Poliklinika Neuron, Croatian Institute for Brain Research, Medical School, University of Zagreb, Zagreb, Croatia [Dr Henigsberg]; Takeda Global Research and Development Center, Deerfield, Illinois [Drs Mahableshwarkar and Chen and Ms Jacobsen]; and Department of Psychiatry, University of Pennsylvania, Philadelphia [Dr Thase].
Potential conflicts of interest:
Dr Henigsberg has participated in clinical trials supported by Takeda and Lundbeck. Drs Mahableshwarkar and Chen and and Ms Jacobsen are employees of Takeda. Dr Thase has been a consultant/advisor for Alkermes, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Dey, Forest, Gerson Lehman Group, GlaxoSmithKline, Guidepoint Global, Lundbeck, MedAvante, Merck, Neuronetics, Novartis, Otsuka, Ortho-McNeil, Pamlab, Pfizer, PGx Health, Shire, Supernus, Takeda, and Transcept; has received grant support from the Agency for Healthcare Research and Quality, Eli Lilly, Forest, GlaxoSmithKline, National Institute of Mental Health, Otsuka, and Sepracor; has participated as a speaker for AstraZeneca, Bristol-Myers Squibb, Dey, Eli Lilly, Merck, and Pfizer; has equity holdings in MedAvante; and receives royalties from the American Psychiatric Foundation [Guilford Publications].
This study was supported by the Takeda Pharmaceutical Company, Ltd, as part of a joint clinical development program with H. Lundbeck A/S. Assistance with writing and manuscript preparation was provided by Sara Sarkey, PhD, an employee of the Takeda Pharmaceutical Company.
A randomized, double-blind, placebo-controlled 8-week trial of the efficacy and tolerability of multiple doses of Lu AA21004 in adults with major depressive disorder.
by Henigsberg N, Mahableshwarkar AR, Jacobsen P, Chen Y, and Thase ME.
Journal of Clinical Psychiatry. 2012 73:953-959.
OBJECTIVE: Lu AA21004 is an investigational multimodal antidepressant. This randomized controlled trial evaluated the efficacy and tolerability of multiple doses of Lu AA21004 versus placebo in adults with major depressive disorder [MDD].METHOD: Adults diagnosed with MDD [based on DSM-IV-TR criteria] with a Montgomery-Asberg Depression Rating Scale [MADRS] score ≥ 26 were randomly assigned [1:1:1:1] to receive Lu AA21004 1 mg, 5 mg, or 10 mg or placebo for 8 weeks [between August 2008 and August 2009]. The primary endpoint was reduction in 24-Item Hamilton Depression Rating Scale [HDRS-24] total score after 8 weeks of treatment compared with placebo for Lu AA21004 10 mg. Additional outcomes included response and remission rates, Sheehan Disability Scale [SDS], Clinical Global Impressions-Global Improvement scale [CGI-I], MADRS total score, and HDRS-24 total score in subjects with baseline Hamilton Anxiety Rating Scale [HARS] score ≥ 20. Adverse events were assessed throughout the study.RESULTS: A total of 560 subjects [mean age = 46.4 years] were randomized. There was a statistically significant reduction from baseline in HDRS-24 total score at week 8 for Lu AA21004 10 mg vs placebo [P < .001]. There were improvements [nominal P values < .05 with no adjustment for multiplicity] in HDRS-24 total score, response and remission rates, CGI-I score, MADRS total score, and HDRS-24 total score in subjects with baseline HARS score ≥ 20 at week 8 for all Lu AA21004 treatment groups vs placebo. No significant differences were seen in SDS scores between any dose of Lu AA21004 and placebo. The most common adverse events were nausea, headache, and dizziness.CONCLUSIONS: After 8 weeks of treatment with Lu AA21004 10 mg, there was a significant reduction in HDRS-24 total score compared with placebo in adults with MDD. Lu AA21004 was well tolerated in this study.ClinicalTrials.gov identifier: NCT00735709.
Investigative Depression Drug Does Better in Europe than United States
by Deborah Brauser
May 18, 2011
"The multidose study gives us reason to think that this particular compound may indeed have value and there may be a range of doses that are valuable," investigator Michael Thase, MD, professor of psychiatry at the University of Pennsylvania School of Medicine in Philadelphia, told Medscape Medical News. He reported that before conducting that study, the investigators speculated that the 5- and 10-mg doses of Lu AA21004 would do well but were pleasantly surprised when the 1-mg dose was effective also.
As for the second study, Dr. Thase said he’s not sure if it failed because of the dose assessed "or because many studies fail in the US right now. "That study humbles us because even half the studies of drugs that we know work have failed to show they work in the United States. And this is partly because the placebo response has been growing dramatically over the last 30 years."He said placebo response rate was around 20% in 1970 and is about 45% now. "Anytime the placebo response in a depression study goes over 40%, the chance of the study failing goes well over 50%. And the US study did have a high placebo response rate," said Dr. Thase. "Although we won’t know more until there are 3 or 4 or 5 more studies, our [multicountry] trial gives us reason to believe we’re on the right track with this multiaction agent. And the US study tells us it’s just not easy to demonstrate that an antidepressant works under these circumstances"…
Why even bother to vet a 4 year old study presented two APAs ago? It’s time for a change in the clinical trials for psychiatric medications. The presentation of these industry studies is so uniformly jury-rigged that they ought to be banned from our peer reviewed literature. Attempts at reform like clinicaltrials.gov have failed because the companies just don’t post the results. There’s now a move afoot to insist that they publish their raw data [AllTrials] which would be the only way to really vet the studies instead of just pick at them as I have done here and in academic?…. And this practice of pulling in a quaisi-academic KOL who is as experience distant from the study as the reader is just inappropriate theatrics.
Dr. Thase’s comments about the placebo effect, particularly in the US, are delivered with irritation [at who knows what]. In my way of thinking, it can only reflect that the study subjects weren’t particularly ill in the first place – a recruitment issue that says something about the whole CRO enterprise. But back to why vet these studies. Right now, the FDA is considering this drug for approval based on four later studies that are yet unpublished and have no results posted on clinicaltrials.gov [way past time…]. They are industry funded, likely CRO run studies just like these. They were presented at the 2013 APA just like these. They were discussed by an apparently uninvolved quaisi-academic KOL just like these.