Monday, March 16, 2015

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

Website for the BROADEN™ study, which was terminated


In these days of irrational exuberance about neural circuit models, it's wise to remember the limitations of current deep brain stimulation (DBS) methods to treat psychiatric disorders. If you recall (from Dec. 2013), Neurotech Business Report revealed that "St. Jude Medical failed a futility analysis of its BROADEN trial of DBS for treatment of depression..."

A recent comment on my old post about the BROADEN Trial1 had an even more pessimistic revelation: there was only a 17.2% chance of a successful study outcome:
Regarding Anonymous' comment on January 30, 2015 11:01 AM, as follows in part:
"Second, the information that it failed FDA approval or halted by the FDA is prima facie a blatant lie and demonstratively false. St Jude, the company, withdrew the trial."

Much of this confusion could be cleared up if the study sponsors practiced more transparency.
A bit of research reveals that St. Judes' BROADEN study was discontinued after the results of a futility analysis predicted the probability of a successful study outcome to be no greater than 17.2%. (According to a letter from St. Jude)

Medtronic hasn't fared any better. Like the BROADEN study, Medtronics' VC DBS study was discontinued owing to inefficacy based on futility Analysis.

If the FDA allowed St. Jude to save face with its shareholders and withdraw the trial rather than have the FDA take official action, that's asserting semantics over substance.

If you would like to read more about the shortcomings of these major studies, please read (at least):
Deep Brain Stimulation for Treatment-resistant Depression: Systematic Review of Clinical Outcomes,
Takashi Morishita & Sarah M. Fayad &
Masa-aki Higuchi & Kelsey A. Nestor & Kelly D. Foote
The American Society for Experimental NeuroTherapeutics, Inc. 2014
Neurotherapeutics
DOI 10.1007/s13311-014-0282-1

The Anonymous Commenter kindly linked to a review article (Morishita et al., 2014), which indeed stated:
A multicenter, prospective, randomized trial of SCC DBS for severe, medically refractory MDD (the BROADEN study), sponsored by St. Jude Medical, was recently discontinued after the results of a futility analysis (designed to test the probability of success of the study after 75 patients reached the 6-month postoperative follow-up) statistically predicted the probability of a successful study outcome to be no greater than 17.2 % (letter from St. Jude Medical Clinical Study Management).

I (and others) had been looking far and wide for an update on the BROADEN Trial, whether in ClinicalTrials.gov or published by the sponsors. Instead, the authors of an outside review article (who seem to be involved in DBS for movement disorders and not depression) had access to a letter from St. Jude Medical Clinical Studies.

Another large randomized controlled trial that targeted different brain structures (ventral capsule/ventral striatum, VC/VS) also failed a futility analysis (Morishita et al., 2014):
Despite the very encouraging outcomes reported in the open-label studies described above, a recent multicenter, prospective, randomized trial of VC/VS DBS for MDD sponsored by Medtronic failed to show significant improvement in the stimulation group compared with a sham stimulation group 16 weeks after implantation of the device. This study was discontinued owing to perceived futility, and while investigators remain hopeful that modifications of inclusion criteria and technique might ultimately result in demonstrable clinical benefit in some cohort of severely debilitated, medically refractory patients with MDD, no studies investigating the efficacy of VC/VS DBS for MDD are currently open.
In this case, however, the results were published (Dougherty et al., 2014):
There was no significant difference in response rates between the active (3 of 15 subjects; 20%) and control (2 of 14 subjects; 14.3%) treatment arms and no significant difference between change in Montgomery-Åsberg Depression Rating Scale scores as a continuous measure upon completion of the 16-week controlled phase of the trial. The response rates at 12, 18, and 24 months during the open-label continuation phase were 20%, 26.7%, and 23.3%, respectively.

Additional studies (with different stimulation parameters, better target localization, more stringent subject selection criteria) are needed, one would say. Self-reported outcomes from the patients themselves range from “...the side effects caused by the device were, at times, worse than the depression itself” to “I feel like I have a second chance at life.”

So where do we go now?? Here's a tip: all the forward-looking investors are into magnetic nanoparticles these days (see Magnetic 'rust' controls brain activity)...


UPDATE to the update (March 22 2015): The Vancouver Sun reported (on 3/17/2015) that the sponsor ended the trial:
A procedure that treats depression by using electrodes implanted deep in the brain won’t be available to the public soon, says the researcher who pioneered the procedure more than a decade ago with a team at the University of Toronto.

Neurologist Dr. Helen Mayberg, now at Emory University in Atlanta, said in Vancouver Tuesday that 80 per cent of her recent patients find sustained relief from severe depression after fine wires are surgically implanted to deliver electrical current to a specific part of the brain.

But a medical equipment maker halted its tests to commercialize the discovery six months after implanting devices in 125 recruits in 2013.

Data from that work has not yet been released by St. Jude Medical Inc. based in St. Paul, Minn., although a spokesman for the company said Tuesday that it will be made public. The patients still have the implanted devices and the study was not stopped for safety reasons.


Footnote

1 BROADEN is an tortured acronym for BROdmann Area 25 DEep brain Neuromodulation. The target was subgenual cingulate cortex (aka BA 25). The trial was either halted by the FDA or withdrawn by the sponsor.


References

Dougherty DD, Rezai AR, Carpenter LL, Howland RH, Bhati MT, O'Reardon JP, Eskandar EN, Baltuch GH, Machado AD, Kondziolka D, Cusin C, Evans KC, Price LH, Jacobs K, Pandya M, Denko T, Tyrka AR, Brelje T, Deckersbach T, Kubu C, Malone DA Jr. (2014). A Randomized Sham-Controlled Trial of Deep Brain Stimulation of the Ventral Capsule/Ventral Striatum for Chronic Treatment-Resistant Depression. Biol Psychiatry Dec 13. [Epub ahead of print].

Morishita, T., Fayad, S., Higuchi, M., Nestor, K., & Foote, K. (2014). Deep Brain Stimulation for Treatment-resistant Depression: Systematic Review of Clinical Outcomes. Neurotherapeutics, 11 (3), 475-484. DOI: 10.1007/s13311-014-0282-1



DBS for MDD targets as of November 2013
(Image credit: P. HUEY/SCIENCE)

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