From the get-go, it was clear that the small number of participants would place restraints on scientists’ ability to power clinical trials. But as word about DIAN began to spread in other countries, scientists and families there became interested as well, opening the prospect of larger, more powerful trials. Last July at the 2011 Alzheimer’s Association International Conference (AAIC) in Paris, France, some 25 physician-researchers from a dozen European countries and Canada met with Bateman, DIAN’s principal investigator John Morris of Washington University, and other DIAN leaders for a dialogue on making DIAN trials more broadly available. As it turned out, 17 European research sites said at this gathering that they are working with 145 families including some 300 asymptomatic and 180 symptomatic individuals, many of whom may well be interested in participating in trials, Bateman told the pharma consortium at the October meeting in Washington. There may be even more families in Europe. In fact, at AAIC, researchers from several European groups independently presented data on autosomal-dominant families. For example, David Wallon from INSERM in Rouen, France, presented a poster with Dominique Campion and other geneticists from across France, which characterized 143 families with early-onset AD. Of those, 83 had a presenilin 1 mutation, 15 had an APP mutation, 12 had an APP duplication, and for 25 families the genetic reason for their disease is presently unknown. In these French families alone, 314 relatives are at risk for their parent’s disease, and 31 have chosen to find out their genotype after genetic counseling, Wallon told Alzforum.
It is not clear yet whether any additional European sites besides London will become bona fide DIAN sites, start up their own studies, or simply decide to offer DIAN treatment trial participation to their families regardless of whether that family participates in a requisite observation study. To enable trial participation, DIAN intends to launch an expanded registry website hosted at WashU with links from the DIAN website, from Alzforum, the Alzheimer’s Association, and national AD organizations in Europe. Through this registry, families with autosomal-dominant AD or their physicians can take first steps toward participating in a DIAN clinical trial. They can contact the DIAN research coordinator to obtain information; if needed, submit a saliva sample for confidential testing of whether an autosomal-dominant mutation indeed runs in the family; and then be matched to appropriate prevention and treatment trials within DIAN if they wish, Bateman said.
How to Test Drugs in This Unique Population?
Trial design took up much discussion at the pharma consortium meeting. In general, there was great interest in flexible designs that use run-in data from the observational period of DIAN to assess intra-individual change, as well as in trials with some adaptive elements roughly modeled after the I-SPY 2 process of breast cancer trials (see ARF related news story on adaptive trials). There are still many open questions and restraints. For example, it’s not decided yet up to what stage early symptomatic participants will be eligible. And even with the expanded registry, sample sizes will remain small enough so that most dose finding will have to have happened in company-run trials of each drug prior to the DIAN trials. That said, a draft design has taken shape, and the grant application DIAN scientists submitted to the NIA in October 2011 articulates it. The grant proposes a two-phase study backed by letters of support from the three companies whose drugs are named in the application, as well as support from the Alzheimer’s Association, ADCS, Alzheimer’s Disease Neuroimaging Initiative (ADNI), DIAN participants, and multiple external scientists. The first phase would determine whether the drug engages its intended target and whether it affects any downstream biomarkers of neurodegeneration. It would do that primarily by imaging whether amyloid deposition changes in response to the drug, and secondarily by comparing cognitive performance, biofluids, and other imaging markers before and after drug. The second phase would then look for a cognitive benefit of treatment, using primarily a to-be-determined composite panel of tests that are sensitive at that early stage, and secondarily, biochemical and imaging biomarkers of AD pathology and neurodegeneration, for example, MRI.
Importantly, the first phase would compare three different drugs to a shared placebo group. Each drug arm would enroll 80 people, assigning non-carriers to placebo to maintain genetic status blinding, and randomizing mutation carriers to drug versus placebo in a 3 to 1 ratio (a 75 percent chance of receiving drug). This design reconciles the twin dilemmas whereby participants may not want to find out their mutation status in order to join a trial, yet scientists do not want to randomize too many carriers to placebo or non-carriers to drug, either. That is because carriers lose time on placebo and non-carriers expose themselves to needless procedures, adding risk to themselves and cost to the study while adding little information to the study. In the proposed design, three groups of 30+ carriers each would receive one of three chosen investigational drugs, while the others would be pooled into one shared placebo group.
This first phase would go on for two years, at which point drugs that met primary aims would be considered for longer-term cognitive endpoint studies. Those drugs would then be tested in the entire population for three more years. Such a larger, longer trial is necessary for this second phase because its cognitive endpoints are likely to be subtle and change slowly in asymptomatic or very mildly symptomatic family members. If none of the three drug hits its target or a downstream biomarker in the first four-arm phase, then it would also likely fail to provide a cognitive benefit later on. Three new drugs would then be chosen for a second stab at Phase 1. In their grant, the DIAN scientists named three of the 12 drugs nominated to date by the participating pharma companies for this plan, but could not say which ones they are at this time.
The price tag for this plan? Sixty million dollars over five years. The NIA, so the DIAN scientists hope, will pitch in $3 million per year, and each sponsor of the three drugs would pay for one of the remaining thirds.—Gabrielle Strobel.
This is Part 1 of a three-part series. See also Part 2 and Part 3. Download a PDF of the entire series.