scholarly journals COVIDOSE: Low-dose tocilizumab in the treatment of Covid-19

2020 ◽  
Author(s):  
Garth W Strohbehn ◽  
Brian L Heiss ◽  
Sherin J Rouhani ◽  
Jonathan A Trujillo ◽  
Jovian Yu ◽  
...  
Keyword(s):  
Low Dose ◽  
Controlled Trial ◽  
Pulmonary Infiltrate ◽  
Primary Objective ◽  
Dose Finding ◽  
Repeat Dose ◽  
Rapid Improvement ◽  
Phase 2 Trial ◽  
Biological Studies ◽  
Epidemiologic Risk

Background Interleukin-6 (IL-6)-mediated hyperinflammation may contribute to the high mortality of coronavirus disease 2019 (Covid-19). Tocilizumab, an IL-6 receptor blocking monoclonal antibody, has been repurposed for Covid-19, but prospective trials and dose-finding studies in Covid-19 are lacking. Methods We conducted a phase 2 trial of low-dose tocilizumab in hospitalized adult patients with Covid-19, radiographic pulmonary infiltrate, fever, and C-reactive protein (CRP) >= 40 mg/L who did not require mechanical ventilation. Dose cohorts were determined by a trial Operations Committee, stratified by CRP and epidemiologic risk factors. A range of doses from 40 to 200 mg (low-dose tocilizumab) was evaluated, with allowance for one repeat dose at 24-48 hours. The primary objective was to assess the relationship of dose to fever resolution and CRP response. Outcomes were compared with retrospective controls with Covid-19. Correlative studies evaluating host antibody response were performed in parallel. Findings A total of 32 patients received low-dose tocilizumab. This cohort had improved fever resolution (75.0% vs. 34.2%, p = 0.001) and CRP decline (86.2% vs. 14.3%, p < 0.001) in the 24-48 hours following drug administration, as compared to the retrospective controls (N=41). The probabilities of fever resolution or CRP decline did not appear to be dose-related in this small study (p=0.80 and p=0.10, respectively). Within the 28-day follow-up, 5 (15.6%) patients died. For patients who recovered, median time to clinical recovery was 3 days (IQR, 2-5). Clinically presumed and/or cultured bacterial superinfections were reported in 5 (15.6%) patients. Correlative biological studies demonstrated that tocilizumab-treated patients produced anti-SARS-CoV-2 antibodies comparable to controls. Interpretation Low-dose tocilizumab was associated with rapid improvement in clinical and laboratory measures of hyperinflammation in hospitalized patients with Covid-19. Results of this trial and its correlative biological studies provide rationale for a randomized, controlled trial of low-dose tocilizumab in Covid-19.

scholarly journals P125: Low dose intravenous ketorolac in renal colic, a pilot randomized controlled trial

CJEM ◽  
2020 ◽  
Vol 22 (S1) ◽  
pp. S109-S110
Author(s):  
J. Chao ◽  
P. Brasher ◽  
K. Cheung ◽  
R. Sharma ◽  
K. Badke ◽  
...  
Keyword(s):  
Dose Group ◽  
Low Dose ◽  
Renal Colic ◽  
Standard Dose ◽  
Controlled Trial ◽  
Pain Reduction ◽  
Primary Objective ◽  
Recruitment Rate ◽  
Convenience Sample ◽  
Increased Risk

Introduction: Non-steroidal anti-inflammatory drugs (NSAIDs) are first-line analgesics for emergency department (ED) patients with renal colic. Lower doses of intravenous (IV) ketorolac may provide similar pain relief to standard dosing in patients with acute pain. Patients with renal colic may be at increased risk of acute kidney injury; exposing them to lower doses of NSAIDs may put them at lower risk while providing equally effective analgesia. We conducted a pilot study to determine the feasibility of a randomized trial comparing the effectiveness and safety of low with standard ketorolac dosing in ED patients with suspected renal colic. The primary objective was to demonstrate the ability to achieve an enrolment target of 2 patients per week. Methods: We enrolled a convenience sample of adults presenting to an academic urban ED with unilateral flank pain suspected to be renal colic. We randomized patients to 10 mg (low dose, intervention) or 30 mg (standard dose, control). Participants, treating physicians and nurses, and researchers were blinded to treatment allocation. Our main feasibility outcome was the recruitment rate. Secondary outcomes were changes in pain scores (0-10) at 30 and 120 minutes post-ketorolac administration, vital signs, adverse events and ED length of stay. Results: We approached 82 patients, of whom 47 (57.3%) were eligible. Of these, 36 consented to participating and 30 were randomized. The proportion of screened patients who were enrolled was 36.6% (30/82). We completed enrolment over a 21-week period, with an average recruitment rate of 1.5 patients/week (range 0-4). The average baseline pain score for all participants was 6.9 (SD = 2.1). At 30 minutes post-ketorolac administration, the low dose group had a mean pain reduction of 2.0 points compared to a pain reduction of 1.7 in standard dose group (difference = 0.3, 90% CI: -0.7 to 1.4). Conclusion: These preliminary results support the possibility that low dose ketorolac may be efficacious in this patient population. We did not meet our target recruitment of 2 patients per week as this was primarily due to restricted recruitment hours. To successfully conduct a larger trial, we would need to expand both recruitment hours and the number of sites.

scholarly journals Prolonged Low-Dose Methylprednisolone in Patients With Severe COVID-19 Pneumonia

2020 ◽  
Vol 7 (10) ◽  
Author(s):  
Francesco Salton ◽  
Paola Confalonieri ◽  
G Umberto Meduri ◽  
Pierachille Santus ◽  
Sergio Harari ◽  
...  
Keyword(s):  
Low Dose ◽  
Controlled Trial ◽  
Invasive Mechanical Ventilation ◽  
Rapid Improvement ◽  
Clinical Trial Registration ◽  
Multicenter Observational Study ◽  
Reactive Protein ◽  
End Point ◽  
High Dependency ◽  
Ventilator Dependence

Abstract Background In hospitalized patients with coronavirus disease 2019 (COVID-19) pneumonia, progression to acute respiratory failure requiring invasive mechanical ventilation (MV) is associated with significant morbidity and mortality. Severe dysregulated systemic inflammation is the putative mechanism. We hypothesize that early prolonged methylprednisolone (MP) treatment could accelerate disease resolution, decreasing the need for intensive care unit (ICU) admission and mortality. Methods We conducted a multicenter observational study to explore the association between exposure to prolonged, low-dose MP treatment and need for ICU referral, intubation, or death within 28 days (composite primary end point) in patients with severe COVID-19 pneumonia admitted to Italian respiratory high-dependency units. Secondary outcomes were invasive MV-free days and changes in C-reactive protein (CRP) levels. Results Findings are reported as MP (n = 83) vs control (n = 90). The composite primary end point was met by 19 vs 40 (adjusted hazard ratio [aHR], 0.41; 95% CI, 0.24–0.72). Transfer to ICU and invasive MV were necessary in 15 vs 27 (P = .07) and 14 vs 26 (P = .10), respectively. By day 28, the MP group had fewer deaths (6 vs 21; aHR, 0.29; 95% CI, 0.12–0.73) and more days off invasive MV (24.0 ± 9.0 vs 17.5 ± 12.8; P = .001). Study treatment was associated with rapid improvement in PaO2:FiO2 and CRP levels. The complication rate was similar for the 2 groups (P = .84). Conclusion In patients with severe COVID-19 pneumonia, early administration of prolonged, low dose MP treatment was associated with a significantly lower hazard of death (71%) and decreased ventilator dependence. Treatment was safe and did not impact viral clearance. A large randomized controlled trial (RECOVERY trial) has been performed that validates these findings. Clinical trial registration. ClinicalTrials.gov NCT04323592.

A Double-blind, Placebo-controlled Trial of Low Dose Infliximab in Ankylosing Spondylitis

2010 ◽  
Vol 37 (6) ◽  
pp. 1203-1210 ◽  
Author(s):  
ROBERT D. INMAN ◽  
WALTER P. MAKSYMOWYCH
Keyword(s):  
Ankylosing Spondylitis ◽  
Low Dose ◽  
Controlled Trial ◽  
Primary Objective ◽  
Spinal Mobility ◽  
Extension Phase ◽  
Controlled Study ◽  
Open Label ◽  
Double Blind ◽  
Double Blind Placebo

Objective.The tumor necrosis factor-α (TNF-α) inhibitor infliximab (IFX) has been proven effective for the treatment of ankylosing spondylitis (AS). The primary objective of this double-blind, placebo-controlled study was to assess the safety and efficacy of low-dose (3 mg/kg q8w) IFX therapy in AS.Methods.In the 12-week double-blind phase of the study, patients (N = 76) were randomized to infusions of placebo or IFX (3 mg/kg) at Weeks 0, 2, and 6. The primary endpoint was 20% improvement in ASsessments in Ankylosing Spondylitis criteria (ASAS20) at 12 weeks. In the open-label extension phase, all patients received scheduled IFX infusions (q 8 weeks) up to 46 weeks. Patients who did not meet target response criteria (i.e., BASDAI score did not improve by at least 50% and was > 3) at Weeks 22 or 38 had a dose increase to IFX 5 mg/kg.Results.At 12 weeks, 53.8% of IFX-treated patients achieved ASAS20, compared with 30.6% of placebo-treated patients (p = 0.042). IFX-treated patients showed significant improvement in measures of disease activity, spinal mobility, and quality of life over the course of the study. During the extension phase, 68% of patients in the IFX group did not meet the clinical target and had an increase in the dose of IFX to 5 mg/kg by 38 weeks. In general, IFX was safe and well tolerated. Ten patients withdrew from the study for various reasons, with only 2 (2.6%) attributed to adverse events.Conclusion.IFX 3 mg/kg was effective in reducing the signs and symptoms of active AS, and was generally safe and well tolerated. Dose escalation to 5 mg/kg every 8 weeks was warranted in most patients to achieve the target clinical response of the study.

CONTROLLED TRIAL OF IL2R ANTIBODY BASILIXIMAB (SIMULECT) VS LOW DOSE OKT3 IN CADAVER KIDNEY TRANSPLANT RECIPIENTS.

2000 ◽  
Vol 69 (Supplement) ◽  
pp. S156 ◽  
Author(s):  
Hamid Shidban ◽  
M. Sabawi ◽  
S. Aswad ◽  
G. Chambers ◽  
I. Castillon ◽  
...  
Keyword(s):  
Kidney Transplant ◽  
Low Dose ◽  
Controlled Trial ◽  
Transplant Recipients ◽  
Kidney Transplant Recipients ◽  
Cadaver Kidney

scholarly journals Early combination therapy with etanercept and methotrexate in JIA patients shortens the time to reach an inactive disease state and remission: results of a double-blind placebo-controlled trial

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Ekaterina Alexeeva ◽  
Gerd Horneff ◽  
Tatyana Dvoryakovskaya ◽  
Rina Denisova ◽  
Irina Nikishina ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Controlled Trial ◽  
Randomized Study ◽  
Primary Objective ◽  
Disease State ◽  
Inactive Disease ◽  
Open Label ◽  
Standard Regimen ◽  
Double Blind ◽  
Early Combination Therapy

Abstract Background Remission is the primary objective of treating juvenile idiopathic arthritis (JIA). It is still debatable whether early intensive treatment is superior in terms of earlier achievement of remission. The aim of this study was to evaluate the effectiveness of early etanercept+methotrexate (ETA+MTX) combination therapy versus step-up MTX monotherapy with ETA added in refractory disease. Methods A multi-centre, double-blind, randomized study in active polyarticular JIA patients treated with either ETA+MTX (n = 35) or placebo+MTX (n = 33) for up to 24 weeks, followed by a 24-week open-label phase. The efficacy endpoints included pedACR30 criteria improvement at week 12, inactive disease at week 24, and remission at week 48. Patients who failed to achieve the endpoints at week 12 or at week 24 escaped to open-label ETA+MTX. Safety was assessed at each visit. Results By intention-to-treat analysis, more patients in the ETA+MTX group reached the pedACR30 response at week 12 (33 (94.3%)) than in the placebo+MTX group (20 (60.6%); p = 0.001). At week 24, comparable percentages of patients reached inactive disease (11 (31.4%) vs 11 (33.3%)). At week 48, 11 (31.4%) and eight (24.2%) patients achieved remission. The median (+/−IQR) times to achieve an inactive disease state in the ETA+MTX and placebo+MTX groups were 24 (14–32) and 32 (24–40) weeks, respectively. Forty-four (74/100 patient-years) adverse events (AEs) were reported, leading to treatment discontinuation in 6 patients. Conclusions Early combination therapy with ETA+MTX proved to be highly effective compared to the standard step-up regimen. Compared to those treated with the standard regimen, more patients treated with a combination of ETA+MTX reached the pedACR30 response and achieved inactive disease and remission more rapidly.

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