Effect of Therapeutic Drug Monitoring vs Standard Therapy During Maintenance Infliximab Therapy on Disease Control in Patients With Immune-Mediated Inflammatory Diseases: A Randomized Clinical Trial.

Importance: Proactive therapeutic drug monitoring (TDM), consisting of individualized treatment based on scheduled assessments of serum drug levels, has been proposed as an alternative to standard therapy to optimize efficacy and safety of infliximab and other biologic drugs. However, it remains unclear whether proactive TDM improves clinical outcomes during maintenance therapy. Objective: To assess whether proactive TDM during maintenance therapy with infliximab improves treatment efficacy by preventing disease worsening compared with standard infliximab therapy without TDM. Design, Setting, and Participants: Randomized, parallel-group, open-label clinical trial including 458 adults with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis undergoing maintenance therapy with infliximab in 20 Norwegian hospitals. Patients were recruited from June 7, 2017, to December 12, 2019. Final follow-up took place on December 14, 2020. Interventions: Patients were randomized 1:1 to proactive TDM with dose and interval adjustments based on scheduled monitoring of serum drug levels and antidrug antibodies (TDM group; n = 228) or to standard infliximab therapy without drug and antibody level monitoring (standard therapy group; n = 230). Main Outcome and Measures: The primary outcome was sustained disease control without disease worsening, defined by disease-specific composite scores or consensus about disease worsening between patient and physician leading to a major change in treatment (switching to another biologic drug, adding an immunosuppressive drug including glucocorticoids, or increasing the infliximab dose), during the 52-week study period. Results: Among 458 randomized patients (mean age, 44.8 [SD, 14.3] years; 216 women [49.8%]), 454 received their randomly allocated intervention and were included in the full analysis set. The primary outcome of sustained disease control without disease worsening was observed in 167 patients (73.6%) in the TDM group and 127 patients (55.9%) in the standard therapy group. The estimated adjusted difference was 17.6% (95% CI, 9.0%-26.2%; P < .001) favoring TDM. Adverse events were reported in 137 patients (60%) and 142 patients (63%) in the TDM and standard therapy groups, respectively. Conclusions and Relevance: Among patients with immune-mediated inflammatory diseases undergoing maintenance therapy with infliximab, proactive TDM was more effective than treatment without TDM in sustaining disease control without disease worsening. Further research is needed to compare proactive TDM with reactive TDM, to assess the effects on long-term disease complications, and to evaluate the cost-effectiveness of this approach. Trial Registration: ClinicalTrials.gov Identifier: NCT03074656.

Evaluation of the Effects of Remdesivir and Hydroxychloroquine on Viral Clearance in COVID-19 : A Randomized Trial.

BACKGROUND: New treatment modalities are urgently needed for patients with COVID-19. The World Health Organization (WHO) Solidarity trial showed no effect of remdesivir or hydroxychloroquine (HCQ) on mortality, but the antiviral effects of these drugs are not known. OBJECTIVE: To evaluate the effects of remdesivir and HCQ on all-cause, in-hospital mortality; the degree of respiratory failure and inflammation; and viral clearance in the oropharynx. DESIGN: NOR-Solidarity is an independent, add-on, randomized controlled trial to the WHO Solidarity trial that included biobanking and 3 months of clinical follow-up (ClinicalTrials.gov: NCT04321616). SETTING: 23 hospitals in Norway. PATIENTS: Eligible patients were adults hospitalized with confirmed SARS-CoV-2 infection. INTERVENTION: Between 28 March and 4 October 2020, a total of 185 patients were randomly assigned and 181 were included in the full analysis set. Patients received remdesivir (n = 42), HCQ (n = 52), or standard of care (SoC) (n = 87). MEASUREMENTS: In addition to the primary end point of WHO Solidarity, study-specific outcomes were viral clearance in oropharyngeal specimens, the degree of respiratory failure, and inflammatory variables. RESULTS: No significant differences were seen between treatment groups in mortality during hospitalization. There was a marked decrease in SARS-CoV-2 load in the oropharynx during the first week overall, with similar decreases and 10-day viral loads among the remdesivir, HCQ, and SoC groups. Remdesivir and HCQ did not affect the degree of respiratory failure or inflammatory variables in plasma or serum. The lack of antiviral effect was not associated with symptom duration, level of viral load, degree of inflammation, or presence of antibodies against SARS-CoV-2 at hospital admittance. LIMITATION: The trial had no placebo group. CONCLUSION: Neither remdesivir nor HCQ affected viral clearance in hospitalized patients with COVID-19. PRIMARY FUNDING SOURCE: National Clinical Therapy Research in the Specialist Health Services, Norway.

Routine vs. on-demand analgesia in colonoscopy: a randomized clinical trial.

BACKGROUND AND STUDY AIMS: Colonoscopy is frequently performed with opioid analgesia, but the impact of drug delivery timing has not been studied in detail. Low-dose opioids administered before the procedure may provide better pain control than on-demand administration when the patient experiences pain. PATIENTS AND METHODS: A total of 119 outpatients were randomized to receive 50 µg of fentanyl either before colonoscopy (routine group) or on demand if needed during the colonoscopy (on-demand group). Additional fentanyl or midazolam was allowed in both groups if required. The primary outcome was pain measured on both a 100-mm visual analog scale (VAS; 0 = no pain, 100 = worst possible pain) and a four-point Likert scale (no, slight, moderate, or severe pain) immediately after the procedure. RESULTS: A total of 61 patients in the routine group and 58 patients in the on-demand group were included in the study. Mean VAS pain scores were 27.4 mm in the routine group and 30.5 mm in the on-demand group (mean difference - 3.2 mm; 95 % confidence interval - 11.9 to 5.5; P = 0.5). On the Likert scale, moderate or severe pain was experienced by 25.0 % and 31.5 % of patients in the routine and on-demand groups, respectively (p = 0.5). Cecal intubation rate and time to reach the cecum were similar between the groups. More patients in the on-demand group (81.0 %) than in the routine group (62.3 %) were able to leave the clinic without the need for recovery time (P = 0.03). CONCLUSION: Routine administration of fentanyl did not provide better analgesia during colonoscopy than on-demand fentanyl, and more patients needed time for recovery. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01786434).

Risk stratification to predict pain during unsedated colonoscopy: results of a multicenter cohort study.

BACKGROUND AND STUDY AIMS: Colonoscopy without sedation has several advantages over sedated colonoscopy, but a considerable proportion of patients experience pain. The aim of this study was to develop a risk stratification model of pre-examination risk factors to enable targeted sedation during colonoscopy. PATIENTS AND METHODS: Between October 2011 and January 2012, consecutive outpatients who were willing to start colonoscopy without sedation at 11 Norwegian centers were prospectively recruited. Patients recorded pain on a validated 4-point scale (none, slight, moderate, or severe pain). Potential risk factors for a painful procedure (defined as moderate or severe pain) were evaluated using multivariate logistic regression analyses, and the area under the receiver operating characteristics curve (AUROC) was calculated to assess the discriminatory ability of the derived model. RESULTS: A total of 1198 patients (635 men and 563 women) were included. Seven independent, pre-procedural risk factors for patient pain were identified: female sex, age < 40 years, previous abdominal surgery, abdominal pain as indication for colonoscopy, anticipation of pain, previous painful colonoscopy, and a history of diverticulitis. In patients with 0, 1, 2, or ≥ 3 risk factors, a painful colonoscopy was experienced by 35 %, 43 %, 52 %, and 63 % of women and 18 %, 24 %, 35 %, and 63 % of men, respectively. The model showed modest discrimination abilities (AUROC = 0.69). CONCLUSION: Female sex was a strong risk factor for pain during colonoscopy, and sedation or analgesia should be considered for all women prior to colonoscopy. For male patients, the presence of multiple risk factors should encourage the endoscopist to offer sedation.

[Pain in connection with colonoscopy in Norway]. / Smerter ved koloskopi.

BACKGROUND: Colonoscopies are common examinations at Norwegian hospitals. In contrast to many other countries, the majority of colonoscopies in Norway are conducted without routine sedation or analgesia. We wanted to investigate whether current Norwegian practice offers adequate pain relief. MATERIAL AND METHOD: The material consists of prospectively recorded outpatient colonoscopies in the period January 2003-December 2011 performed at Norwegian hospitals in the quality assurance network for gastrointestinal endoscopy (Gastronet). We analysed demographic patient data and data from colonoscopies. Patients' experience of pain (none, slight, moderate or severe pain) in connection with the examination was established with the aid of a validated questionnaire. RESULTS: Data from 61,749 colonoscopies (55% on women) performed at 29 different hospitals were analysed. Colonoscopies were perceived as moderately or very painful by 33% of the patients (41% of the women, 24% of the men, p < 0.001). There were substantial differences between hospitals as to the percentage of colonoscopies that were perceived as moderately or very painful (from 9% to 43%, p < 0.001) and the use of sedatives and analgesics for the colonoscopies (from 1% to 92% of the examinations, p < 0.001). Only 23% of those who found the colonoscopy painful received analgesics. Pethidine was used in 95% of the cases in which analgesics were used during the examination. INTERPRETATION: Many patients find colonoscopies painful. Pain relief practice varies substantially between hospitals. Pethidine is an analgesic with a slow onset of action, and should perhaps be replaced with more rapidly acting opiates.