Having just given poor old NHL posters the benefit of my unhappy thoughts about their company … I thought I would try and get in the good karmic books with Santa … by jotting down a few rare “happy” thoughts I have about a ASX life sciences micro-cap.
ZLD’s P2 A trial to evaluate an oral medicinal cannabis extract for insomnia: My take on the design.
The study has completed enrollment and is due report results in February 2020. It is a relatively small study with only 30 participants. The treatment is a sublingual oral medicinal cannabis extract (ZTL-101) containing cannabinoids. The placebo is the same as the treatment – it contains the same excipient sunflower oil as the investigational product - but does not contain cannabinoids. The treatment period is 14 days.
The primary outcome is insomnia symptoms as measured by the Insomnia Severity Index (ISI) questionnaire. The questionnaire is administered by an investigator at baseline and 14 days. The ISI has 7 items – scores range 0-28 with higher scores indicating worse levels of insomnia.
The minimally important difference (MID) for the ISI is around a 6-point reduction which is the change required to indicate a clinically meaningful response to treatment in an individual patient.
Secondary outcomes (13 of them) include sleep lab laboratory polysomnography (PSG) measures, quality of life, depression etc.
A cross-over design is used. Participants are randomly allocated to one of two groups – group 1 receives A (treatment) – washout (1 week) – B (placebo). Group 2 receives B (placebo) – washout (1 week) – A (treatment). Simplified in notation to AB/BA.
The study is being conducted by the Centre of Sleep Science at UWA.
What to make of it all?
The cross-over design is very efficient. In this design each participant contributes two observations (one for each treatment) and so you achieve power with far fewer subjects. This has a couple of advantages.
First it keeps costs down for when you have relatively expensive laboratory testing (as this study does here with 3 sleep lab tests). Second a small number of subjects helps you stay single site and avoid the problems associated with multiple sites which adds more moving parts.
The trial site – a well respected academic sleep centre - is the perfect choice here. They wouldn’t be the cheapest or the quickest, but they are most likely to deliver a high-quality implementation. I assume they have contributed (led) to the design work.
This is important because ZLD have to produce positive results in a very well designed and conducted study to convince a very conservative medical / scientific community. A poorly designed - conducted trial with positive results wouldn’t convince the skeptics.
The dangers in a crossover study are carryover / period effects and dropouts.
Carryover effects occur when treatment effects “linger” on after one treatment ends, and the alternative treatment begins. Hence the one-week washout period - that seems about right.
A period effect occurs when the treatment effect is different over time. That is the treatment effect shouldn’t vary depending on whether you started the
A treatment in the first or second period.
This can happen when the problem being targeted in fluctuating / or unstable. This is addressed in the trial design by a long baseline phase prior to participants entering the intervention phase.
The third potential problem is that crossover designs are more sensitive to drop-outs causing bias than parallel group designs. This is because you lose you intent to treat analysis when a participant drops out because they don’t provide your second measurement point. Remembering that participants in this design are effectively their own controls.
I started with very negative headset but more I looked at the design the more I appreciated the way it has been put together; the blend of subjective / objective measures, the measures chosen, the laboratory testing, the cross-over design.
Negatives
The sleep centre and their researchers do not appear to have done much interventional trial work. There might be a little bit of a learning curve.
With effectively 14 outcomes there is around a 51% probability of getting a statistically significant result by chance alone. In a P2 trial it is most unlikely the researchers will apply a correction for multiple testing.
There appears to be a little bit of disjointedness between what the researchers think they are doing and what the company thinks it is doing.
According to the researchers the trial will provide “preliminary” evidence of efficacy. From ZLD’s perspective I suspect positive results from this trial will be as good as it gets – there will be no more trials.
Recruitment and implementation have been very slow which is usually a red flag. Here I give the benefit of the doubt - an academic research group knows all too well recruiting the wrong participants (participants unlikely to comply with the trial regime) is worse than not recruiting at all.
The idea of the trial is not well understood by retail shareholders. Particularly from those with a traditional background in drug development. Hence a lot misdirected criticism about patents, small size etc. Think of this as a positive … possible market mispricing.
For high levels of transparency the researchers should have made public the basis of the sample size chosen and lodged the protocol in the registration.
Overall
ZLD claim the trial has been designed to the highest standards of scientific rigour. I would agree. The design reflects a quality and cleverness not often seen at this level of the market.
My gut tells me this trial is really a test of the theory of ZLD.
ZLD’s claim to fame is that it has data packs – anecdotal / observation evidence relating to which specific cannabis brews work for what problems in which people. And it is this data that gives ZLD the edge in generating evidence not for registration purposes but to help consumers doctors in the unregistered cannabis medicine domain.
It’s an novel idea but the proof will be in the pudding. Positive results in this trial validate the investment thesis. Negative results the reverse. So high stakes.
In terms of probability of success? Very hard to even guess because there is no way to evaluate the strength of the anecdotal evidence supporting the formulation’s efficacy for insomnia. So obviously high risk; but good design is correlated with good results; so I would be more positive than I think the market is on this one. We'll see what happens.
ZLD Price at posting:
5.5¢ Sentiment: None Disclosure: Not Held
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