End of Trial and Open-Label Extension (OLE) Frequently Asked Questions (FAQ)

Last doses of study drug and study visits occurred in November 2019.  Safety follow-up visits occurred within 4-12 weeks after last dose of study drug.

Top level results of the current trial were announced on February 10^th, 2020 (see press release posted on the DIAN website at: https://dian.wustl.edu/our-research/clinical-trial/research-updates/).  Secondary analyses were presented to DIAD family members by Dr. Bateman via webinar on March 21^st, 2020, which is available to DIAD family members upon request to dianexr@wustl.edu.  A presentation of results to the scientific community was made in the first week of April, 2020, at the virtual ADPD meeting.

The level of success was determined by several different factors.  There is a measure called the primary outcome, which is the one thing that is used to determine whether the study is positive.  The level of effect was pre-specified (documented prior to study results or data analysis) in a detailed statistical plan that was agreed upon, approved, and shared with our partners, including regulatory authorities and others.  That is one of the main driving factors for measuring the drug(s)’ success; however, we also considered the other (secondary) outcome measures, which are the additional measures (tests) that were done during the trial. The amount of a drug’s effect, and any other information that we have from a trial, can be used to help determine whether a drug is beneficial or not.

The answer can be complicated and is not always a simple ‘success’ or ‘failure’.  There is a lot of information and degrees of success. The size of the effect we see can influence the decisions about continuing with the Open Label Extension.  In the case of both solanezumab and gantenerumab, the primary outcome was determined to be negative.  However, there were some positive biomarker measures of disease activity and progression in the trial.

Open Label Extension, or OLE, is a phase of a study that occurs after the randomized (blinded) portion of the trial is completed if a drug is found to have the potential for benefit.  Eligible trial participants take the active form of the drug without placebo.  OLE allows active drug to be given to all participants at the same time and to follow them over time.  OLE allows more scientific data to be collected and it offers the opportunity for participants who were previously on placebo to take the active drug.  OLE enables a trial to continue to measure the drug’s effectiveness, how long that effect may last, and if the effect will be sustained (continued).

Yes, there will be an exploratory OLE for gantenerumab. There will not be an OLE for solanezumab, but the participants in the solanezumab arm will also be eligible for gantenerumab OLE.

Although results of effect on cognitive measures (memory and thinking) were negative for both drugs, further analyses of trial data for gantenerumab demonstrated improvement in biomarkers of disease activity and progression, including measures of tauopathy and neurodegeneration. Gantenerumab reduced the pathology of amyloid plaques, reduced soluble cerebrospinal fluid (CSF) tau and phospho-tau, and slowed increases in the neurofilament light chain (believed to be a marker of neurodegeneration) when compared to placebo. Similar changes were not observed in participants in the solanezumab arm of the study.

Open Label Extension is planned to start during the second quarter of 2020 (April-June 2020) and may vary based on your particular site and/or country’s approval to do so.

The gantenerumab exploratory OLE is scheduled to last 2 years, however there are plans to extend the treatment to at least 3 years. Having the OLE period does not indicate that gantenerumab will be approved for DIAD, and there is the potential that the OLE period would be stopped/closed early.

It is scientifically best to start the OLE as soon as possible after the controlled trial. The COVID-19 pandemic is complicating the start of OLE, but we intend to initiate the OLE as soon as possible, offering it to all eligible participants in the randomized study. Once a participant can enroll in the gantenerumab Exploratory OLE, which we expect will be second to third quarter of 2020, the participant will have limited time to enroll. Once enrollment is complete, participants will not be able to join later.

By continuing the study of gantenerumab through an exploratory OLE, we hope to determine whether the drug can completely remove amyloid plaques as measured on PET scans and return to normal levels, and by doing so, determine if other pathologies related to disease progression (for example neurodegeneration) are substantially improved as well. It is possible that long-term improvement of amyloid levels by gantenerumab could have a benefit on cognition (memory and thinking) as well.

You may request to find out whether or not you were on placebo or active drug at the end of the OLE period. If you decide not to enroll in OLE, you may ask your principal investigator for the information at that time, however this would make you ineligible for OLE. The decision not to enroll in the OLE is final.

Additional information will be needed during the OLE that will help to determine the potential benefit of gantenerumab. Because of this, it is important to keep the OLE period of the trial as close to the original, blinded part of the trial as possible. If participants and site investigators find out who was on active drug or placebo during the blinded period of the trial, it could influence performance on important cognitive tests during the OLE period.

If you participated in the solanezumab arm, you will be able to enroll in the gantenerumab OLE. If you prefer, you may also decline participation in the OLE and instead, if you are eligible, enroll in the Cognitive Run-In (CRI) period of the next new drug study, which will later add a drug that targets the tau protein.

Individuals who participated in the blinded period of the trial may be eligible to continue in the OLE. Participants must know that they are positive for the Alzheimer’s disease-causing mutation, and the study doctor must confirm it is safe for each participant to receive active drug. You cannot join OLE if you did not participate in either the gantenerumab or solanezumab blinded drug arms.

Yes, since placebo will not be offered, only participants who know they are positive for the genetic mutation, and therefore have potential to benefit from the treatment, will be able to enroll into OLE to receive gantenerumab. Because only the active drug will be administered, there is no benefit for mutation negative participants to continue with study procedures.

It is possible that you could enroll into the Cognitive Run-In (CRI) period of the DIAN-TU trial, and the next/future drug arm(s), without learning your genetic status.

The design of the next tau studies have not been finalized. Several are planned, and it is likely they will be tau-only trials that will not allow concurrent experimental therapy such as gantenerumab. Thus, it is unlikely that you could participate in both the OLE and some future studies to be planned, including tau trials. However, the investigators and companies are interested in combination therapy, and will be exploring the possibility of a tau therapy combination that might be designed to include gantenerumab OLE participants.

Neurofilament light (NfL) is released from nerve cells in the brain called neurons when they are damaged, and NfL can be measured in the CSF and blood. In a variety of diseases which damage the brain, increased NfL is a marker of ongoing brain damage. NfL increases (goes up) in DIAD participants, and the treated group in our blinded study showed less increase than those on placebo suggesting that there is less brain damage. It is not known if NfL is related to potential delay in symptoms.

Both of these drugs (known as an antibody) remain in the body for five to six months after the last drug administration. This is why having a wash-out of 6 months is necessary. Because of this, you may continue to experience potential effects for months after you stop receiving doses. Changes in Alzheimer’s disease are generally slow, often measured in years, so we expect changes in your disease will not be large from going a few months without receiving drug. However, this is also why we hope to start the OLE as soon as possible since participants will have washed out prior drug, and we would like to maintain the effects for those who were already on gantenerumab.

Yes, you will have an annual site visit and monthly home health nurse visits to administer the drug and cognitive testing at certain visits.

Yes, a study partner will still be needed during OLE to complete assessments about your memory and thinking. This will help us continue to study the drug’s effect.

You will have cognitive testing every 6 months. There may be additional safety measurements including safety MRIs during drug escalation/titration (dose increase). At the annual visits, you will have a lumbar puncture, PET scans (PIB-PET, FDG PET, and AV-1451 tau PET), MRI, bloodwork, and clinical and cognitive testing. These assessments are designed to be very similar to the blinded portion of the trial.

Dose titration is the process of slowly increasing your dose of drug to minimize any potential side effects. Because you will not know whether you were on active drug or placebo in the blinded period, all participants will need to dose titrate/escalate and start at the lower dose and increase to the highest dose.

Contact your DIAN-TU site coordinator to request genetic counseling and disclosure of test results. You may receive genetic counseling remotely via phone and/or video chat (in-person counseling may also be requested, if available) and will not need to have a new blood draw. You will be able to receive results from genetic testing performed when you first enrolled in the trial. This process is only available for those eligible for the gantenerumab exploratory OLE. If you cannot reach your site coordinator, please contact the DIAN Expanded Registry at dianexr@wustl.edu.