Monday, 9 January 2017

#ThinkHand & #ResearchSpeak: how good is the 9-hole peg test?

Looks like we have no option, but to go with the 9-HPT as our primary outcome. #ThinkHand #ResearchSpeak #MSBlog

As you know we are planning to do a trial in people with more advanced-worsening MS and to include people who are already in wheelchairs. The aim of the study is to see if we can slow down worsening, or loss of function, in the arms and hands. We are planning to do a phase 2, proof-of-concept study, but some commentators are saying to us: 'Why waste your time? Just go straight to Phase 3'. We now know a lot about how to power trials in worsening-advanced MS, formerly known as secondary and primary progressive MS or chronic progressive MS. We have two drugs that have recently been shown to be effective in this stage of the disease (ocrelizumab and siponimod). If we do a phase 3 trial what primary outcome measure would we use? We have the most experience, and supporting data, for the 9-hole peg test (9HPT) and importantly it has been shown to have face validity from linking it to changes as measured using the ABILHAND patient related outcome measure (PRO or PROM) in the ASCEND Trial (natalizumab in SPMS). The problem with the 9-HPT is that it has quite a lot of variability with test-retest results. The study below addresses this problem and assesses using the 9HPT as it would be used in a clinical trial. They show the variation in the 9HPT retest results a week apart to be acceptable for a clinical trial. 

What is hidden in the analysis below is the the results of the 9HPT at each time point represent the average of two tests per hand. When you compare these results with each other, i.e. test-1 vs. test-2, we have found the coefficients of variation to be much higher. The good news is that we have been told that the regulators, at least the FDA, will accept the 9HPT as a primary outcome in a clinical trial. The question is would the EMA be as accommodating and will we need to do two trials rather our planned one trial? 

The other big decision we need to make is what drug to use in this group of people with MS? People with more advanced-worsening MS often have associated comorbidities that would make them susceptible to complications of long-term immunosuppression, for example bladder infections. Therefore we need to choose a drug that does not affect innate immunity. Ideally, we would also like a drug that penetrated the CNS to target intrathecal cells, in particular B-cells and plasma cells, and we would like a drug that is easy to administer and has low monitoring requirements. We would also want the drug to be a high-efficacy drug to give us the best chance of having a positive outcome. Any suggestions, or guesses, on what drug(s) we are thinking of using in this trial?  


We have developed a cheap, environmentally friendly, cardboard 9HPT for home use (c9HPT). We were hoping to make the c9HPT available online for purchase last year, but have had to delay the launch of the online portal to get the test CE-marked. According the the MHRA the 9HPT is a device and hence we can't distribute it or sell it unless we have it CE-marked. The good news is that the cHPT has now been CE-marked and we should be launching it officially very shortly. We have also updated our www.clinicspeak.com web-portal to accommodate the c9HPT. Please  note we are promoting the c9HPT as a self-monitoring tool. 

Hervault et al. Reliability, precision, and clinically important change of the Nine-Hole Peg Test in individuals with multiple sclerosis. Int J Rehabil Res. 2017 Jan 2. doi: 10.1097/MRR.0000000000000209.



Background: This study evaluated the reliability, precision, and clinically important change of the Nine-Hole Peg Test (9-HPT) over a 1-week period. 

Methods: Sixty-nine patients with multiple sclerosis completed the 9-HPT on two occasions 1 week apart. Test-retest reliability was based on intraclass correlation coefficient, and precision was based on standard error of measurement and coefficient of variation. Clinically important change was based on the minimal detectable change. 

Results: Intraclass correlation coefficients exceed 0.90 for all 9-HPT metrics. Standard error of measurements for dominant (DH) and nondominant (NDH) hand time were 1.58 and 2.69 s, and 0.03 peg/s for both DH and nondominant NDH speed, respectively. Coefficient of variations for DH and NDH time were 4.3 and 3.8%, and 4.5 and 4.6% for DH and NDH speed. Minimal detectable changes for DH and NDH time were 19.4 and 29.1%, and 18.6 and 20.5% for DH and NDH speed. 

Conclusions: These data provide evidence on reliability, precision, and clinically important change of the 9-HPT over a 1-week period in multiple sclerosis for clinicians and researchers.

CoI: multiple, Biogen kindly provide an unrestricted grant for the design and initial production of the c9HPT.

7 comments:

  1. Surely you need to go with the most effective DMTs out there? As this is investigator led I would recommend rituximab or cladribine. Based our Bart's bias I suspect it will be cladribine.

    ReplyDelete
  2. I would suggest to get advice from EMA on the 9HPT test as primary outcome to avoid duplication of your trial, especially if you envisage a Phase III. Regulatory Affairs executives from the pharma companies involved should be able to assist you in organizing this with you. If you are using already registered MS drugs, have the budget & regulators agreement on your protocol, going to the phase III would save time. Time to market is important for the pharma but also for patients there, currently without medication. However if there is still discussion/uncertainties or use of a non yet registered MS drug, go for the phase II. Worst thing to avoid is the endless debate.

    ReplyDelete
  3. I assume you will test Cladribine.

    But I just don't know if it works by killing the plasma cells, but I think it will be Cladribine.

    ReplyDelete
    Replies
    1. I suspect it will be nothing...Are any funders going to touch this? The cost will be outside most charities to do full trial with clinical outcome and are too busy with stem cells,remyelination and progression.. NIHR have sunk alot into MS and are they interested in immune DMT...I doubt it. God forbid they fund something that works and has immediate impact:-(

      Will pharma come to the show .,..A risk they may not be willing to take.

      I best go and do a meta analysis to cheer myself up.

      Delete
    2. Yeah, I had forgotten about those factors involved. But it would be a great option, a damage for us that we have in terms an option this wasted...

      Delete
  4. I have problems coordinating both hands together - so the 9HPT would not show anything of interest on me. I wonder how many MSers are like me.

    ReplyDelete
  5. Would pre-existing malignancies exclude one from the trial?

    ReplyDelete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.