Trials and Tribulations: Does ADAPT Have to Adapt?
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When planning prospective clinical trials, one of trickiest challenges facing researchers lies in picking the right targets and drugs. In planning a prevention trial, for example, they must integrate strict safety requirements with data from existing research while also minimizing the possibility that future studies conducted during the trial’s multi-year duration will not call into question the original design.
This perennial problem was underscored recently, when the Washington-based consumer advocacy group Public Citizen sent an open letter to the Department of Health and Human Services, recommending that an ongoing 7-year AD prevention trial of two non-steroidal anti-inflammatory drugs be suspended. The letter charged that the drugs tested in this multicenter trial, naproxen and celecoxib, had insufficient scientific support and that the informed consent document used to enroll trial participants was inadequate. (See at http://www.citizen.org/publications/release.cfm?ID=7195.)
The Alzheimer Research Forum interviewed the study’s principal investigator, John Breitner of University of Washington, Seattle, about the issues underlying this letter. The Breitner Q&A and comments from 11 other scientists in the field appear below.-Gabrielle Strobel.
Q&A with John Breitner
Q&A with Todd Golde
Q&A with Greg Cole
Q&A with Karen Hsiao Ashe
Comment by Marcia Gordon
Q&A with Giulio Pasinetti
Comment by Pat McGeer
Comment by Curtis Meinert
ADAPT: Read the Official Response from NIA (.pdf) to Government Watchdog Group
References
Other Citations
External Citations
Further Reading
News
- Stockholm: Bad News Official: The Rofecoxib and Naproxen Clinical Trial Has Failed
- Stockholm: Not All NSAIDs Are Equally Good When it Comes to Alzheimer’s
- Early Clinical Results of Cox 2 Inhibitor: No Pain, No Gain?
- Large Prospective Study Finds NSAIDs Reduce Risk of Developing AD
- Anti-inflammatory Drugs Side-Step COX Cascade to Target Aβ
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Comments
Many of Sidney Wolfe's accusations of ADAPT are unfounded although I appreciate their caution that giving these drugs to elderly individuals can be potentially dangerous. I will focus only on those aspects that concern our work as I think our results have been misrepresented or misinterpreted.
First, NSAIDs are not secretase inhibitors, as claimed in the letter. They only modulated β-secretase activity by reducing Aβ42 in favor of shorter Aβ peptides. β-secretase inhibitors have their limitations as potential therapeutics, as well, through inhibiting notch cleavage, etc.
Second, the dosage of NSAIDs we had to use to achieve this effect is very high, a key issue we have to address scientifically. What's FDA approved and what were given in the Rotterdam study are likely much lower than what we gave to the mice. Therefore, whether very high doses are necessary and achievable in humans in order to see the Aβ42 effect remains to be proven. Consequently, making a strong conclusion that our results imply that it is the Aβ42 effect that underlies the proposed beneficial effects of NSAIDs in humans is a stretch, to say the least.
Third, we have never discounted the inflammatory responses. We never claimed the inflammatory responses are a result of AD. Even if the inflammatory responses are secondary doesn't mean that modulating these responses cannot alter the risk for AD or the disease course. It is likely that AD treatment must be approached via different angles.
Finally, reanalysis of the Rotterdam study did not take into account our results of all the FDA-approved NSAIDs. The authors assumed that all compounds not mentioned as positive must therefore be negative, which is incorrect (though not their fault, we just didn't have all the data when our Nature paper came out). Even if true, Wolfe ignored the fact that the confidence level is a lot lower in the reanalyzed data.
German Center for Neurodegenerative diseases (DZNE)
Dear John,
I have read the public letter sent by the US advocacy group Public Citizen to the Department of Health and Human Services, asking its secretary Tommy Thompson to suspend the ADAPT trial. I appreciate the important watchdog function of lay and patient organizations, yet if they make scientific judgments these should be thoroughly founded. I profoundly disagree with the interpretation of the existing evidence and the scientific argument in mentioned letter. The authors of the letter partly base their opinion on our research findings from the Rotterdam Study, which is why I would like to comment on their arguments and give you my current views on whether anti-inflammatory drugs might be beneficial in the prevention of Alzheimer's disease.
Public Citizen postulates that there is no longer any biological basis for the ADAPT trial. Their arguments include that 1) the inflammatory hypothesis of AD no longer holds and Aβ accumulation is central to Alzheimer's disease; 2) there is convincing evidence now that some NSAIDs do lower Aβ, whereas others do not; and 3) the NSAIDs that are being used in the ADAPT trial were not effective in preventing disease progression.
1. The inflammatory hypothesis no longer holds…
There is ample evidence that inflammation processes do play a role in Alzheimer's disease. Whether inflammation is causal, contributes to the progression of the disease, or merely marks the ongoing pathologic process is unclear. The fact that amyloid deposition in the brain triggers a local inflammatory response does not preclude that inflammation may contribute to disease initiation or progression. Our observation in the Rotterdam Study that persons with higher high plasma levels of inflammatory proteins were at an increased risk of dementia and Alzheimer's disease is compatible with inflammation contributing to the pathogenesis of dementia.
It is highly likely that Aβ accumulation in the brain does play a central role in Alzheimer's disease. However, what causes this accumulation in the majority of cases is largely unclear. Alzheimer's disease is a multifactorial and heterogeneous disorder. This implies that there is no single cascade of events that ultimately leads to the clinical syndrome. Moreover, it implies that there may be different mechanisms on which one could intervene to prevent or delay onset of disease.
Most basic research focuses on specific Alzheimer pathology. However, there is now convincing evidence that the larger proportion of elderly dementia patients actually has a mixture of degenerative as well as vascular pathologies in their brains that may all have contributed to the clinical syndrome. Prevention of vascular pathology may be an effective strategy to postpone onset of clinical Alzheimer's disease. Since inflammation is involved in the occurrence and progression of atherosclerosis, anti-inflammatory strategies might prove effective in the prevention of Alzheimer's disease through an effect on vascular pathology.
2. Some NSAIDs lower Aβ, others do not.
Observations that some specific NSAIDs do have an effect in vitro or mice on amyloid processing are extremely interesting. However, they do not rule out that those or other NSAIDs may also have effects on different yet relevant mechanisms. Also, it is unknown whether the NSAIDs that lowered Aβ have an effect on amyloid processing in humans.
Triggered by the cell culture and mouse observations, we re-analyzed the Rotterdam Study data. Our findings in that re-analysis are compatible with the view that different NSAIDs may have different effects on risk of Alzheimer's disease. However, our findings should be interpreted carefully. As in any observational study, there may have been residual confounding. Also, we had limited power. The lab and epidemiological data strongly suggests that this is a research area that merits further investigation.
As yet there is no proof that lowering Aβ levels reduces the risk of Alzheimer's disease, nor that that might be achieved through specific NSAIDs.
The NSAIDs being used in ADAPT were ineffective in preventing disease progression. The fact that a drug is not effective in stopping progression of overt disease does not imply that the drug may not be effective at a completely different stage. Indeed, since different processes are likely to be involved at different stages of the disease, it is to be expected that drugs that prevent onset of disease have no effect on disease progression and vice versa.
USC Alzheimer’s Therapeutic Research Institute
I have read the letter and was quite distressed by it. I am not involved in the ADAPT, though I have had a number of discussions with John Breitner about it, and have shared data from the ADCS NSAID study with the ADAPT investigators. Also, I was involved with the NIA review of the ADAPT application.
I would describe the letter as an inflammatory tirade rather than a scientific argument. While it does review some relevant scientific observations, the discussion is one-sided. I do not agree with the conclusions and recommendations of the letter. Celecoxib and naproxen were chosen based on a number of considerations, including epidemiologic data suggesting that NSAIDs reduce the risk of AD, and basic research suggesting that a number of inflammatory processes, including cyclooxygenase activity, may contribute to neurodegeneration in AD, as well as tolerability issues.
The recent evidence suggesting that a subset of NSAIDs favorably influence AβPP processing is quite interesting, and may be important. But it represents one recent addition to a huge body of data on inflammation and anti-inflammatory drugs in AD. I believe that this new line of evidence warrants further investigation, perhaps including clinical studies.
It is quite difficult, though not necessarily impossible, to alter a large clinical trial that is under way. One major issue is expense: it would require a huge additional investment to add an ibuprofen arm. Indomethacin would probably not be a good choice, because of toxicity concerns. Ibuprofen or sulindac would be preferable. I believe that discussion of additional trials that would test the hypothesis that ibuprofen or sulindac can favorably alter the course of AD is appropriate at this time.
Former professor at UCSD
The addition of a third arm with ibuprofen is a consideration. It would be logistically difficult but possible to do. The real question is does ibuprofen make any more sense than naproxen since tolerated doses over five years may well be too low to block formation of Aβ42.
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