Can procalcitonin levels determine which patients will benefit from azithromycin in lower RI? 

17th January 2023

Low procalcitonin levels in patients with a lower respiratory infection (RI) do not indicate those who might benefit from azithromycin

Low procalcitonin levels in patients with a non-pneumonia lower respiratory tract infection, fails to identify those who might benefit from azithromycin therapy according to the findings of a randomised trial by US researchers.

Antibiotics are commonly prescribed for acute respiratory infections, although most of these infections are viral in nature and for which antibiotics are ineffective. It is therefore necessary to implement strategies that are able to identify those patients unlikely to benefit from antibiotics, thus mitigating the development and spread of resistant pathogens. Procalcitonin is a peptide for which serum levels are believed to increase during bacterial, but not during viral, infections. In fact, procalcitonin levels have been shown to improve the accuracy of currently recommended approaches for the diagnosis of community-acquired pneumonia, thereby complementing clinical signs and symptoms. Normal human procalcitonin serum levels are less than 0.1 ng/ml, whereas if levels increase above 0.25 ng/ml, this may indicate the presence of a bacterial infection.

In the present study, US researchers hypothesised that in patients with a procalcitonin concentration of 0·25 ng/mL or less, a placebo would be just as good, i.e., non-inferior (in terms of clinical efficacy) to antibiotics such as azithromycin, in adults with suspected lower respiratory tract infection. The team recruited adults aged 18 years or older, with clinically suspected non-pneumonia lower respiratory tract infection and a low procalcitonin level (i.e., 0·25 ng/mL or less). These individuals were randomised 1:1 to either oral azithromycin 250 mg or matching placebo (two capsules on day 1 followed by one capsule daily for 4 days). The primary outcome was the efficacy of azithromycin versus placebo in terms of clinical improvement at day 5 (assessed with several different measures) and the non-inferiority margin (to placebo) was set as a lower confidence interval of -12·5%.

Low procalcitonin and azithromycin outcomes
A total of 499 participants with a mean age of 52.3 years (35% female), all of whom had procalcitonin levels below 250 ng/ml, were included and randomised to azithromycin (249) or placebo.

A clinical improvement at day 5 was observed in 63% in the placebo group and 69%, in the azithromycin group (between-group difference -6%, 95% CI -15 to 2). As the lower confidence interval for this difference was numerically greater than –12·5%, it was not possible to conclude that there was non-inferiority for the placebo compared with azithromycin. This was despite there being no significant difference in the rates of any of the individual parameters comprising the primary outcome for clinical improvement. However, at day 11, clinical improvement was observed in 76% of the placebo group and 81% in the azithromycin group (between-group difference –4%, 95% CI –12 to 3). This time, since the lower confidence interval value was less than -12.5, non-inferiority for the placebo and azithromycin was demonstrated.

The authors concluded that it was not possible to confirm non-inferiority for a placebo and azithromycin in terms of clinical improvement at day 5 in adults with a lower respiratory tract infection and a low procalcitonin concentration. Consequently, it remained unclear whether antibiotics would be of benefit to such patients.

Citation
Tsalik EL et al. Efficacy and safety of azithromycin versus placebo to treat lower respiratory tract infections associated with low procalcitonin: a randomised, placebo-controlled, double-blind, non-inferiority trial. Lancet Infect Dis 2022

Significant placebo response to pain in cannabinoid clinical trials

5th January 2023

The placebo response appears to play a significant role in pain reduction in clinical trials assessing a patient’s response to cannabinoids

A placebo response makes a significant contribution to the reduction in pain scores seen in cannabinoid clinical trials according to the findings of a systematic review and meta-analysis by Swedish researchers.

Pain is one of the most common symptoms experienced by patients in different health care settings, often leading to loss of function for the affected individual as well as a decline in their quality of life. Although there are wide range of medicines which act as pain-killers, in recent years, there has been increasing interest in the medical properties of cannabinoids. However, the evidence supporting the value of cannabinoids in pain management is limited.

In fact, a 2021 systematic review concluded on how the available evidence neither supports nor refutes claims of efficacy and safety for cannabinoids, cannabis, or cannabis-based medicines in the management of pain. These findings suggest that there may be an important placebo response in such trials and which arise from patients’ positive expectancies.

Furthermore, it is believed that different systems and mechanisms trigger placebo effects that highly impact pain processing, clinical outcomes and create a sense of well-being.

But how large is the placebo response in clinical trials examining the role of cannabinoids in the management of pain? This was the key question addressed in the current study where researchers set out to evaluate the size of placebo responses in double-blind randomised clinical trials in which cannabinoids, cannabis, and cannabis-based medicine were compared with placebo in the treatment of clinical pain. 

The researchers measured the change in pain intensity from before to after treatment, measured as bias-corrected standardised mean difference (Hedges g), which provides an assessment of the effect size. A small effect is represented by a value of 0.2, whereas a medium effect is 0.5 and a large effect 0.8.

Placebo response in cannabinoid trials

The researchers identified a total of 20 eligible trials with 1459 individuals (mean age = 51 years, 56% female). Studies included patients with neuropathic pain and multiple sclerosis.

The effect size of the active drug (cannabinoids) on pain intensity was large (mean Hedges g = 0.95, p  <0 .001). However, pain intensity was associated with a significant reduction in response to placebo, with a moderate to large effect size (mean Hedges g = 0.64, p < 0.001).

In a further analysis, the researchers looked at the media attention paid to these findings and found that this attention was independent of how biased the study was, the extent of the placebo response or how low the treatment effect was.

The authors concluded that placebos contribute significantly to the pain reduction seen in cannabinoid clinical trials. In addition, the positive media attention and wide dissemination possibly leads to high expectations and hence may shape the placebo response in future trials.

Citation
Gedin F et al. Placebo Response and Media Attention in Randomized Clinical Trials Assessing Cannabis-Based Therapies for Pain: A Systematic Review and Meta-analysis. JAMA Netw Open. 2022.

Treatment-resistant depression trials show large placebo response

6th October 2021

In trials of treatment-resistant depression, researchers have identified a large and consistent placebo response to all modalities.

Treatment-resistant depression (TRD) can be defined as a major depressive disorder (MDD) in adults who failed to respond to at least two different antidepressant treatments in their current moderate-to-severe depressive episode. It is a common problem with a prevalence estimated from one analysis to affect 30.9% of patients.

Although the efficacy of an antidepressant in clinical trials is assessed by comparison against placebo, a common problem is the large and positive placebo response often observed. The magnitude of average placebo response in studies of major depression has been found to be 29.7%, but ranged between 12.5 and 51.8%.

Moreover, in an analysis of 252 antidepressant controlled trials with 26,324 patients assigned to placebo, a placebo response was seen in 35 to 40% of patients, although the analysis did not specifically examine treatment-resistant depression.

However, what remains uncertain, is the magnitude of the placebo response in patients with TRD who are exposed to a range of different modalities. This prompted a team from the Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada, to not only assess the size of the placebo response in patients with TRD, but to also identify relevant factors associated with the placebo response.

The team undertook a comprehensive literature search and included studies that were parallel-arm, double-blind and placebo-controlled, specifically recruiting patients with treatment-resistant depression. They set the primary outcome as the Hedges g value, which is a measure of the effect size, for the placebo response.

The value of Hedges g indicates the extent to which two groups differ, based on the size of the standard deviation, e.g., a value of 1 indicates that groups differ by one standard deviations, 2 denotes two standard deviations and so on. As a secondary outcome, the team used meta-regression to explore potential moderators of the placebo effect.

Findings

A total of 50 clinical trials with 3228 patients, with a mean age of 45.8 years (20.7% women), where included in the final analysis. The placebos included pills, liquids, parenteral injections and several sham procedures such as sham transcranial magnetic stimulation, transcranial direct current stimulation or invasive brain stimulation.

The pooled placebo effect size for all treatment modalities was large (Hedges g = 1.05, 95% CI 0.91 – 1.1) although this did vary with the type of placebo intervention. For example, with pill placebos, g = 1.14, parenteral placebo, g = 1.33. The pooled placebo response rate in all trials was 21.2% with a pooled remission rate of 13%.

In the TRD trials, meta-regression revealed that industry-sponsored trials, year of publication and studies with an open-label prospective phase before randomisation, all had a significantly higher placebo effect.

Discussing these findings, the authors felt that their results offered future researchers a benchmark for expected placebo responses in TRD trials. They concluded by calling for more consistent reporting of data, an agreement on the definition of TRD, and an assessment and reporting of participant’s expectations and experiences within a clinical trial.

Citation

Jones BDM et al. Magnitude of the Placebo Response Across Treatment Modalities Used for Treatment-Resistant Depression in Adults: A Systematic Review and Meta-analysis. JAMA Netw Open 2021.

Large placebo response in subjective and objective measures in RA trials

9th October 2020

It is largely expected that in a randomised, double-blind clinical trial, individuals assigned to placebo will experience some level of improvement in relevant outcomes and this can lead to an underestimation of the effectiveness of the therapy being tested.

Consequently, researchers often use a combination of objective and subjective measures when assessing the response to treatment. For instance, it is known that subjective measures, for example, pain scores can be high, hence the need for independent, objective measures. However, in a new analysis of the placebo response among patients in trials for rheumatoid arthritis therapies, a team from the Brigham and Women’s Hospital, Boston, USA, found significant improvements in both measures. The team examined the placebo arm responses for five double-blind trials conducted internationally of at least 24 weeks duration between 2005 and 2009 among patients with rheumatoid arthritis. They extracted the individual level patient data from trials and focused on pain scores (subjective) and C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) values, both of which are objective measures. Pain scores were assessed using a standardised measure, namely a 0 to 100 mm visual analogue scale (VAS) and CPR and ESR were measured by blood testing. As some patients in the trials crossed-over to the active treatment, the researchers pre-selected 12 weeks from baseline to assess responses. Study medications included methotrexate and other disease-modifying antirheumatics.

Findings
The data set included 788 patients (82% women) with a mean age of 51 years. There was a statistically significant reduction in pain intensity (-14mm, 95% CI – 12 to 16 mm), CRP levels (-0.51mg/dl 95% CI -0.47 to -0.56) and ESR (-11mm/h, 95% CI -10 to -12), all with p values less than 0.001. Commenting on their findings, the authors were surprised by the clinically meaningful reductions in subjective and objective measures observed in placebo participants, indicating that it was more than a psychological placebo effect.

Furthermore, the cautioned that simply using objective rather than subjective measures in future trials would not necessarily lead to clearer results and that there was a need to further understand the effect of confounding factors and baseline covariates in placebo responders.

Reference
Vollett J et al. Assessment of placebo response in objective and subjective outcome measures in rheumatoid arthritis clinical trials. JAMA Netw Open 2020;3(9):e2013196. doi:10.1001/jamanetworkopen.2020.13196