Episode 4 – Dr Victor W. Nitti

I’m Joseph Ischia

I’m Nathan Lawrentschuk

Joseph: And we’re talking Urology where we discuss the key points of the landmark papers that guide your practice everyday. Our goal is to empower doctors to develop a deeper understanding of the literature to ensure we apply the right evidence to the right patient.

We are all about “bringing the literature to life”.

And today we are looking at one of the pivotal papers that defines the use of onabotulinum toxin A for the treatment of idiopathic OAB. The paper is with first author Victor Nitti and is titled “OnabotulinumtoxinA for the Treatment of Patients with Overactive Bladder and Urinary Incontinence: Results of a Phase 3, Randomized, Placebo Controlled Trial” and it was published in the Journal of Urology in 2013. And Victor Nitti was kind enough to take some time out of his heavy schedule at the AUA to talk to us about the trial.

Victor: I am Victor Nitti, I am a professor of Urology and Obstetrics and Gynaecology at the New York University Langone Medical Centre.

Nathan: But we have been using onabotulinum toxin A for many years, why is this paper published in 2013 so important? Look at from the perspective of regulators. Onabotulinum toxin A has been approved and used for neurogenic detrusor over activity (stroke, spinal cord injury, MS or Parkinson’s). There have been non-randomised, or single centre studies but this is a big pharma sponsored, regulator directed trial.

Joseph: Quite right. And I asked Victor if he had any reservations with this being a drug sponsored trial.

Victor: There are no concerns for me because this is what we call a registration trial and in order for treatment to be approved you have to do appropriate registration trials and you need 2 of them. So we have the 1 North American study and we had the one European study and they were designed the same.

[Interrupting….Joseph: That’s the trial with first author Chris Chapple published in European Urology in August 2013.]

Victor: So those are two identical trials. When a study goes through a registration trial, the protocol for the study is reviewed by the regulatory agency so the FDA and the US, the European regulatory agency to make sure that that study is looking at proper end points, is properly designed and then it would be up to those regulatory agencies to make the decision that whatever the drug is or whatever the treatment is, if it’s efficacious over placebo or a comparator; and it seems to be safe then if the protocols were approved by the regulatory agency you would assume that that would have a good chance of being approved for the indication that the trial was designed to show. I think there is no other way to do it if you want it to be something that is approved for use in any given country or region.

Nathan: Idiopathic overactive bladder affects around 15% of the population- a third will have a degree of incontinence as well. First line pharmacological treatment involves anticholinergics or the new class of B3 agonists, mirabegron. However, they are not always sufficiently effective and anticholinergics can have intolerable systemic side effects.

Joseph: Therefore the aim was to broaden the on-label use of onabotulinum toxin A beyond the neurogenic population. This trial enrolled patients with idiopathic OAB who experienced 3 or more urgency urinary incontinence episodes in a 3-day period and an average of 8 or more micturitions per day.  They had to have failed prior anti-cholinergic therapy, and have a PVR of <100 ml.

Nathan:  Double-blind treatment with onabotulinum toxin A 100 U reconstituted with 10 ml normal saline or placebo which was just the 10 ml normal saline.

Joseph: This study looks at onabotulinum toxin A but does the type of botulinum toxin matter?

Victor: I think it does. Different types of toxins work in slightly different ways in effecting the snap 25 complex, which is the ultimate mechanism of action. Also, different toxins come in different concentrations or different dosages that are really not transferable, so you can’t say that 100 units of Onabotulinumtoxin A is equivalent to x units of AbobotulinumtoxinA or one of the B toxins, so I think each toxin works uniquely and really there isn’t any significant data in the urinary tract, particularly in overactive bladder on toxins other than OnabotulinumtoxinA.

Nathan: There have been a number of studies that have used different doses in idiopathic OAB. One single centre study used 200 U with great effect.  We asked Victor, how they arrived at the dose for this trial?

Victor: I think when the study was designed obviously the most important thing was choosing the dose. So there was a dose ranging study that was published a few years prior, Roger Demicowski was the lead author on that study and that was where 50, 100, 150, 200 and 300 units were looked at. The dose was really chosen for a combination of ethically versus adverse events and particularly elevated post void residual and then the need to catheterise. So it was felt that the 100 units was going to give the best efficacy vs. side effect profile.

Joseph: Ok, so we have the dose and the onabotulinum toxin A was delivered by the standard technique of 20 evenly distributed intradetrusor injections of 0.5 ml per injection site, sparing the trigone. Injections were spaced approximately 1 cm apart and the needle was inserted approximately 2 mm into the detrusor muscle.

Nathan: The study ran for 24 weeks- main analysis was done at 12 weeks (as patients could have further treatment after this time). 3 day bladder diaries collected the usual OAB data. Patients recorded their perception of treatment benefit at each post-treatment visit using the treatment benefit scale rating their condition as

Greatly improved

Improved

Not changed

Worsened.

The impact of OAB on QoL was assessed at week 12 using 2 validated patient questionnaires, including the Incontinence Quality of Life Instrument and King’s Health Questionnaire.

Joseph:

• Co-primary objectives were 1. The change from baseline in the daily average frequency of UI episodes, and 2. The proportion of patients with a positive treatment response on the treatment benefit score (i.e. condition greatly improved or improved) at post-treatment week 12.
• Secondary objectives
• Improvements in number of micturitions or urgency episodes,
• QoL measures.
• Voided volumes
• PVRs,
• AEs such as UTIs, need for CIC.

Nathan:

• On that point- CIC was initiated if PVR was 200 ml or greater, with associated symptoms, or PVR was > 350 ml regardless of symptoms.
• UTI- positive urine culture with a bacteriuria count of greater than 10⁵ cfu/ml together with leukocyturia greater than 5 per high power field regardless of symptoms.

Joseph: Let’s look at the study population:

• 557 patients were randomized including
• 280 who received onabotulinum toxin A 100 U
• 277 who received placebo.
• Unhappy patients
• The average duration of OAB symptoms was 6.7 years;
• Patients had used an average of 2.5 anti-cholinergics for a mean of 2.4 years before study entry.
• Baseline number of urgency incontinence episodes over 4 per day.

Nathan: Results.

• At 12 weeks, the decrease in the mean daily frequency of UI episodes for onabotulinum toxin A 100 U vs. placebo was –2.65 vs. –0.87.
• e. 47.9% percent reduction from baseline for onabotulinum toxin A 100 U vs. –12.5% for placebo.
• Treatment benefit score, the proportion who reported a positive treatment response to a predefined level was 61% in the Botox arm vs. 29% in placebo.
• Also- large, significant differences in the improvements of mean number of micturitions, urgency episodes, nocturia, and voided volumes in the onabotolinum toxin A compared to the placebo arm.

Joseph:

• QOL outcomes- significant improvements were seen from baseline for onabotulinumtoxinA compared to placebo.
• AEs- the rate of UTI was significantly greater in the onabotulinum toxin A arm at 16% vs. 6% for placebo. And the proportion of patients who initiated CIC at any time during the first 12 weeks was 6% for onabotulinum toxin A none in the placebo group.

Victor: The quote unquote UTI rate is UTI’s were defined in the study as really the detection of bacteria with white cells in the urine. So many of those patients were asymptomatic. I can tell you that some of those patients were patients from my side and they were never treated for UTI. So it was a very broad definition of a UTI. Having said that, there does seem to be an increase risk of bacteriuria and probably even UTI in the botox group or the OnabotulinumtoxinA group vs. placebo. I’m not 100% sure why that is, and I’m not sure anybody is. It seems to be in many cases independent of post void residual, independent of the need to catheterise, so they may be some effect of the OnabotulinumtoxinA on the urothelium that makes it a little bit more susceptible to bacteriuria and maybe even UTI’s. I can tell you in clinical practice, issues with urinary tract infections I don’t think are a major limitation to the use of OnabotulinumtoxinA.

Nathan: PVR significantly increased in patients treated with onabotulinumtoxinA vs. placebo with the highest volume at post-treatment week 2 and decreasing over the next 10 weeks. For more than half the patients who initiated CIC, the duration was 6 weeks or less.

Joseph: Need for CIC is probably one of the key limiting considerations in planning onabotulinum toxin A for patients. We asked Victor if he had any tips or tricks on how we can reduce the catheterization rate?

Victor: I don’t know of anything in an individual patient that one can do to reduce the catheterisation rate. I think patient selection is important. We think that patients who are older, patients who have detrusor under activity if they’ve undergone urodynamics and remember in this large study patients were not subjected to urodynamics. We found at our site that if patients have detrusor under activity they are a higher risk of needing to catheterise, we know diabetics are higher risk of needing catheters. So, in an individual patient at this time other than dosing and these are all 100-unit dosages; if you inject the trigone, don’t inject the trigone etc. those are all interesting questions. But we really don’t have the answer so patient selection is really the best thing that we have to try and choose patients that are at less risk but it still remains a risk in any patient.

Nathan: Overall there was a two to fourfold improvement over placebo in all OAB symptoms, which is far greater than any benefits seen in previous studies investigating anticholinergics.

Joseph: While we know that OnabotulinumtoxinA directly inhibits efferent acetylcholine mediated detrusor contractions, it may have multiple other effects in the overactive bladder wall, which we just don’t understand yet. — Synergistic effects with other agents.

Nathan:  We asked Victor if he thought there were any unanswered questions regarding onabotulinum toxin A in overactive bladder?

Victor: I think for me the biggest unanswered question is patient selection, and can we better choose patients who are no. 1 likely to respond and no. 2 likely to not have an adverse event. Are there a group of patients for example where the need to catheterise rate is 0%. Interestingly at NYU we’ve identified one such group preliminarily which seems to be men who have had radical prostatectomy, those patients when given 100 units of OnabotulinumtoxinA seem to never have issues with bladder emptying. So that’s just one small example but there may be others where we can assure a patient that the risk of adverse event is less and then of course how the toxin is delivered. In the future will there be better delivery methods other than 20 separate injections into the bladder.

Joseph: In practice if someone fails at the 100 units with idiopathic overactive bladder incontinence, do you increase the dose?

Victor: That’s a great question and there’s a couple of different scenarios. So if I have a patient who is a responder and comes in and has had a poor response to a particular injection but was previously a responder; I would probably re-inject 100 units and assume that for whatever reason the injection that the patient got on that particular day where they had less of a response was just maybe not as technically good as previous injections were. If it’s a patient in whom I’m fairly confident that that dose didn’t work whether it’s a first time treated patient or not, I guess you really have two options. One option would be another 100 unit injection early, so at the 3 month point to inject a second 100 units assuming that there is still an effect of the first 100 units vs. increasing the dose and going up. In the US that’s an off label indication but I have certainly done it and you can go up to 150 units or you can go up to 200 units, as long as the patient is willing to accept a slightly higher risk of needing to catheterise, I would do that in select patients.

Nathan: How about the use of onabotulinum toxin A in patients with overactive bladders without incontinence?

Victor: On the US label it is indicated for overactive bladder but in all fairness, every patient had incontinence and most of them had pretty significant urgency incontinence so the question is – does it work well in the OAB dry patient, and I can tell you that my own experience is only anecdotal; so I don’t know that I have enough experience to say it works as well in the OAB dry patients as it does in the OAB wet patient. That is certainly I think an area for future research.

Nathan: So the take home message is that OnabotulinumtoxinA 100 U is effective in idiopathic OAB by nearly every measure. Beware retention and the need for CIC.

Joseph: We’ve been talking urology with Victor Nitti. If you have any burning issues or concerns, please email us at talkingurology@gmail.com. All negative feedback and trolling can be directed to your hospital administrator who just axed a service for your patients to reduce costs so they can achieve their annual bonus.

Remember, there are lots of great podcasts on our website Talkingurology.com.au. You can also follow us on Twitter @talking_urology, Apple podcasts or SoundCloud for the latest podcast releases. We would love you to rate us and spread the word.