paper A Flashcards
(20 cards)
what is least squares mean ?
Least squares mean is a statistical method for finding the best fit lien through datapoints and it minimises the sum of squares of the vertical distance between data points and the line. it gives a statistical mean after accounting for variables that may affect the results. it gives a more accurate and fair comparison between vibegron and placebo. for example at week 12 vibegron has a -2.40 and placebo has a -1.30 drop in daily micturitions, however vibegron is more effective at is has a bigger drop in daily micturations than the placebo
what is standard deviation ?
standard deviation is the number that tells how how spread out data is. if a standard deviation is low, this means the data points are all close to the average. if the start deviation s large, this means that the numbers are ver spread out and a lot of the datapoints may not be close to the average - they are spread out. in clinical trials, standard deviation tells us how much variation there is in patient responses, whether the treatment is effective or stable and helps build error bars over the graph.
what is the mode of action of alpha blockers ?
Alpha blockers are drugs that can inhibit the alpha -1 adrenergic receptors that are located on the smooth muscles of the bladder neck, urethra and prostate
In benign prostatic hyperplasia there is prostate enlargement and compresses the urethra leading to increased urethral resistance
Alpha blocker inhibit the alpha 1 adrenergic receptors leading to smooth muscle relaxation in the urethra, bladder neck and the prostate
Leading to reduced urethral resistance, improved urianry Flo and reduced lower urianry tract symptoms such as hesitancy and weak or intermittent stream
what is the mode of action of 5 Alpha reductase inhibitors ?
5 alpha reductase inhibitors inhibit the alpha reductase enzyme which converts testosterone to dihydrotestosterone
DHT is a potent androgen that stimulates prostate growth
5-ARIs block the alpha reductase enzyme and this leads to reduced levels of DHT in the prostate
This leads to reduced prostate growth over time, improved mechanical obstruction and improved urinary flow and symptoms.
what is the mode of action of beta 3 agonists ?
overactive bladder is characterised by symptoms such as frequency, nocturia, and voiding problems. Bladder filling and emptying stages are communicated through the parasympathetic and sympathetic nervous system.
The detrusor muscle is located on the smooth muscle of the bladder neck, urethra and prostate. bladder filling is dependant on the inhibition of the parasympathetic nervous systems and sympathetic hypogastric nerves releasing norepinephrine which acts on the beta 3 receptors and is responsible for mediating detrusor muscle relaxation.
vibegron is a selective beta 3 agonist receptor. Vibegron binds to the receptor B3 and undergoes a conformational change to adenylyl cyclase which promotes the formation of cAMP. increased intracellular cAMP activates cAMP dependant PKA which phosphorylates myosin light chain. this is responsible for the inhibition o the interaction of actin with myosin attached calcium. for the detrusor muscle contraction, there needs to the actin interaction with myosin. therefore, this causes increased bladder filling time and reduced symptoms such as urgency, frequency and nocturia, and improves urinary flow.
comment on the baseline characteristics of the participants and the data shown
There is no P value in the data set - difficult to determine the significance of the differences between the placebo numbers and the vibegron participants
no data relating to employment status and job types - this can be important information as people who for example, down have access to a tilt at work may have less micturations er day or may not have access to taking their tablet as well.
no fluid intake restriction or it is not accounted for
majority of participants are white, therefore unfair to apply this data set to other races
they include if the participant is using prior alpha blocker and/or 5 alpha reductase inhibitor however, there is no data on which alpha blocker of 5ARI is being used - different drugs can have different modes of action and half lifespan that can impact micturations.
there is no measure of hepatic or renal function which could require a dose reduction
no weight mentioned - could impact the drugs volume of distribution if aptiutn had lean body mass or more body weight
no mention of making status, drinking etc
how was the data analysed for the coprimary end point of daily micturition ?
for the co primary end point which was the means number of daily micturition, they used a mixed model for repeated measurements statistical model. this accounts for changes over time and adjusts for other factors which affected the results:
- starting symptom severity
- whether the patient was on 5-alpha-reductase inhibitors
- if they had incontinence
- their location (US or not)
- the interaction between visit time and treatment
How was the data analysed for the coprimary endpoint of daily urgency episodes and urge urinary incontinence
They included the baseline value of the symptoms - how many urgency episodes a person had at the beginning
whether the person was urinating 12 or fewer times per day vs whether a person was urinating 12 or more times a day. Because people who urinate more often to begin with might respond differently to treatment.
however, they did not include whether a person had urge urinary incontinence episodes at the start at baseline in the MMRM model. This means their model for UUI was slightly less precise, because they didn’t control for whether someone already had incontinence, which can affect how much they improve.
what did the trial do to adjust for multiplicity ?
multiplicity is when there is a several outcomes being analysed, and the chances of getting false positive results increases
In this study they had 2 primary outcomes (micturations and urgency) and several secondary outcomes (nocturia and UUI, etc).
to adjust for multiplicity they did sequential testing. this is when they examine the first primary outcome. if it had a p value <0.05 being statistically significant then they moved onto the 2nd primary outcome. if this was statistically significant as well, then they oddly assess the secondary outcomes. but if any primary outcomes failed with p value >0.05 they stopped there. Any outcomes after that point were considered not significant, even if their individual P-values looked good.
This is a strict method. It prevents cherry-picking “good-looking” results and helps protect against false positives.
however the order should be pre-specified in the paper to avoid bias, but this is not clearly stated in the paper.
what does the author mean by 2-sided alpha of 0.05 ?
a 2 sided alpha of 0.05 means that the study only considers a results statistically significant if the portability of it happening by chance is less than 5%, in either direction of the expected outcome. So, the test is looking to see if the treatment is either significantly better or worse — not just better.
a 2 sided alpha is more conservative and unbiased and a default standard in clinical trials and scientific research because it doesn’t assume the direction of the effect beforehand.
comment on the safety aspect discussed in the paper of patients and treatment emerged adverse events.
According to the paper, there was no significant difference between treatment emerged adverse events in placebo vs vibegron treatment group, there is no p value which makes it difficult to determine the statistical significance of this conclusion.
6 participants were diagnosed with neoplasms in the study who took vibegron and 1 was diagnosed with neoplasm who took placebo. the investigator considers this not to be treatment related however this introduces bias as as the opinion of the investigator is not standardised and the study does no incite how this confusion was made by the investigator. The cluster in this arm of treatments of cancerous cells growth is hard to ignore and considerably raises the risk assessment.
Safety looks tolerable, but not clean when clinical benefits is tiny and safety profiles especially the number of neoplasms is hard to ignore, especially in older more morbid men.
Comment on the conclusion of the study.
The conclusion of this study states that treatment with vibegron was statistically and clinically meaningful - it does show statistical manful as p <0.05 but the clinical significance of this study is week. This is evidenced by not even 1 less toilet trip per night, and 1 less night time waking every 4-5 nights, - is it worth taking a pill daily for this?
Also there is no mention of quality of life or patient reported outcomes were used used to support claims of clinical benefit.
why was Vibegron considered a suitable candidate for patients with overactive bladder despite BPH treatment?
vibegron is a beta 3 agonist which works by stimulating the b3 receptors and relaxing the smooth muscle causing reduced detrusor muscle activity and leading to increased bladder filling stage, delays urgency signals and improves urinary flow. Unlike anticholinergics it avoids cognitive side effects and has a favourable cardiovascular side effect profile - which is particular important older patient whom are <45 in this trial. its mechanism of action directly targets OAB symptoms making it appropriate for patients that are unresponsive to BPH alone.
Describe the trial design. Why is a double-blind, placebo-controlled design important?
The trial was a multicentre, double blind placebo controlled study, it consisted on a participants being randomised to treatment in a 1:1 ration of placebo to vibegron over 24 weeks, there was les than 5 weeks screening period and 2 week trial run to help patients understand the drug and what is expected of them surfing the study where the effect were not measured.
a double blind is important as it reduced any risk of bias form the participants and the investigators as no one knows who is receiving the placebo or who is racing the treatment drug.
placebo controlled is important as it controls and help to differentiate from the drugs effect from the natural symptom variation or placebo response when ensuring internal validity.
the trial makes reference to blood pressure monitoring with the use of vibegron - explain why this is of importance
vibegron is a beta 3 agonist which works by stimulating beta 3 receptors in the detrusor muscle of the bladder. this promotes muscle relaxation during the storage phase and reducing LUTS symptoms.
however beta adrenergic receptors are also located in the cardiovascular system specifically beta 1 and beta 2 receptors. it raises concerns about off target cardiovascular effects including tachycardia and hypertension.
in the courage trial hypertension occurred in 9.0% of patients receiving vibegron versus 8.3% in the placebo group, while urinary retention occurred in <1% in both groups. These similar rates suggest that vibegron does not significantly impact systemic blood pressure or bladder emptying, despite its mechanism of action involving smooth muscle relaxation. This is a crucial finding because:
The study population (mean age ~67 years) often has multiple comorbidities, including pre-existing hypertension (present in ~65% of participants). Any increase in blood pressure could have serious implications for cardiovascular risk in this demographic.
Urinary retention is a known risk with drugs that act on bladder function, especially in patients with benign prostatic hyperplasia (BPH) where bladder outlet obstruction (BOO) may be present. If vibegron excessively relaxes the detrusor muscle or worsens post-void residual volume, it could theoretically exacerbate retention. However, this was not observed in the trial.
Compared to anticholinergic drugs, which are another class used to treat OAB, vibegron appears safer. Anticholinergics are associated with not only urinary retention, but also dry mouth, constipation, and cognitive decline, especially in older adults. Vibegron’s lack of interaction with muscarinic receptors is thus a major advantage.
The absence of significant cardiovascular effects was further validated in previous studies, such as ambulatory blood pressure monitoring trials, showing no meaningful increase in blood pressure or heart rate even in patients with hypertension.
“95% Confidence Interval = [–1.02, –0.46]” what does this mean
this means we are 95% confidence that the true added benefit of vibegron lies between -1.02 and -0.46 reduction in micturations per day
“P < .0001” what does this mean
he p value tells us the probability of the results happening by chance
p <0.001 means less than 0.01% chance this result is random and shows very strong evidence that vibegron does work.
what are advantages and disadvantages of MMRM
MMRM is a linear statistical method used to analyse data collected from multiple time points from the same participants.
it accounts for repeated measurements within individuals, assign data without excluding participants, and covariates like between values and treatment groups.
advantages of MMRM is
- it accounts for within-subject variability
- includes all available data
- adjusts for coviaretes
- no need for data imputation
- increases statistical power
disadvantages are
- it is complex to implement
- assumes data is missing at random points
- results can be harder to interpret
- model mis-specification risk
Evaluate the use of a 12-week primary endpoint in the COURAGE trial. What are the strengths and limitations of using this timepoint to assess treatment efficacy? (5%)
the trial assessed the daily micturations and urgency episodes from week 12 endpoint. this is a common timeframe for OAB conditions and are chosen to evaluate mid to short term effects of vibegron
advantages of this 12 weeks endpoint are
- clinically relevant time frame: a 12 week period is long enough to capture the scent and timeframe of a drug like vibegron
enhances the adherence of participants and reduces drop out rate
comparable cars studies - many studies in OAB use a 12 week trail s well therefore easier to compare results.
limitations of a 12 weeks period endpoint
- OAB and BPH are chronic conditions therefore a 12 week frame may not be significant enough been this window
effects like receptor desisitsation or delayed adverse events may occur beyond this window
long term effectiveness continues ebyogn a 12 weeks endpoint and requires a longer than 12 week followup period
what are strengths and weakness of using bladder diaries
strengths are:
it uses patient own diligence and patent involved - provided ecological validity rather than recall basis
detailed, quantifiable measures - provided objective and frequency for primary and secondary endpoints allowing robust and statistical comparisons
standardised measurement
limitations are:
Hawthorne effect - Awareness of being observed may have altered patient behaviour.
robust bias - relais on patients çoverreportign or underreporting
missing or incomplete diaries - Not all participants may have filled out diaries consistently, contributing to data gaps
