Dominantly Inherited Alzheimer Network Trial: An Opportunity to Prevent Dementia. A Study of Potential Disease Modifying Treatments in Individuals at Risk for or With a Type of Early Onset Alzheimer's Disease Caused by a Genetic Mutation.
Condition: Alzheimers Disease; Dementia; Alzheimers Disease, Familial
MeSH terms: Alzheimer Disease; Dementia
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      The purpose of this study is to assess the safety, tolerability, biomarker and cognitive
      efficacy of investigational products in subjects who are known to have an Alzheimer's
      disease-causing mutation by determining if treatment with the study drug slows the rate of
      progression of cognitive impairment and improves disease-related biomarkers.

      This is an analysis study for an MPRP: DIAN-TU-001 Master NCT01760005
    

Detailed description: 
      The mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2) and amyloid precursor protein
      (APP) that are associated with dominantly inherited Alzheimer's disease have very high
      penetrance (near 100%). This study will target individuals who are either known to have a
      disease-causing mutation or who are at risk for such a mutation (the child or sibling of a
      proband with a known mutation) and unaware of their genetic status. Because the age at onset
      of cognitive changes is relatively consistent within each family and with each mutation, an
      age at onset is determined for each affected parent or mutation. This study will enroll
      subjects who are either asymptomatic and are within a specific window of time of expected age
      at onset for their family and/or mutation or who have symptoms of mild Alzheimer's disease.

      The ability to identify individuals destined to develop Alzheimer's disease (AD) within the
      next 10-15 years with a high degree of confidence provides a unique opportunity to assess the
      efficacy of therapies while individuals are asymptomatic and/or very early stages of
      dementia. Families with known disease-causing mutations are extremely rare and are
      geographically dispersed throughout the world. These constraints necessitate a specialized
      study design. Many of the subjects in this study will not yet have any cognitive symptoms of
      AD; they will be "asymptomatic" carriers of mutations that cause dominantly inherited
      Alzheimer's disease and would be expected to perform normally on standard cognitive and
      functional testing. Imaging and fluid biomarkers will be used to demonstrate that the
      treatment compounds have engaged their therapeutic targets. A set of cognitive measures
      designed to assess the very earliest and most subtle cognitive changes will be collected.
      Additionally, because many at-risk individuals decide not to know whether they have the
      disease-associated mutation or not, some of the at-risk individuals enrolled in this study
      will not have the disease causing mutations; they will be "mutation negative". It is
      important to enroll non-carrier subjects to avoid coercion (e.g., potential subjects may be
      pressured into genetic testing to learn their genetic status in order to be eligible for the
      trial). These mutation negative individuals will be assigned to the placebo group; and will
      not be included in the primary efficacy or futility analyses. Subjects and site study staff
      will remain blinded as to these individuals' active or placebo group assignment and mutation
      status. Thus, the study will be double blinded for placebo and for mutation status, except
      for mutation positive subjects who are aware of their genetic status. There may be
      exceptional circumstances when required by local regulation or health authorities where
      enrollment may be restricted to mutation carriers only but such mandates will be thoroughly
      documented and agreed upon by the governing regulatory agency and sponsor. Several different
      therapies (each referred to as a study drug arm) will be tested in order to increase the
      likelihood that an effective treatment will be discovered. The compounds are selected for
      this trial based on mechanism of action and available data on efficacy and safety profile.

      The study design includes a pooled placebo group shared by all study drug arms. Mutation
      positive subjects will be assigned to a study drug arm and subsequently randomized within
      that arm in an overall 3:1 ratio to active drug:placebo. Mutation negative subjects will all
      receive placebo treatment. Importantly, subjects and study staff will not be blinded as to
      which study drug arm (gantenerumab or solanezumab) each subject has been assigned; they will
      be blinded as to whether subjects have been randomized to active drug or placebo. Biomarker
      data will be analyzed for pre-specified endpoints consistent with the drug's mechanism of
      action and known effects on the tested biomarkers. The primary cognitive endpoint will be the
      same for all study drug arms. This study is an adaptive platform based study. Interim
      analyses of the imaging or fluid biomarker endpoint will assess safety and whether each study
      drug engages its biological targets. This biomarker approach is particularly important in
      this study as most study subjects will be cognitively normal at baseline and most will remain
      cognitively normal during the first 2 years of the study. The cognitive composite is designed
      to assess subtle cognitive changes that may be detectable before the onset of dementia. The
      cognitive multivariate disease progression model (MDPM) endpoint design will allow for
      detection of these subtle cognitive changes.
    

Intervention name(s): Gantenerumab; Solanezumab; Matching Placebo (Gantenerumab); Matching Placebo (Solanezumab)
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): Subcutaneously every 4 weeks at escalating doses; Intravenous infusion every 4 weeks at escalating doses; Subcutaneous injection of placebo every 4 weeks; Intravenous infusion of placebo every 4 weeks
Other intervention name(s): RO4909832; LY2062430
Intervention MeSH terms: Antibodies, Monoclonal
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Interventional
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Alzheimer's; Alzheimer's Disease; Dementia; Mutation; Genetic Mutation; Dominantly Inherited Alzheimer's Disease; Dominantly Inherited Alzheimer Network; Autosomal Dominant Alzheimer's Disease; Early Onset Alzheimer's Disease; DIAN; DIAN-TU; DIAN TU; DIAD