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

[Chicagogirl]

Visit 9 - Week 6 (4th infusion) - This infusion (every 2 weeks) is the 6th week since baseline infusion at Week 0

Took 2 tries to get the infusion line in, but "What is a couple of sticks between friends?" No adverse reactions.

The next day I had the scheduled MRI, which has to occur before Visit 10 - Week 8 (5th infusion). At times there is a muted sound like a jackhammer in the background.... but not as loud since I had special ear plugs and a covering over my ears that also helped to keep my head stable during the scan.

The results of the MRI (which will be compared to the original MRI that was needed for acceptance into the study) will determine my continued participation in the trial. The radiologist and the study doctor review the scan and then it goes to the Mayo Clinic for the final review.

Whether you are a participant in this trial or not, know you all are all warriors in this quest to find a solution for all of us. Till next time! Take care!

[Chicagogirl]

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MRI (Done before infusion #5) MRI # 2

The results of the MRI were reviewed by the radiologist and the study doctor before being sent to Mayo Clinic for final review.

They found no significant differences from the original MRI done. So, I continue in the study with Visit 10 being the full dose infusion.

Visit 10 - Week 8 (5th infusion) - This infusion (every 2 weeks) is the 8th week since the baseline infusion at Week 0.

This and all remaining infusions will be at full dose of either the drug or the placebo. Took 2 tries to get the infusion line in. Unfortunately, there was an hour wait for the medication/placebo to show up. It has to be ordered and delivered from a central location within so many hours of infusion time. There was a 2-hour observation period after the infusion before I could leave.

Next visit will be Visit 11 - Week 10 (6th infusion)

Whether you are a participant in this trial or not, know you are all warriors in this quest to find a solution for all of us. Till next time! Take care!

[NF52]

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MRI (Done before infusion #5)
The results of the MRI were reviewed by the radiologist and the study doctor before being sent to Mayo Clinic for final review.
They found no significant differences from the original MRI done. So, I continue in the study with Visit 10 being the full dose infusion.

So glad to hear that you had no signs of ARIA-E (edema) or ARIA-H (microhemorrhages) after your first four half-doses of either placebo or lecanemab. Afterr this first full-dose infusion, you should be able to go home after a half-hour monitoring, which includes a final blood pressure, pulse and temperature check. Hope they will wait to put the line in until the dose has arrived. Until then, I'm always enjoying coffee or water and a good book--and then the same, just one-handedly!

[Chicagogirl]

NF52 posted the chart below in a different thread in this forum. If you click on the image, you can see it better.

The W 2, etc. means Week 2 since the baseline visit (1st infusion at Week 0). The 5th infusion is at full dose, the prior infusions are at half dose.

Also, there are more MRIs after the 26th infusion. Chart just doesn't show.

I found it extremely helpful in helping me understand the timetable of the MRIs. Thanks NF52!

Hope you do too.

If you can't see the image here is the information:

MRI within 1 year prior to start of the trial
MRI prior to the 5th infusion (which is the first full dose infusion)
MRI prior to the 7th infusion
MRI prior to the 14th infusion
MRI prior to 26th infusion for select patients (I think this is for e4/4

At any time if symptoms suggest an ARIA occur there will be an MRI

MRI SCHEDULE_1.jpg

[Julie G]

I just wanted to share this encouraging study with our E4 friends who qualified for this trial. A University of California, Irvine-led team of researchers have discovered that the oldest-old, those who live to be 90+ and have superior cognitive skills, have similar levels of brain pathology as Alzheimer's patients. Just as the Nun Study previously showed, "AD" pathology may or may not be pathological. You can read the PR here.

[NF52]

I just wanted to share this encouraging study with our E4 friends who qualified for this trial. A University of California, Irvine-led team of researchers have discovered that the oldest-old, those who live to be 90+ and have superior cognitive skills, have similar levels of brain pathology as Alzheimer's patients. Just as the Nun Study previously showed, "AD" pathology may or may not be pathological. You can read the PR here.

I purchased the original article, available here: https://content.iospress.com/articles/j ... /jad221062.

Unfortunately, no information is included on ApoE status, so it is impossible to tell how many, if any, of these "Superior Global Cognitive Performers" (SGCP) had ApoE 4/4 or ApoE 3/4.

What the article does specify is that:

• Of 407 participants whose donated brains have been studied, only 117, or 26% of the total autopsied, had a "normal cognitive diagnosis" at the time of death (p.562).

• Of 102 in that "normal" group with an MMSE available, only 71 met the cut-off of MMSE at or above 28 to be "Superior Global Cognitive Performers" (SGCP) group: 16% of those autopsied.

• 84% of people in The 90+ Study who donated brains had diagnosed and/or autopsy-confirmed cognitive impairment.

• While most of SGCP group had amyloid on autopsy, they were mostly in the "low to intermediate" level.

The question I don't see answered is the one that made me enroll in the AHEAD prevention trial:
Can people with ApoE 4/4 who are found to have elevated amyloid on a PET scan in their 60's or early 70's live another 20-30 years and be cognitively healthy at the age of 93 without any treatment for that amyloid?

My beloved Scottish grandmother, a Phi Beta Kappa in 1903 and member of her college girl's basketball team at 5"3", played chess, ice-skated, grew her own vegetables, volunteered at a nursing home and lived independently into her late 80's. But she still died at age 93 thinking Richard Nixon had been her student as a HS math teacher and was bringing her ice cream. Maybe she had other pathologies; but I assume she had ApoE 4 and her presentation was classic AD. Even more concerning, my maternal uncle who died in his sleep at age 97 was the only one of 10 siblings who made it into his 90's without AD, Parkinson's, or vascular dementia. The rest lived with one or more of those for 6-18 years.

My own personal risk/benefit calculation is that amyloid beta oligomers and plaques, not the "normal" amyloid monomers, may be a "pathology" I should remove from my brain, in the same way I made sure to have a large pre-cancerous polyp surgically removed from my colon, at an age and with a family history on both sides that now makes my children eligible for colonoscopy screening at age 40. Sometimes our genetic inheritance is setting us up for early problems requiring early intervention, I believe.

As a corollary to a study of Super-Agers 90+, in the Leisure World Retirement Community of Orange County, here's a 2016 summary ofAssociation of Elevated Amyloid Levels With Cognition and Biomarkers in Cognitively Normal People From the Communityby the Mayo Clinic using the long-standing, highly stable Olmstead County, MN population and many more cognitive tests than the MMSE:

Objective To explore the effect of elevated amyloid levels on subsequent changes in cognition and biomarkers.

Design, Setting, and Participants A total of 564 cognitively normal individuals (median age, 78 years) from the Mayo Clinic Study of Aging, a population-based longitudinal study in Olmsted County, Minnesota, with serial cognitive data were selected for this study....Individuals included in this study had undergone magnetic resonance imaging...(FDG-PET), and Pittsburgh Compound B (PiB) PET at baseline, were not cognitively impaired at baseline and had at least 1 clinical follow-up. A subset of 286 individuals also underwent serial imaging. Elevated amyloid level was defined as a standardized uptake value ratio of greater than 1.5 on PiB PET

Results At baseline, 179 (31.7%) individuals with elevated amyloid levels had poorer cognition in all domains measured, reduced hippocampal volume, and greater FDG-PET hypometabolism. Elevated amyloid levels at baseline were associated with a greater rate of cognitive decline in all domains (0.04 to 0.09 z score units per year) except language and a greater rate of amyloid accumulation (1.6% per year), hippocampal atrophy (30 mm3 per year), and ventricular enlargement (565 mm3 per year). Elevated amyloid levels were also associated with an increased risk of mild cognitive impairment (hazard ratio, 2.9; 95% CI, 1.7-5.0;...for PiB+ [i.e. PET amyloid positive] APOE4 carriers .

Conclusions and Relevance In persons selected from a population-based study, elevated amyloid levels at baseline were associated with worse cognition and imaging biomarkers at baseline and with greater clinical decline and neurodegeneration.

With people already diagnosed MCI/mild AD in the CLARITY trial, it was a shock to see that 17% had ApoE 4/4: roughly 8X the odd ratio expected for 2% of those population with ApoE 4/4. This also happens to be close to the predicted Odds Ratio for ApoE 4/4s to develop Alzheimer's disease, compared to ApoE 3/3s. ApoE 3/4's were about 53% of the CLARITY population; about 2X their percentage of the population but perfectly in line with reported 2x odds of getting AD. Overwhelmingly, what they and their spouses talked about in the FDA hearing was "time saved" to the next stage of moderate dementia.

I hope for "time saved" to be cognitively normal; time will tell if I made the right bet.

[Julie G]

I hope for "time saved" to be cognitively normal; time will tell if I made the right bet.

My hope too. Please know that I think you and all in these trials are incredibly brave. The only reason I shared that study was to share encouragement and hopefulness, not to challenge you in any way.

[Chicagogirl]

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Visit 11 - Week 10 (6th infusion) - This infusion (every 2 weeks) is the 10th week since the baseline infusion at
Week 0.

It was a good day! The medication/placebo was delivered on time, and it only took 1 try to get the infusion line in. There was a one-hour observation period after the infusion before I could leave. Thanks to the study staff for such a pleasant visit.

Reported some very mild symptoms after the 5th infusion:

-Slight headache the 2 days after the infusion. If I was busy, I didn't notice. That is how slight it was.

-The day after the infusion I had 4-5 slight pings in my brain. It felt like someone flicked their finger at my head, but the feeling never lasted. Once it pinged it went away.

They will log it in my record for the study. I was also encouraged to report information like this to the study coordinator when it happens and not to wait until my next visit.

Upcoming MRI

I was already scheduled for the 3rd MRI next week on Monday. This one is scheduled before infusion #7, after my first 2 full-dose infusions (of the placebo or the actual drug).

Next visit (after the MRI) will be Visit 12 - Week 12 (7th infusion).

Whether you are a participant in this trial or not, know that we are all warriors in this quest to find a solution for all of us. Till next time! Take care!

[Chicagogirl]

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MRI #3 - Done after Visit 11 - 2nd full dose.

Had the MRI done this past Monday. This morning, Wednesday I received a call from the Study Doctor to inform me that I have brain edema, but no microbleeds.

We chatted for a while about the side effects I had reported at Visit 11, the results of the MRI and what would happen.

I confirmed that this meant that I was on Lecanemab, not the placebo. I feel fine and was surprised about the results. I continued to do my swim classes and my schedule hasn't changed.

I am not happy about the brain edema, BUT I am thankful that the protocols they have for the trial caught this early and that they can pause to monitor it. I also feel confident that the Study Doctor will follow this closely.

So, I will probably will not post as often as I was, until I hear further.

If any of you in the trial have had a "pause in the trial" or questions I would love to hear about it.

Whether you are participant in this trial or not, know that we all warriors in this quest to find a solution for all of us. Till next time! Take Care!

[NF52]

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MRI #3 - Done after Visit 11 - 2nd full dose.

Had the MRI done this past Monday. This morning, Wednesday I received a call from the Study Doctor to inform me that I have brain edema, but no microbleeds.

We chatted for a while about the side effects I had reported at Visit 11, the results of the MRI and what would happen.

I confirmed that this meant that I was on Lecanemab, not the placebo. I feel fine and was surprised about the results. I continued to do my swim classes and my schedule hasn't changed.

I am not happy about the brain edema, BUT I am thankful that the protocols they have for the trial caught this early and that they can pause to monitor it. I also feel confident that the Study Doctor will follow this closely.

So, I will probably will not post as often as I was, until I hear further.

If any of you in the trial have had a "pause in the trial" or questions I would love to hear about it.

Whether you are participant in this trial or not, know that we all warriors in this quest to find a solution for all of us. Till next time! Take Care!

HI ChicagoGirl,

Thanks for sharing your latest update. This is a great example of systems designed to monitor the safety of participants with frequent, early MRIs and "pausing" of infusions if ARIA occurs. As noted in the quoted "Appropriate Use" recommendations below (and in the AHEAD protocol), four half-doses (5mg/kg of weight) to titrate up, and then two full doses (10 mg/kg). Per protocols for AHEAD, you had three early MRIs:

• a baseline MRI to rule out observable multiple micro-hemorrhages or other contraindications

• an MRI after four half-doses (5mg/kg of weight) of "titration" and prior to the 5th infusion--first full dose of 10mg/kg

• an MRI after 2 full doses and prior to the 7th infusion

It's because of the data from CLARITY that your Study Site doctor can conclude that you are on Lecanemab, even though he, you, the Study Site staff and even the pharmacist at your site are technically still "blinded" as to your assignment. Your symptoms would suggest "mild symptomatic ARIA-E" since it sounds like you did not need to make any changes in your regular routine, nor do you require treatment with either oral or IV steroids, which are used in cases of severe edema, from my understanding.

I'm sure that no one goes into a clinical trial, or on any prescribed medication, hoping to have one of the listed side effects. Yet one of the benefits of the 1800 person Clarity trial was the experience of participants that allowed researchers to develop Lecanemab: Appropriate Use Recommendations, excerpted below. In my view show a clear focus on safety first and frequent, informed communication with the patient.

ARIA is typically mild-moderate radiographically, asymptomatic, or mildly symptomatic clinically, and self-limited (reversible)...Radiographic ARIA rates and the rates of ARIA with symptoms were substantially higher among patients with an APOE ε4 (APOE4) genotype, especially those homozygous for APOE4, compared to noncarriers (Table 5). In the CLARITY AD trial, the rate of ARIA in APOE4 noncarriers was 5.4%, in APOE4 heterozygotes it was 10.9%, and in APOE4 homozygotes the rate was 32.6%. Rates of symptomatic ARIA were 1.4%, 1.7%, and 9.2%, respectively. These observations support APOE genotyping of all patients (who agree) to inform risk discussions with treatment candidates and their care partners (discussed in more detail below). Table 5 shows the rates of ARIA-E and ARIA-H for the Phase 2 and the Phase 3 (CLARITY AD) lecanemab trials (2, 9)...
We recommend obtaining MRI scans prior to the 5th, 7th, and 14th infusions...In CLARITY AD, ARIA-E tended to occur early, with most episodes (71%) detectable on the first or second MRIs obtained at weeks 9 and 13. Eighty-one percent resolved spontaneously within 4 months of radiographic detection. Initial episodes of ARIA-E continued to occur on safety MRIs at 24 and 52 weeks in APOE4 carriers but were infrequent in non-carriers after week 13....
For those with moderate or severe radiographic ARIA or those with symptoms, lecanemab infusions should be suspended. Patients should receive careful clinical monitoring, management of symptoms, and monthly non-contrast MRI until ARIA-E resolves...

Once ARIA symptoms and radiographic ARIA-E changes resolve, restarting lecanemab can be considered based on a discussion of risks and benefits with the patient and family.

Enjoy a "pause" from infusions and posting; we'll be watching for any updates!