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. Master Protocol DIAN-TU001

Sponsor

Washington University School of Medicine (Other)

Overall Status

Recruiting

CT.gov ID

NCT01760005

Collaborator

Eli Lilly and Company (Industry), Hoffmann-La Roche (Industry), Alzheimer's Association (Other), National Institute on Aging (NIA) (NIH), Avid Radiopharmaceuticals (Industry), Accelerating Medicines Partnership (AMP) (Other)

490

Enrollment

Locations

Arms

115

Anticipated Duration (Months)

12.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Alzheimers Disease Dementia Alzheimers Disease, Familial	Drug: Gantenerumab Drug: Solanezumab Drug: Matching Placebo (Gantenerumab) Drug: Matching Placebo (Solanezumab) Drug: Gantenerumab	Phase 2/Phase 3

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 (Ryman, Acosta-Baena et al. 2014), 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.

A cognitive run-in (CRI) period may open for recruitment if no study drug arm is available for immediate enrollment, or if a treatment arm is stopped prior to the planned completion (e.g., at biomarker interim, drug toxicity). The CRI period will enhance study enrollment by identifying eligible subjects and engaging them with the cognitive process, and can reduce fluctuations in practice effects by allowing subjects to become accustomed to the testing process.

For the solanezumab and gantenerumab double blind treatment arms: Primary Completion Date= Nov 2019 and Study Completion= March 2020 (NCT04623242)

An open-label extension for gantenerumab is enrolling by invitation under this master protocol. Primary Completion Date= Sept 2024

Study Design

Study Type:

Interventional

Anticipated Enrollment :

490 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Interventional with a non-interventional run-in component (Future interventions to be added)Interventional with a non-interventional run-in component (Future interventions to be added)

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

One arm is Open-label as noted in the arm descriptions

Primary Purpose:

Treatment

Official Title:

A Phase II/III Randomized, Double-Blind, Placebo-Controlled, Cognitive Endpoint, Multi-Center Study of Potential Disease Modifying Therapies in Individuals at Risk for and With Dominantly Inherited Alzheimer's Disease

Actual Study Start Date :

Dec 1, 2012

Anticipated Primary Completion Date :

Jul 1, 2022

Anticipated Study Completion Date :

Jul 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Gantenerumab	Drug: Gantenerumab Subcutaneously every 4 weeks at escalating doses Other Names: RO4909832
Experimental: Solanezumab	Drug: Solanezumab Intravenous infusion every 4 weeks at escalating doses Other Names: LY2062430
Placebo Comparator: Matching placebo (Gantenerumab)	Drug: Matching Placebo (Gantenerumab) Subcutaneous injection of placebo every 4 weeks
Placebo Comparator: Matching Placebo (Solanezumab)	Drug: Matching Placebo (Solanezumab) Intravenous infusion of placebo every 4 weeks
No Intervention: Cognitive Run-in
Active Comparator: Gantenerumab Open Label Extension Subcutaneously every 4 weeks at escalating doses	Drug: Gantenerumab Open-label administered Subcutaneously every 4 weeks at escalating doses Other Names: RO4909832

Outcome Measures

Primary Outcome Measures

Assess cognitive efficacy in individuals with mutations causing dominantly inherited AD as measured by the change from baseline in the DIAN-Multivariate Cognitive Endpoint (DIAN-MCE) [Baseline and Weeks 52, 104, 156, and 208]
The DIAN-Multivariate Cognitive Endpoint (DIAN-MCE) consists of 4 cognitive measures: Wechsler Memory Scale-Revised Logical Memory Delayed Recall Test, Wechsler Adult Intelligence Sale Digit Symbol Substitution Test (WAIS), International Shopping List Task (ISLT), Mini-Mental State Examination (MMSE)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Between 18-80 years of age
Individuals who know they have an Alzheimer's disease-causing mutation or are unaware of their genetic status and have dominantly inherited Alzheimer's disease (DIAD) mutation in their family.
Are within -15 to + 10 years of the predicted or actual age of cognitive symptom onset. For Cognitive Run-In (CRI): includes participants who are younger than 15 years prior to the expected age of cognitive symptom onset, in addition to those 15 years younger and no more than 10 years older than expected or actual age of cognitive symptom onset.
Cognitively normal or with mild cognitive impairment or mild dementia, Clinical Dementia Rating (CDR) of 0-1 (inclusive)
Fluency in DIAN-TU trial approved language and evidence of adequate premorbid intellectual functioning
Able to undergo Magnetic Resonance Imaging (MRI), Lumbar Puncture (LP), Positron Emission Tomography (PET), and complete all study related testing and evaluations.
For women of childbearing potential, if partner is not sterilized, subject must agree to use effective contraceptive measures (hormonal contraception, intra-uterine device, sexual abstinence, barrier method with spermicide).
Adequate visual and auditory abilities to perform all aspects of the cognitive and functional assessments.
Has a Study Partner who in the investigator's judgment is able to provide accurate information as to the subject's cognitive and functional abilities, who agrees to provide information at the study visits which require informant input for scale completion.

Exclusion Criteria:

History or presence of brain MRI scans indicative of any other significant abnormality
Alcohol or drug dependence currently or within the past 1 year
Presence of pacemakers, aneurysm clips, artificial heart valves, ear implants, or foreign metal objects in the eyes, skin or body which would preclude MRI scan.
History or presence of clinically significant cardiovascular disease, hepatic/renal disorders, infectious disease or immune disorder, or metabolic/endocrine disorders
Anticoagulants except low dose (≤ 325 mg) aspirin.
Have been exposed to a monoclonal antibody targeting beta amyloid peptide within the past six months.
History of cancer within the last 5 years, except basal cell carcinoma, non-squamous skin carcinoma, prostate cancer or carcinoma in situ with no significant progression over the past 2 years.
Positive urine or serum pregnancy test or plans or desires to become pregnant during the course of the trial.
Subjects unable to complete all study related testing, including implanted metal that cannot be removed for MRI scanning, required anticoagulation and pregnancy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama in Birmingham	Birmingham	Alabama	United States	35294
2	University of California San Diego Medical Center	La Jolla	California	United States	92037
3	USC Keck School of Medicine	Los Angeles	California	United States	90033
4	Yale University School of Medicine	New Haven	Connecticut	United States	06510
5	Emory University	Atlanta	Georgia	United States	30329
6	Advocate Lutheran General Hospital	Park Ridge	Illinois	United States	60068
7	Indiana University School of Medicine	Indianapolis	Indiana	United States	46202
8	Washington University in St. Louis	Saint Louis	Missouri	United States	63110
9	Columbia University	New York	New York	United States	10032
10	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213
11	Butler Hospital	Providence	Rhode Island	United States	02096
12	Texas Health Hospital	Arlington	Texas	United States	76011
13	University of Washington	Seattle	Washington	United States	98195
14	Instituto de Investigaciones Neurologicas Raul Carrea, FLENI	Ciudad Autonoma de Buenos Aire		Argentina	C1428AQK
15	Neuroscience Research Australia	Randwick	New South Wales	Australia	2031
16	Mental Health Research Institute	Melbourne	Victoria	Australia	3010
17	The McCuster Foundation of Alzheimer's Disease Research	Nedlands	Western Australia	Australia	6009
18	Hospital das Clínicas da Faculdade de Medicina da USP	São Paulo		Brazil	05403-000
19	UBC Hospital	Vancouver	British Columbia	Canada	V6T 2B5
20	Sunnybrook Health Sciences Centre	Toronto	Ontario	Canada	M4N 3M5
21	McGill Center for Studies in Aging	Verdun	Quebec	Canada	H4H 1R3
22	CHU de Quebec - Hôpital de l' Enfant Jésus	Québec		Canada	G1J 1Z4
23	Grupo de Neurociencias Sede de la Universidad de Antioquia	Medellín		Colombia
24	CHU de Toulouse - Hôpital Purpan	Toulouse	Haute Garonne	France	31059
25	Hopital Roger Salengro - CHU Lille	Lille	Nord	France	59037
26	Groupe Hospitalier Pitie-Salpetriere	Paris cedex 13	Paris	France	69677
27	Hopital Neurologique Pierre Wertheimer	Bron cedex	Rhone	France	69677
28	CHU de Rouen - Hôpital Charles Nicolle	Rouen	Seine Maritime	France	76031
29	Universitaetsklinikum Tubingen	Tübingen	Baden Wuerttemberg	Germany	72076
30	LMU-Campus Grosshadern	Muenchen	Bayern	Germany	81377
31	St Vincent's University Hospital	Dublin		Ireland	DUBLIN 4
32	IRCCS Centro San Giovanni di Dio Fatebenefratelli	Brescia		Italy	25125
33	Azienda Ospedaliera Universitaria Careggi	Firenze		Italy	50134
34	University of Tokyo Hospital	Bunkyō-Ku	Tokyo-To	Japan	113-8655
35	Instituto Nacional de Neurologia y Neurocirugia Manuel Velasco Suarez	Mexico	Distrito Federal	Mexico	14269
36	Brain Research Center	Amsterdam		Netherlands	1081 GM
37	University of Puerto Rico, School of Medicine	San Juan		Puerto Rico	00936
38	Hospital Clínic I Provincial de Barcelona	Barcelona		Spain	8036
39	The National Hospital for Neurology and Neurosurgery	London	Greater London	United Kingdom	WC1B 3BG