AHEAD 3-45 STUDY CLINICAL TRIAL (LECANEMAB - BAN 2401)

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SusanJ
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Re: AHEAD 3-45 STUDY CLINICAL TRIAL (LECANEMAB - BAN 2401)

Post by SusanJ »

Chicagogirl wrote:So the journey continues.......
Thank you for sharing your journey. Hoping it continues to be a worthwhile experience for you as the trial steps go forward.
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Re: AHEAD 3-45 STUDY CLINICAL TRIAL (LECANEMAB - BAN 2401)

Post by karelena »

Hi Chicagogirl!
I am also APOE 4/4 and enrolled in the AHEAD study. I was called yesterday and sadly my amyloid blood test was qualifying so I will have a 1B appointment, scheduled for the end of the month. I'm in California. I had also volunteered for the TRAILBLAZER study but did not qualify due to my tau blood test being too low.

I have been reading about the cognitive testing they do for appointment 1B, There is the MMSE, a score of > 27 is needed but that should be no problem, all the tasks are easy. Then there is a word memorization task called the "Free and Cued Selective Reminding" test where they show you 4 pictures and you pick the category for each of the words then they take the pictures away and you recall the words. It's 16 words, 3 times and if you don't remember then they remind you of the category. There is no disqualifying score for that one. The average normal adult recalls 7 of 16 in free recall and then another 8 with the category cues.

The other test that they are looking for a certain score, besides the MMSE, is the "Wechsler Memory Scale Logical subscale II" where they tell you a short story and then you have to recall as many details as you can, immediately and then again 20-30 minutes later. It's the 20-30 minute later score that counts for this study. The maximum possible score is 25 but they are looking for a score of 8-15, so it is possible to do too well on that one apparently, something to keep in mind. I understand why they do not want low scores but I am puzzled why a high score is a problem.

They will also give the digital symbol substitution test (from the adult Wechsler Intelligence Scale) where you have to code numbers for symbols as fast as you can. The highest possible score is 93 but average normal adult score is 45. This score does not affect qualification.

I'm not sure what other tests are done, they are calculating a score called the "Preclinical Alzheimers Cognitive Composite 5," and I just started reading about it today, after my bad news yesterday.

My study partner is my husband, they offered to do his consents over the phone so he doesn't have to take time from work.

Good luck with your 1B visit, let me know how it goes on this thread or by PM.
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Re: AHEAD 3-45 STUDY CLINICAL TRIAL (LECANEMAB - BAN 2401)

Post by J11 »

Karalena, I am not sure whether you need the help, though I wanted to tell you a trick that I just learned that helped in learning a sample ADAS-cog test.

In the below word recall list, I noticed that it was much easier to remember the words when I thought of them all as occurring in one place. Instead of thinking about the forest and lake as being somewhere else, it became so much easier for me when I thought of the girl in the temple and the forest and the lake as all part of one scene. Thought this might be helpful.

BOTTLE
 POTATO
 GIRL
 TEMPLE
 STAR
 ANIMAL
 FOREST
 LAKE
 CLOCK
 OFFICE
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Re: AHEAD 3-45 STUDY CLINICAL TRIAL (LECANEMAB - BAN 2401)

Post by J11 »

Karalena, I am interested in your thinking.

Lecanemab will be approved in less than 3 months.
At that time you could receive an off label prescription for Lecanemab; perhaps you might have to pay for it.
Yet, you would be guaranteed not to receive a placebo and you could choose whatever dosing schedule you liked.
Choosing your own dosing would mean that you could control the risk of ARIA side effects to what you felt comfortable with.

Do you feel that the AHEAD 3-45 is a better option relative to off label treatment?
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Re: AHEAD 3-45 STUDY CLINICAL TRIAL (LECANEMAB - BAN 2401)

Post by NF52 »

Karelena wrote:
J11 wrote: Thu Oct 13, 2022 10:23 pm Karalena, I am interested in your thinking.

Lecanemab will be approved in less than 3 months.
At that time you could receive an off label prescription for Lecanemab; perhaps you might have to pay for it.
Yet, you would be guaranteed not to receive a placebo and you could choose whatever dosing schedule you liked.
Choosing your own dosing would mean that you could control the risk of ARIA side effects to what you felt comfortable with.

Do you feel that the AHEAD 3-45 is a better option relative to off label treatment?
Hi J11,
I copied Karelena in on this to be sure she sees your question.

I won't respond for her, but from discussions I've had with people involved with AD clinical trials, including AHEAD, it seems very unlikely that lecanemab would be prescribed off-label to someone with normal cognition anytime soon. It seems likely to get full approval for use in MCI and mild AD in spring 2023, but no PCP would be willing to manage the need to get proof of amyloid plaques in the brain (not just on the Precivity blood test), followed by an MRI to rule out a large number of prior micro-hemorrhages (which would increase ARIA-H risk) and then the need to have a skilled infusion site with monitoring after each dose and knowledge of management for symptoms of ARIA, including when to suspend a dose and when to get an MRI to check for ARIA. (All those risks are small and manageable, including for people with ApoE 4/4 like Karelena and me, but I wouldn't want my lovely internist figuring this out on the fly.)

It also doesn't seem likely that anyone will get to choose their own dose; right now the dosing is based on weight for IV infusions. If subcutaneous dosing occurs, which seems likely at some point, it would likely be in pre-packaged syringes given biweekly with careful monitoring. And the estimated cost for lecanemab that I've seen is in the neighborhood of around $ 30,000/year, without factoring in MRIs, etc. So the ethical route seems to be to get evidence of efficacy and the FDA approval for prevention and then Medicare, Medicaid and insurance approval for use in appropriate preclinical populations, including those in under-resourced communities.

I think it's wonderful that Karelena is in screening for AHEAD; the more people enroll in that well-designed Phase III trial, the sooner the important question of the safety and effectiveness of lecanemab for prevention of cognitive impairment can be answered. By the time she would be at an age when she might be at risk for cognitive decline--15 years or more from now-- she will have helped to make sure we have a host of options.

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Re: AHEAD 3-45 STUDY CLINICAL TRIAL (LECANEMAB - BAN 2401)

Post by Chicagogirl »

karelena wrote: Thu Oct 13, 2022 8:54 pm Hi Chicagogirl!
I am also APOE 4/4 and enrolled in the AHEAD study. I was called yesterday and sadly my amyloid blood test was qualifying so I will have a 1B appointment, scheduled for the end of the month. I'm in California. I had also volunteered for the TRAILBLAZER study but did not qualify due to my tau blood test being too low.
Karelena..... So good to hear from someone else in the Lecanemab AHEAD 3 - 45 Study.

Thought I would document my journey for those who are considering this study:

VISIT 1B - Approximately 3 hours. (There is a 2, 3, 4, and 5 visit before acceptance into the study)


We (Husband & I) met with the Study Nurse for any other questions we might have and she went through the consent the Study Partner has to sign.

We were separated and I started the Cognitive assessments, while my Husband went with the Screener and was asked about my memory, etc and 2 events that we may have done in the past 3 months. After that was done, he could have left the center if needed. Screener then came in and asked vague questions about what we had been doing recently. She had quite a bit of facts and waited to see if I came up with them. If I didn't she nudged with questions, but never giving out the answer. She also asked about what I did with my time and whether I still participated in them at the same level I did a year ago. She also inquired about my assessment of my memory and if it had also changed in the past year.

The Study Nurse came back and did some more cognitive screening before passing me off to the infusion room.

They took my vitals, ECG and Physical and Neurological Exam.

The Study Nurse then explained that everything would be sent to central place who would review and make a decision whether I could proceed. She hopes to hear back in 2 weeks or so.

VISIT 2 will cover the following:

It will last approximately 2-3 hours. This is the Amyloid PET scan to measure the amount of amyloid buid-up in your brain using a tracer called NAV4694. Only individuals with intermediate or elevated amyloid levels will qualify to participate in one of the two branches of this trial: AHEAD 3 or AHEAD 45. Before the PET Scan begins, the radiotracer will be injected in a vein in your arm. You will then rest for approximately 50 minutes before having the PET Scan.

The AHEAD-3 Trial is for intermediate levels of amyloid in the brain. This group will come once every 4 weeks for the infusion. You will receive the actual drug or placebo.

The AHEAD-45 Trial is for elevated levels of amyloid in the brain. This group will come once every 2 weeks for the first 2 years, then every four weeks for the last 2 years. You will receive the actual drug or placebo.

Information received from the Study Partner's Consent Form:

How many visits?

Screening Stage 1B to sign the consent form and to answer questions about the study participant.

They may come to Screening Stage 3 where the participant receives the result of the Amyloid PET scan and the APOE genetic test (if you want).

Then there will be 5 additional visits over the next 4 years. Weeks 48, 96, 132, 168 and 216 (or an early termination visit). They prefer in-person visits but will accept over the phone visits.

Will study partner be paid?

They will be paid $50 for up to 7 study visits over the 4 years.

STAY TUNED - The Journey continues .......
Last edited by Chicagogirl on Sat Oct 15, 2022 8:11 am, edited 4 times in total.
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Re: AHEAD 3-45 STUDY CLINICAL TRIAL (LECANEMAB - BAN 2401)

Post by J11 »

Chicagogirl, what is your polygenic AD score? A high polygenic AD score could be considered e 444 (for a e44) while a low score would mean that a nominal e44 would be more similar to an e 34.

When you sign your consents, do you provide broad authorization for your biological samples to be investigated? For example, could your DNA be genotyped to determine the polygenic AD score without you being informed of this specific result or even that such a test were conducted?
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Re: AHEAD 3-45 STUDY CLINICAL TRIAL (LECANEMAB - BAN 2401)

Post by karelena »

J11 wrote:
When you sign your consents, do you provide broad authorization for your biological samples to be investigated? For example, could your DNA be genotyped to determine the polygenic AD score without you being informed of this specific result or even that such a test were conducted?
The consent form states "we will extract your DNA from your blood sample for genetic tests, including whole genome sequencing." They say they will disclose APOE status if a separate consent form is signed. If disclosure is chosen, they report this result at visit 3 when they also report the amyloid scan result. There is also an option on the consent form to agree to "blood and genetic samples may be stored and used for future research."

In response to your earlier question about just waiting for FDA approval and requesting a prescription off-label, I agree with NF52's response that the upcoming approval will be based on the previous studies, for MCI and AD and not pre-clinical AD with elevated amyloid. It will probably not be possible to have such an expensive and possibly problematic treatment (ARIA-E and ARIA-H risks are highest for APOE 4/4, as you know) prescribed off-label, or have the expense covered by insurance.

Yes, I would love to be able to administer the drug subcutaneous and have a potentially lower risk of ARIA due to lower peak concentration of subQ vs. IV infusion. But the subQ hasn't even started any trials yet.

I do have time to decide, as volunteer research subjects can withdraw from a study at any time. Also, I may still fail to qualify for this study, and even if qualified, I may receive placebo. I just think that it is likely that this drug class may be most effective as a preventive strategy and the only way to know is through a study like this. It may not be of benefit to me at all but may help future generations.
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Re: AHEAD 3-45 STUDY CLINICAL TRIAL (LECANEMAB - BAN 2401)

Post by J11 »

NF_52, thank you very much for your insight into the potential for off label use of Lecanemab. I had not been sure about this; though I am sure that there would be many who would be highly interested in off label use. I did realize how much problem this would cause the AHEAD trial if such prescriptions became widespread.

"Even critics of the amyloid hypothesis told Alzforum they would prescribe lecanemab, or even consider getting a PET scan themselves and trying to get access to the drug in an N-of-1 personal prevention mode."
alzforum October 7, 2022

That is what the critics have to say! I am very unsure how the wave of patients seeking off label use will be held back, when they realize what the experts who do not believe in the amyloid hypothesis have to say. Without such treatment, this will be so difficult after Lecanemab is approved and people with clear preclinical signs are expected to wait until the cognitive tests confirm that they have had enough neurodegeneration to officially qualify for mab treatment.

I don't see how the no off label use stance will be maintainable politically. By the time that one has achieved an official MCI diagnosis a large amount of brain harm has already occurred -- brain harm that still cannot be reversed.
I suspect that if people were to undergo serial MRIs of their hippocampus while it underwent atrophy as a result of the progression of preclinical AD, then this would be highly motivating for them to take proactive steps with off label mab treatment.

My impression is that fairly low doses of mabs could be applied to such patients. Those people who endogenously had very very low levels of Aducanumab never developed AD. It really might not be necessary to dose at gram scale with mabs when people are years away from disease onset. The no ARIA dose in mice was hundreds of times lower than the dose used in active treatment when frank dementing illness arose.

The clinical trials were constrained by racing against the clock within an 18 month trial to show efficacy while also having acceptable safety. With off label preclinical use, there might often not be the same urgency. People might be content to dose fairly modestly and have an objective of achieving zero amyloid possibly even years into the future. With such a dosing strategy, one could imagine that the risk of ARIA would be greatly reduced. Of course, it would be very helpful for clinical trials to establish exactly what dosing levels would be safe.

We know that the hippocampus undergoes shrinkage years before global dementia becomes apparent. These subjective memory complaints would be an obvious red flag of approaching Alzheimer's especially for those most genetically at risk. I am very unclear how the white line of not prescribing off label will hold. I think that it is fairly urgent that clinical trials be conducted that establish a safe dose (which would not cause ARIA) for mabs for these preclinical patients. There is a near certain chance that some will want to go off label, so I think from the harm reduction perspective it is only reasonable that this is acknowledged by conducting the necessary clinical trials.

In terms of Lecanemab's path to approval, I wonder whether full approval could even be advanced to the accelerated approval date. The press release for the topline of Clarity made no reference to the amount of amyloid clearance. Yet, anchoring the cognitive readout to the amyloid biomarker was the entire basis for accelerated approval. The stance has already subtly shifted to a readout exclusively on the p-value.

What is the safety protocol used in AHEAD to monitor for ARIA?

I am surprised that there does not seem to have been a plan to create a global central MRI reader site. I thought that this idea would gain traction after the fatality of the Canadian patient on Aducanumab possibly related to a low skill base for reading MRIs. It is very important that the MRIs are read correctly or serious consequences can occur. throwing this down to the local level does not seem to be the best strategy. They could upload the MRIs and a team of experts possibly with AI backup could do a high quality job that would be unmatchable by small or even medium sized imaging centers. This might be one of those times where patients could keep throwing money around until someone realizes how big the opportunity involved is and then responds appropriately.
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Re: AHEAD 3-45 STUDY CLINICAL TRIAL (LECANEMAB - BAN 2401)

Post by Julie G »

Quick reminder to the 4/4s who've tested positive for amyloid: As several of you have indicated, it's not unexpected (given our high risk) and doesn't always correlate with cognitive decline. remember the Nun Study. That said, you're still very brave to quantify and courageous to move forward with the study.

Perhaps because of the media storm proclaiming "historical" results with Lecanemab, I don't see a discussion about its efficacy.

1) Lecanemab does not improve cognition and does not stabilize Alzheimer’s. It simply slows decline in the early stages.
2) The slowing of decline was in between that of aducanumab (22% slowing in its best trial, none in another trial) and donanemab (32% slowing).
3) As mentioned by other posters, the side effects include brain microhemorrhage and brain edema. Thus some people may actually get worse instead of slowing their decline.
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