A Randomized Clinical Trial to Evaluate Two Doses of an Intra-Articular Injection of LMWF-5A in Adults with Pain Due to Osteoarthritis of the Knee

<div><p>Objective</p><p>The Low Molecular Weight Fraction of 5% human serum Albumin (LMWF-5A) is being investigated as a treatment for knee pain from osteoarthritis.</p><p>Methods</p><p>This was a multicenter randomized, vehicle-controlled, double-blind, parallel study designed to evaluate the safety and efficacy of two doses of an intra-articular injection of LMWF-5A. Patients with symptomatic knee osteoarthritis were randomized 1∶1∶1∶1 to receive a single 4 mL or 10 mL intra-articular knee injection of either LMWF-5A or vehicle control (saline). The primary efficacy endpoint was the difference between treatment groups in the Western Ontario and McMaster Universities (WOMAC) pain change from baseline over 12 weeks. Safety was examined as the incidence and severity of adverse events (AEs).</p><p>Results</p><p>A total of 329 patients were randomized and received treatment. LMWF-5A resulted in a significant decrease in pain at 12 weeks compared to vehicle control (−0.93 vs −0.72; estimated difference from control: −0.25, p = 0.004); an injection volume effect was not observed (p = 0.64). The effect of LMWF-5A on pain was even more pronounced in patients with severe knee OA (Kellgren Lawrence Grade IV): the estimated difference from control was −0.42 (p = 0.02). Adverse events were generally mild and were similar in patients who received vehicle control (47%) and LMWF-5A (41%).</p><p>Conclusions</p><p>This clinical trial demonstrated that LMWF-5A is safe and effective at providing relief for the pain of moderate to severe OA of the knee over 12 weeks when administered by intra-articular injection into the knee.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="http://clinicaltrials.gov/show/NCT01839331" target="_blank">NCT01839331</a></p></div

Summary of Adverse Events (AEs).

<p>Summary of Adverse Events (AEs).</p

CONSORT Flow diagram.

<p>CONSORT Flow diagram.</p

Summary of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Mean Change in Pain (SE) over Time.

<p>Control: Saline vehicle control.</p>*<p>Data were collected at in-person clinic visits; data at all other Weeks were collected via telephone.</p>†<p>P values were calculated using ANCOVA, with adjustment for baseline WOMAC A pain score.</p

Summary of Additional Efficacy endpoints, reported as Mean Change (SE) at Week 12, ITT.

*<p>WOMAC, Western Ontario and McMaster Universities Osteoarthritis.</p><p>Control: Saline vehicle control; Index. PGA, Patient Global Assessment of disease severity; K-L, Kellgren-Lawrence.</p>†<p>P values were calculated using mixed-effects repeated measures ANCOVA, with adjustment for baseline score.</p

Summary of the percent improvement in the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) pain subscore.

<p>Summary of the percent improvement in the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) pain subscore.</p

Demographics and baseline characteristics: ITT population.

<p>Control, saline vehicle control; BMI, Body Mass Index; K-L Grade, Kellgren Lawrence Grade; PGA, Patient Global Assessment; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.</p><p>The BMI is the weight in kilograms divided by the square of the height in meters. The PGA scores can range from 0 to 5. Scores for the WOMAC can range from 0 to 5.</p

Risk of COVID-19 after natural infection or vaccinationResearch in context

Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health

Risk of COVID-19 after natural infection or vaccinationResearch in context

Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health