Tuesday, October 10, 2017

BROADEN Trial of DBS for Treatment-Resistant Depression No Better than Sham

Website for the BROADEN™ study, which was terminated by
the sponsor.


A multi-site, randomized, double-blind, placebo-controlled clinical trial of deep brain stimulation (DBS) for treatment-resistant depression has failed, according to a new article in Lancet Psychiatry. The targeted brain region was bilateral subcallosal cingulate white matter, which had been called the “Depression Switch” based on acute stimulation studies at Emory. These disappointing results were not surprising, since they were covered by Neurotech Business Report in December 2013 and then in depth by my posts here and here. The new paper followed the patients for a longer period of time, up to 24 months for some in the cohort.

The main portion of the trial was six months in length. All patients received implantation surgery. Two weeks later, they were randomized to either the treatment group (n=60), who received stimulation right away, or the “sham” control group (n=30), who did not. After six months, the blinding was uncovered and both sham and treatment groups were offered open label DBS for another six months.

In the figure below, Control (red line) and Stimulation (blue line) groups both showed slight improvements over time, with no significant difference in depression severity measured by the Montgomery-Åsberg Depression Rating Scale (MADRS). This was the primary endpoint. We don't see a difference between groups at six months or any other time.


- click on image for a larger view -


Fig. 2. (Holtzheimer et al., 2017). At months 9 and 12, the control group was receiving active stimulation; therefore, for the control group, 9 months refers to 3 months of active stimulation, and 12 months refers to 6 months of active stimulation. Error bars indicate standard deviations.


Concerning the endpoint more specifically (Holtzheimer et al., 2017):
The primary efficacy endpoint for the study was defined as difference in proportion of patients achieving a response between the stimulation and control groups. Response was defined as a 40% or greater reduction in MADRS and no worsening in GAF from baseline (average of three baseline MADRS assessments) to the average scores at months 4, 5, and 6.


Table 3 (modified from Holtzheimer et al., 2017).


Here's the full scoop for the futility analysis that put an end to the trial (because of the low probability of success). I had erroneously stated in January 2014 that the trial was halted by the FDA. It wasn't. It was stopped by the sponsor, St. Jude Medical (Holtzheimer et al., 2017):
For the futility analysis, based on the first 6 months' data, the proportion of patients with response for the stimulation group was predicted to be 40%, and for the control group was predicted to be 18·5%. In the actual futility analysis, these figures were 20% for the stimulation group and 17% for the control group. It was concluded that the study had a 17% chance of success if continued. Although this did not meet the prespecified definition for futility (<10% chance of success), the sponsor chose to end study enrolment following the futility analysis.

Although “These findings are disappointing given the encouraging data from earlier open-label studies of subcallosal cingulate DBS,” all was not lost, according to the authors. They offered a number of possible explanations (which can be summarized as long duration of illness, suboptimal stimulation parameters, and lack of tractography):
  • “participants in this study had an average current episode duration of about 12 years, which is much longer than the average duration of current episode in previous studies of subcallosal cingulate DBS (approximately 5 years) and might have contributed to the low overall proportion of patients achieving a response.”
  • “possible that stimulation contacts and parameters were suboptimal during the first 12 months of this study, given the somewhat restrictive programming algorithm used. Greater improvement in depression occurred after the 12-month endpoint when more flexibility in stimulation contacts and parameters was allowed.”
  • “Neurosurgical placement of the DBS electrodes, based on this algorithm, was highly accurate and did not differ between eventual responders and non-responders.”
[NOTE: placement was verified by at least two of three experts: HSM, CH, PEH. Nonetheless, the authors argue that placement could improve with more detailed tractography, e.g. Riva-Posse et al. 2017. This refinement of protocol has been discussed for the last 10 years; see Johansen-Berg 2007 and ...But My Subgenual Cingulate Is Sad.]
  • “for maximal efficacy, the active electrode for subcallosal cingulate DBS must be placed such that it affects a crucial network of white matter tracts connecting key brain regions, including the forceps minor, cingulum bundle, and uncinate fasciculus. Therefore, it is possible that prospective targeting on the basis of individual diffusion tensor imaging tractography could optimise electrode placement in subcallosal cingulate DBS.”

In an earlier paper, a group of DBS investigators and ethics experts advised other researchers, industry mavens, and even bloggers on “Being open minded about neuromodulation trials: Finding success in our 'failures'.” (Finns et al., 2017)
“Similarly, another randomized double blind clinical trial comparing active versus sham stimulation for the treatment of severe depression targeting Brodmann Area 25 was also halted for futility prior to completion of the planned study (St Jude Medical sponsored BROADEN trial). While there are neither publications nor official industry statements, uninformed speculations as to causes of the failure are in the public domain [28, 29] to the detriment of the scientific process and progress.

In each of these instances, different combinations of variables can lead to disappointing results. For example, patient characteristics, surgical variability, stimulation algorithms, outcome metrics, and institutional variance, can all contribute to negative outcomes in complex trials that initially seem promising. Further, once a negative report is published, the work can become ‘toxic’, and there is little incentive to engage in small subset analyses that have a limited market.
Finally,
“We believe that investigators, industry, regulators and society need to fully understand what is casually described as success and failure in order to maximize return on investment, all the more so when opportunities for additional knowledge generation remain in place. To do otherwise, would be irresponsible.”

So to call the BROADEN trial a failure is “irresponsible”? Personally, I am aware that a multi-site trial using invasive new technology to treat intractable psychiatric patients with a terrible and (ultimately) ill-defined syndrome is a massive undertaking. And very, very, very expensive. I have no problem with the investigators trying to glean what they can from individual differences to move forward with better targets/parameters/etc. I wanted to see this procedure help a majority of patients.

The bottom line here is that the primary preregistered endpoint was as follows: 12/60 (20%) improved with stimulation, 5/30 (17%) improved with no stimulation, 8/60 (12%) patients with stimulation reported an increase in depressive symptoms (this was not defined or quantified), and 1/30 (3%) patients with no stimulation reported an increase in depressive symptoms.

Let's take a look at the registered clinical trial. Oh we can't.


Clinical Trial NCT00617162

[Trial of device that is not approved or cleared by the U.S. FDA]




However, we can look at other clinical trials using the same device (Libra Deep Brain Stimulation System) with the same sponsor (St. Jude Medical) in Europe and Canada. Oh by the way, an April 2016 news release announced: Abbott to Acquire St Jude Medical (DBS was not mentioned). In January 2017 Abbott Completes the Acquisition of St. Jude Medical (no DBS here, either). I won't speculate any further. I'm too tired.


I'd like to conclude with an upbeat tweet from a prominent neuroscientist who studies pain and the placebo effect.



References

Choi KS, Riva-Posse P, Gross RE, Mayberg HS. (2015). Mapping the "Depression Switch" During Intraoperative Testing of Subcallosal Cingulate Deep Brain Stimulation. JAMA Neurol. 72(11):1252-60.

Fins JJ, Kubu CS, Mayberg HS, Merkel R, Nuttin B, Schlaepfer TE. (2017). Being open minded about neuromodulation trials: Finding success in our "failures". Brain Stimul. 10(2):181-186. 

Holtzheimer PE, Husain MM, Lisanby SH, Taylor SF, Whitworth LA, McClintock S, Slavin KV, Berman J, McKhann GM, Patil PG, Rittberg BR. (2017). Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multisite, randomised, sham-controlled trial. The Lancet Psychiatry. 2017 Oct 4.

Riva-Posse P, Choi KS, Holtzheimer PE, Crowell AL, Garlow SJ, Rajendra JK, McIntyre CC, Gross RE, Mayberg HS. (2017). A connectomic approach for subcallosal cingulate deep brain stimulation surgery: prospective targeting in treatment-resistant depression. Mol Psychiatry. 2017 Apr 11. [Epub ahead of print].


Further Reading

BROADEN Trial of DBS for Treatment-Resistant Depression Halted by the FDA
 NOTE: the trial was actually halted by the sponsor, not the FDA

Update on the BROADEN Trial of DBS for Treatment-Resistant Depression

Deep Brain Stimulation for Bipolar Depression

Modern Tract-Tracing for Historical Psychosurgery

...But My Subgenual Cingulate Is Sad

The Sad Cingulate

Sad Cingulate on 60 Minutes and in Rats

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