Investigating the Miracle Biologic Lecanemab for Alzheimer's Disease - Part 5
Lecanemab’s Phase 3 trial: ethics, flip flops and EMA’s decision
Ethics
The phase III trial BAN2401-G000-301 was registered in EudraCT (the EU register) and given the Number 2018-004739-58
In the US ClinicalTrials.gov, you find it here under the number NCT03887455 “A Study to Confirm Safety and Efficacy of Lecanemab in Participants With Early Alzheimer's Disease (Clarity AD)”
It’s not unusual for the TTE office researchers (that’s Tom and Carl, Carl and Tom) to find some strange stuff. Click on the EUDRACT link above and scroll down to N, and you will find the following timeline for ethics clearance:
The date on which this record was first entered in the EudraCT database: 2019-04-01
Date of Ethics Committee Opinion: 2019-06-12
Date of Competent Authority Decision: 2019-05-15
If you like reading comics, the NEJM report states that 5,967 persons were screened, and 1,795 underwent randomisation at 235 sites in North America, Europe, and Asia from March 2019 through March 2021 (our emphasis). So, the ethics come after recruitment starts.
Flip-flopping outcomes
Take a look at the Trials.gov entry
It says:
First submitted 21 March 2019 2019-03-21
First Submitted that Met QC Criteria 21 March 2019
First Posted 25 March 2019
The 1st version of the trial registry on trials.gov is Version 1: 21 March 2019. It reports four primary outcomes:
Core Study: Change from Baseline in the CDR-SB at 18 Months
Extension Phase: Number of Participants with Treatment-emergent Adverse Events (TEAEs) [ Baseline up to Month 45]
Extension Phase: Change from Core Study Baseline in CDR-SB [Baseline up to Month 45]
Extension Phase: Change from Core Study Baseline in Cerebrospinal fluid (CSF) biomarkers (neurogranin, NFL, Aβ[1-42], t-tau, and p-tau) [Baseline up to Month 45]
We also count 14 changes to the registry entry.
We have seen that the primary outcome changed from trial 201 to 301. This is called outcome switching and it is one of the many manipulations that can be carried out apparently without regulators raising objections.
You can track outcome switching here.
EMA’s decision
Well not quite. In July 2024 the EMA refused marketing authorisation for the following reasons:
The manufacturer has appealed and this is where the media and patient organisations come in. A bit of pressure on EMA will not go amiss. Maybe the odd politicker too?
But if EMA bounced it, what does this say about the decisions making at the MHRA?
This post was written by two old geezers whose view of a bleak future was somewhat lightened by the EMA decision - if they can stand political pressure.
Hey Peter, thank you for your comment. Yes ICH could have worked well. It’s a real shame.
The really disappointing aspect Carl and I were discussing today was the fact that we did not need to challenge the disease course modifying claim of the MAB. All we had to do is what you have read. And the ship started sinking fast. And there’s more to come.
Believe it or not, I regret this state of affairs very much.
Best, Tom
The EMA decision is well justified and succinctly put. I personally wouldn’t recommend this drug to a family member even despite Alzheimer’s being such a devastating condition. I’d rather the money was spent on supportive care and respite. Microbleeds from cerebral amyloid angiopathy (something I have only recently seen diagnosed in a living person) are also devastating and can lead to cumulative effects of worsening cognitive function and mobility so even if rare, if that is a potential risk it is not worth it for that negligible (if any) clinical difference of the drug, which is not an improvement anyway, rather a potential marginally slower decline. Im mystified how can the MHRA reach a different conclusion based on the same facts.