded measurements of oral glucose tolerance tests. The secondary outcome was a change in measured weight. RESULTS We enrolled 5323 women with GDM, 2735 (51%) being at high risk. After invitations, baseline assessment and exclusions, we assigned 466 women to intervention (231) or control (235) groups. Attendance was satisfactory (≥7/20 phone sessions) in 75%. Over an average follow-up of 29.7 (15.6) months, 142 (30.5%) women progressed to diabetes, 75 (32%) in the control and 67 (29%) in the intervention group. There was no reduction in the incidence of diabetes (HR=0.84; 0.60-1.19) and only a non-significant 0.97 kg less weight gain (p=0.09). Among the 305 women randomised more than 1 year before the COVID-19 pandemic, the intervention did not reduce the incidence of diabetes (HR=0.71; 0.48-1.04) despite a 2.09 kg (p=0.002) lesser weight gain. CONCLUSION The strategy to identify women with GDM at high risk proved valid, as women often gained weight and frequently developed diabetes. Over a 30-month follow-up, telephone support for lifestyle changes at postpartum did not reduce weight gain or diabetes incidence, although only 75% attended the minimum number of telephone sessions. The COVID-19 pandemic negatively impacted trial conduction. TRIAL REGISTRATION NUMBER NCT02327286.
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Community-Based Cluster-Randomized Trial to Reduce Opioid Overdose Deaths.
, , Samet, JH, El-Bassel, N, Winhusen, TJ, Jackson, RD, Oga, EA, Chandler, RK, Villani, J, Freisthler, B, Adams, J, et al
The New England journal of medicine. 2024;(11):989-1001
Abstract
BACKGROUND Evidence-based practices for reducing opioid-related overdose deaths include overdose education and naloxone distribution, the use of medications for the treatment of opioid use disorder, and prescription opioid safety. Data are needed on the effectiveness of a community-engaged intervention to reduce opioid-related overdose deaths through enhanced uptake of these practices. METHODS In this community-level, cluster-randomized trial, we randomly assigned 67 communities in Kentucky, Massachusetts, New York, and Ohio to receive the intervention (34 communities) or a wait-list control (33 communities), stratified according to state. The trial was conducted within the context of both the coronavirus disease 2019 (Covid-19) pandemic and a national surge in the number of fentanyl-related overdose deaths. The trial groups were balanced within states according to urban or rural classification, previous overdose rate, and community population. The primary outcome was the number of opioid-related overdose deaths among community adults. RESULTS During the comparison period from July 2021 through June 2022, the population-averaged rates of opioid-related overdose deaths were similar in the intervention group and the control group (47.2 deaths per 100,000 population vs. 51.7 per 100,000 population), for an adjusted rate ratio of 0.91 (95% confidence interval, 0.76 to 1.09; P = 0.30). The effect of the intervention on the rate of opioid-related overdose deaths did not differ appreciably according to state, urban or rural category, age, sex, or race or ethnic group. Intervention communities implemented 615 evidence-based practice strategies from the 806 strategies selected by communities (254 involving overdose education and naloxone distribution, 256 involving the use of medications for opioid use disorder, and 105 involving prescription opioid safety). Of these evidence-based practice strategies, only 235 (38%) had been initiated by the start of the comparison year. CONCLUSIONS In this 12-month multimodal intervention trial involving community coalitions in the deployment of evidence-based practices to reduce opioid overdose deaths, death rates were similar in the intervention group and the control group in the context of the Covid-19 pandemic and the fentanyl-related overdose epidemic. (Funded by the National Institutes of Health; HCS ClinicalTrials.gov number, NCT04111939.).
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Bisoprolol in Patients With Chronic Obstructive Pulmonary Disease at High Risk of Exacerbation: The BICS Randomized Clinical Trial.
Devereux, G, Cotton, S, Nath, M, McMeekin, N, Campbell, K, Chaudhuri, R, Choudhury, G, De Soyza, A, Fielding, S, Gompertz, S, et al
JAMA. 2024;(6):462-470
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IMPORTANCE Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Observational studies report that β-blocker use may be associated with reduced risk of COPD exacerbations. However, a recent trial reported that metoprolol did not reduce COPD exacerbations and increased COPD exacerbations requiring hospital admission. OBJECTIVE To test whether bisoprolol decreased COPD exacerbations in people with COPD at high risk of exacerbations. DESIGN, SETTING, AND PARTICIPANTS The Bisoprolol in COPD Study (BICS) was a double-blind placebo-controlled randomized clinical trial conducted in 76 UK sites (45 primary care clinics and 31 secondary clinics). Patients with COPD who had at least moderate airflow obstruction on spirometry (ratio of forced expiratory volume in the first second of expiration [FEV1] to forced vital capacity <0.7; FEV1 <80% predicted) and at least 2 COPD exacerbations treated with oral corticosteroids, antibiotics, or both in the prior 12 months were enrolled from October 17, 2018, to May 31, 2022. Follow-up concluded on April 18, 2023. INTERVENTIONS Patients were randomly assigned to bisoprolol (n = 261) or placebo (n = 258). Bisoprolol was started at 1.25 mg orally daily and was titrated as tolerated during 4 sessions to a maximum dose of 5 mg/d, using a standardized protocol. MAIN OUTCOMES AND MEASURES The primary clinical outcome was the number of patient-reported COPD exacerbations treated with oral corticosteroids, antibiotics, or both during the 1-year treatment period. Safety outcomes included serious adverse events and adverse reactions. RESULTS Although the trial planned to enroll 1574 patients, recruitment was suspended from March 16, 2020, to July 31, 2021, due to the COVID-19 pandemic. Two patients in each group were excluded postrandomization. Among the 515 patients (mean [SD] age, 68 [7.9] years; 274 men [53%]; mean FEV1, 50.1%), primary outcome data were available for 514 patients (99.8%) and 371 (72.0%) continued taking the study drug. The primary outcome of patient-reported COPD exacerbations treated with oral corticosteroids, antibiotics, or both was 526 in the bisoprolol group, with a mean exacerbation rate of 2.03/y, vs 513 exacerbations in the placebo group, with a mean exacerbation rate of 2.01/y. The adjusted incidence rate ratio was 0.97 (95% CI, 0.84-1.13; P = .72). Serious adverse events occurred in 37 of 255 patients in the bisoprolol group (14.5%) vs 36 of 251 in the placebo group (14.3%; relative risk, 1.01; 95% CI, 0.62-1.66; P = .96). CONCLUSIONS AND RELEVANCE Among people with COPD at high risk of exacerbation, treatment with bisoprolol did not reduce the number of self-reported COPD exacerbations requiring treatment with oral corticosteroids, antibiotics, or both. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN10497306.
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Nutritional management in critically ill patients with COVID-19: a retrospective multicentre study.
Danel, JK, Taborek, M, Nowotarska, A, Winiarska, K, Dylczyk-Sommer, A, Szczeklik, W, Białka, S, Czarnik, T, Sołek-Pastuszka, JK, Krzych, ŁJ
Anaesthesiology intensive therapy. 2024;(1):70-76
Abstract
INTRODUCTION Although nutritional treatment is an established pillar of multidisciplinary care provided in critical illness, there are many concerns regarding this issue in severe COVID-19. This observational, retrospective, multicentre study aimed to analyse the approach to nutritional treatment among selected intensive care units (ICUs) in Poland. MATERIAL AND METHODS The medical records of 129 patients hospitalized in five units due to respiratory failure following COVID-19 were analysed in terms of nutritional management on the eighth day of the ICU stay. The Harris-Benedict equation (HB), Mifflin St. Jeor equation (MsJ) and ESPEN formula (20 kcal kg -1 body weight) were used to estimate the energy target for each patient, and two ESPEN formulas determined the protein target (1 g kg -1 body weight and 1.3 g kg -1 body weight). RESULTS Evaluation of nutritional therapy was performed in 129 subjects. The fulfilment of caloric requirement considering the HB, MsJ and ESPEN formula was 66%, 66.7% and 62.5%, respectively. Two clinical centres managed to provide 70% or more of daily caloric requirements. According to the ESPEN formula, the implementation of the protein target was 70%; however, one of the investigated units provided a median of 157% of the protein demand. The nutritional management varied in the preferred route of nutrition administration. Neither method nor grade of nutrition supply influenced biochemical parameters on the 8th day of ICU stay. CONCLUSIONS Significant differences in nutritional treatment of critically ill COVID-19 patients in Polish ICUs were noted, which underlines the importance of setting up clear guidelines regarding this issue.
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Asciminib monotherapy in patients with chronic-phase chronic myeloid leukemia with the T315I mutation after ≥1 prior tyrosine kinase inhibitor: 2-year follow-up results.
Cortes, JE, Sasaki, K, Kim, DW, Hughes, TP, Etienne, G, Mauro, MJ, Hochhaus, A, Lang, F, Heinrich, MC, Breccia, M, et al
Leukemia. 2024;(7):1522-1533
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Asciminib targets the BCR::ABL1 myristoyl pocket, maintaining activity against BCR::ABL1T315I, which is resistant to most approved adenosine triphosphate-competitive tyrosine kinase inhibitors. We report updated phase I results (NCT02081378) assessing safety/tolerability and antileukemic activity of asciminib monotherapy 200 mg twice daily in 48 heavily pretreated patients with T315I-mutated chronic-phase chronic myeloid leukemia (CML-CP; data cutoff: January 6, 2021). With 2 years' median exposure, 56.3% of patients continued receiving asciminib. Overall, 62.2% of evaluable patients achieved BCR::ABL1 ≤1% on the International Scale (IS); 47.6% and 81.3% of ponatinib-pretreated and -naive patients, respectively, achieved BCR::ABL1IS ≤1%. Of 45 evaluable patients, 48.9% achieved a major molecular response (MMR, BCR::ABL1IS ≤0.1%), including 34.6% and 68.4% of ponatinib-pretreated and -naive patients, respectively. MMR was maintained until data cutoff in 19 of 22 patients who achieved it. The most common grade ≥3 adverse events (AEs) included increased lipase level (18.8%) and thrombocytopenia (14.6%). Five (10.4%) patients experienced AEs leading to discontinuation, including 2 who discontinued asciminib and died due to COVID-19; these were the only deaths reported. These results show asciminib's effectiveness, including in almost 50% of ponatinib pretreated patients, and confirm its risk-benefit profile, supporting its use as a treatment option for T315I-mutated CML-CP.
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Long-term safety and impact of immune recovery in heavily treatment-experienced adults receiving fostemsavir for up to 5 years in the phase 3 BRIGHTE study.
Llibre, JM, Aberg, JA, Walmsley, S, Velez, J, Zala, C, Crabtree Ramírez, B, Shepherd, B, Shah, R, Clark, A, Tenorio, AR, et al
Frontiers in immunology. 2024;:1394644
Abstract
INTRODUCTION Fostemsavir is a gp120-directed attachment inhibitor approved for heavily treatment-experienced (HTE) adults with multidrug-resistant HIV-1. We provide detailed week 240 safety results from the BRIGHTE study and evaluate the impact of immune recovery on safety outcomes. METHODS The phase 3 BRIGHTE trial is ongoing; data for this analysis were collected from the first participant's first visit (February 23, 2015) through the last participant's last visit for week 240 (March 22, 2021). Safety endpoints were assessed in participants who received fostemsavir + optimized background therapy. In participants with baseline CD4+ T-cell count <200 cells/mm3, exposure-adjusted adverse event (AE) rates were assessed among subgroups with or without CD4+ T-cell count ≥200 cells/mm3 at any time during 48-week analysis periods through week 192. RESULTS Through a median of 258 weeks (range, 0.14-319) of treatment, discontinuations due to AEs occurred in 30/371 (8%) participants. Serious AEs were reported in 177/371 (48%) participants, including 16 drug-related events in 13 (4%) participants. Thirty-five (9%) deaths occurred, primarily related to AIDS or acute infections. COVID-19-related events occurred in 25 (7%) participants; all resolved without sequelae. Among participants with baseline CD4+ T-cell count <200 cells/mm3, 122/162 (75%) achieved CD4+ T-cell count ≥200 cells/mm3 at week 192. Exposure-adjusted AE rates were markedly lower among participants achieving CD4+ T-cell count ≥200 cells/mm3 at any time vs those sustaining <200 cells/mm3. No new AIDS-defining events were reported after week 48 in participants with CD4+ T-cell count ≥200 cells/mm3. CONCLUSIONS Cumulative safety findings through the BRIGHTE 240-week interim analysis are consistent with other trials in HTE participants with advanced HIV-1 and comorbid disease. Reduced rates of AIDS-defining events and AEs were observed in participants with immunologic recovery on fostemsavir-based treatment. CLINICAL TRIAL NUMBER NCT02362503, https://clinicaltrials.gov/study/NCT02362503.
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Effect of sodium-glucose co-transporter-2 inhibitors on survival free of organ support in patients hospitalised for COVID-19 (ACTIV-4a): a pragmatic, multicentre, open-label, randomised, controlled, platform trial.
Kosiborod, MN, Windsor, SL, Vardeny, O, Berger, JS, Reynolds, HR, Boumakis, S, Althouse, AD, Solomon, SD, Bhatt, AS, Peikert, A, et al
The lancet. Diabetes & endocrinology. 2024;(10):725-734
Abstract
BACKGROUND Patients hospitalised for COVID-19 are at risk for multiorgan failure and death. Sodium-glucose co-transporter-2 (SGLT2) inhibitors provide cardiovascular and kidney protection in patients with cardiometabolic conditions and could provide organ protection during COVID-19. We aimed to investigate whether SGLT2 inhibitors can reduce the need for organ support in patients hospitalised for COVID-19. METHODS This pragmatic, multicentre, open-label, randomised, controlled, platform trial was conducted across 63 sites in the USA, Spain, Brazil, Italy, and Mexico. Patients aged at least 18 years hospitalised for COVID-19 (moderate or severe illness) were randomly assigned (1:1), via an interactive voice system or web-response system, to receive locally available SGLT2 inhibitor (administered orally, once daily) plus standard-of-care or standard-of-care for 30 days. The primary outcome was organ support-free days evaluated through 21 days, assessed using intention-to-treat approach. This trial is registered on ClinicalTrials.gov, NCT04505774. FINDINGS The first patient was randomly assigned to the SGLT2 inhibitor domain on Dec 3, 2021. On March 31, 2023, at the recommendation of the data and safety monitoring board, enrolment in the SGLT2 inhibitor domain for both moderately and severely ill hospitalised patients was stopped prematurely for futility due to a low likelihood of finding a treatment benefit. The final randomised population consisted of 575 patients (mean age 72 years [SD 13], 242 (42%) female and 154 (27%) Hispanic; 504 in the moderate illness group and 71 in the severe illness group). 573 patients had a known 21-day outcome; 215 (75%) of 285 patients in the SGLT2 inhibitor plus standard-of-care group did not require respiratory or cardiovascular organ support versus 231 (80%) of 288 patients in the standard-of-care group. The adjusted odds ratio (OR) for an SGLT2 inhibitor effect on organ support-free days was 0·74 (95% Credible Interval [CrI] 0·48-1·13; where OR higher than 1 indicated treatment benefit, yielding a posterior probability of futility P(OR <1·2) of 99% and a posterior probability of inferiority P(OR<1·0) of 91%). There were 37 deaths (13%) in the SGLT2 inhibitor plus standard-of-care group and 42 deaths (15%) in the standard-of-care group at 90 days (hazard ratio 0·91 [95% CrI 0·58-1·43], probability of hazard ratio <1 of 66%). No safety concerns were observed with SGLT2 inhibitors, including no cases of ketoacidosis. INTERPRETATION SGLT2 inhibitors did not significantly increase days free of organ support or reduce mortality in patients hospitalised with COVID-19. SGLT2 inhibitors were well tolerated with no observed safety concerns. Overall, these findings do not support the use of SGLT2 inhibitors as standard care in patients hospitalised with COVID-19. FUNDING National Institutes of Health.
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PCSK9 inhibition with orally administered NNC0385-0434 in hypercholesterolaemia: a randomised, double-blind, placebo-controlled and active-controlled phase 2 trial.
Koren, MJ, Descamps, O, Hata, Y, Hengeveld, EM, Hovingh, GK, Ikonomidis, I, Radu Juul Jensen, MD, Langbakke, IH, Martens, FMAC, Søndergaard, AL, et al
The lancet. Diabetes & endocrinology. 2024;(3):174-183
Abstract
BACKGROUND Currently available injectable drugs that target proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce serum LDL cholesterol and improve cardiovascular outcomes. This phase 2 study assessed NNC0385-0434, an oral PCSK9 inhibitor, in individuals receiving oral lipid-lowering therapy. METHODS In this randomised, double-blind, placebo-controlled and active-controlled trial, 42 research sites across seven countries (Belgium, Germany, Greece, Japan, the Netherlands, Poland, and the USA) recruited individuals with established atherosclerotic cardiovascular disease (aged ≥40 years) or at high risk of atherosclerotic cardiovascular disease (aged >50 years), who had LDL cholesterol concentration of at least 1·8 mmol/L and were receiving maximum tolerated statins and stable lipid-lowering therapy. The study randomly allocated participants (3:1) with an interactive web response system to receive either NNC0385-0434 (15 mg, 40 mg, or 100 mg) once a day co-formulated with the oral absorption enhancer sodium N-[8-(2-hydroxybenzoyl)amino] caprylate (500 mg); placebo; or open-label evolocumab (140 mg) every 2 weeks administered subcutaneously. Blinding was performed within each dose level. The primary endpoint was percentage change from baseline in LDL cholesterol measured by β quantification at week 12. All randomly assigned participants received at least one dose of treatment and were included in both safety and efficacy analyses. The trial was registered on ClinicalTrials.gov, NCT04992065, and is completed. FINDINGS Between Aug 16, 2021, and Jan 28, 2022, we randomly assigned 267 patients to one of the three NNC0385-0434 dose cohorts (n=53 per cohort), matching placebo (n=54), or open-label evolocumab (n=54). The study population comprised 82 (31%) women and 185 (69%) men; mean age was 64·3 years (SD 9·0). Baseline mean LDL cholesterol concentration was 2·7 mmol/L (SD 0·8). Treatment with NNC0385-0434 resulted in reductions in LDL cholesterol from baseline to week 12, of 32·0 percentage points (95% CI 20·9 to 43·0) in the 15 mg cohort, 44·9 percentage points (33·8 to 56·0) in the 40 mg cohort, and 61·8 percentage points (50·7 to 72·9) in the 100 mg cohort, compared with the placebo group (p<0·0001 for each). Patients treated with evolocumab had similar LDL cholesterol reductions (59·6% [SE 4·1] decrease from baseline) to patients receiving NNC0385-0434 100 mg (56·2% [4·0]). The estimated treatment difference between NNC0385-0434 100 mg and evolocumab 140 mg was 3·4 percentage points [95% CI -7·8 to 14·7]. The most frequently reported adverse event was COVID-19, which affected 31 (12%) of 267 patients, with similar numbers across treatment groups. Investigative sites reported gastrointestinal disorders as the most frequent treatment-related adverse event (26 patients and 35 events total in the three NNC0385 cohorts and one patient and one event each in the placebo and evolocumab cohorts). No deaths or treatment-related serious adverse events occurred. INTERPRETATION This study showed excellent 12-week LDL cholesterol lowering efficacy and good patient tolerance of an oral PCSK9 inhibitor, NNC0835-0434, similar to an injectable drug. However, the sponsor chose to discontinue further development of NNC0835-0434 due to portfolio considerations. FUNDING Novo Nordisk.
