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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT05552157




Registration number
NCT05552157
Ethics application status
Date submitted
19/09/2022
Date registered
23/09/2022
Date last updated
5/03/2024

Titles & IDs
Public title
A Study of Potential Disease Modifying Treatments in Individuals at Risk for or With a Type of Early Onset AD Caused by a Genetic Mutation
Scientific title
A Phase II/III Multicenter Randomized, Double-Blind, Placebo-Controlled, Two-part Adaptive Design, Platform Trial of Investigational Treatments for Primary Prevention of Disease Progression in Dominantly Inherited Alzheimer's Disease
Secondary ID [1] 0 0
5U01AG059798
Secondary ID [2] 0 0
DIAN-TU-002
Universal Trial Number (UTN)
Trial acronym
DIAN-TU
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Alzheimers Disease 0 0
Dementia 0 0
Alzheimers Disease, Familial 0 0
Condition category
Condition code
Neurological 0 0 0 0
Alzheimer's disease
Neurological 0 0 0 0
Dementias

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Gantenerumab
Treatment: Drugs - Matching Placebo (Gantenerumab)

Experimental: Part 1: Gantenerumab - Active gantenerumab- blinded

Placebo Comparator: Part 1: Matching placebo (Gantenerumab) - Matching placebo

Active Comparator: Part 2: Gantenerumab Open Label - Open label will start after last dose of Part 1


Treatment: Drugs: Gantenerumab
Subcutaneously every 4 weeks at escalating doses

Treatment: Drugs: Matching Placebo (Gantenerumab)
Subcutaneous injection of placebo every 4 weeks
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Part 1: Difference in change from baseline in amyloid deposition as measured by [11C]PiB-PET average cortical composite between active drug and placebo groups.
Timepoint [1] 0 0
Baseline and Week 208
Primary outcome [2] 0 0
Part 2: Odds ratio between treated group and the external control group of being in the lower biomarker disease progression stage based on two-stage modeling of 6 biomarkers.
Timepoint [2] 0 0
Part 2 Week 208

Eligibility
Key inclusion criteria
1. Informed consent form (ICF) is signed and dated by the participant and study partner,
or by the participant's legally acceptable representative (LAR) if applicable,
according to local regulations for the ICF and, if applicable, the DIAN-TU cognitive
run-in (CRI) ICF and/or country-specific ICFs.

2. Participant is at least 18 years old.

3. Women of childbearing potential, if partner is not sterilized, must agree to use
effective contraceptive measures (e.g., hormonal contraception, intra-uterine device,
sexual abstinence, barrier method with spermicide) from Screening visit (V1) until 16
weeks after last dose of study drug.

4. Participants must fulfill mutation status and EYO criteria:

1. Participant is a carrier of a mutation in an APP, PSEN1, or PSEN2 gene that is
associated with DIAD or does not know their mutation status and has a 50% chance
of having an AD-causing mutation (e.g., parent or biological sibling clinically
affected with known AD-causing mutation in family).

2. Participant is -25 to -11 EYO based on their mutation type or family pedigree
(refer to Global Manual of Operations for calculation of EYO).

Note: If the at-risk parent is deemed a non-carrier through confirmed genetic testing
at any time during the study, the participant will be withdrawn.

5. Cognitive status of participant is normal (CDR 0).

6. Participant's confirmed primary language is a DIAN-TU study-approved language.

7. Participant has adequate visual and auditory abilities to perform all aspects of the
cognitive and clinical assessments.

8. If participant is receiving stable doses of medication(s) for the treatment of
non-excluded medical condition(s) for at least 30 days prior to CRI Entry visit and
Screening visit (V1) except for medications taken for episodic conditions (e.g.,
migraine abortive therapy, antibiotics, and other medications for upper respiratory
and gastrointestinal ailments).

9. The participant has a study partner who in the PI's judgment can provide accurate
information as to the participant's cognitive and functional abilities, who agrees to
provide information at the study visits that require study partner input for scale
completion, and who signs the necessary ICF, if applicable.

10. The participant agrees not to donate blood or blood products for transfusion from the
time of Screening (V1) for a study drug arm, for the duration of the study, and for 1
year after the final dose of study drug. Donation of blood or blood products for
transfusion is allowed during the CRI period.

11. In the opinion of the PI, the participant will be compliant and have a high
probability of completing the study.

12. The participant is able and willing to complete all study-related testing,
evaluations, and procedures.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Significant neurologic disease (other than AD) or psychiatric disease that may
currently or during the study affect cognition or the participant's ability to
complete the study. This would include disorders such as: recent or severe head trauma
causing cognitive change, seizure disorder, neurodegenerative disease other than DIAD,
hydrocephalus, cerebral/spinal hematoma, inflammatory disease, CNS infection (e.g.,
encephalitis or meningitis), neoplasm, toxic exposure, metabolic disorder (including
hypoxic or hypoglycemic episodes) or endocrine disorder; psychiatric disorders such as
schizophrenia, schizoaffective disorder, bipolar disorder or major depression, or any
other psychiatric condition/disorder which could significantly interfere with the
participant's cooperative participation (e.g., prominent anxiety, agitation or
behavioral problems). Disorders that are controlled medically or remote history of
these disorders (e.g., history of febrile seizures in childhood) that are not likely
to interfere with cognitive function and compliance with study procedures are not
exclusionary.

2. At high risk for suicide, e.g., significant suicidal ideation or attempt within last
12 months, current major depression (as defined in Diagnostic and Statistical Manual
of Mental Disorders, Fifth Edition [DSM-V]), or increased suicide risk based on
screening Columbia Suicide Severity Rating Scale (C-SSRS). Current stable mild
depression or current use of antidepressant medications is not exclusionary.

3. History of clinically evident stroke or history of clinically important carotid or
vertebrobasilar stenosis, plaque, or other prominent risk factor for stroke or
cerebral hemorrhage (including atrial fibrillation and anticoagulation, documented
transient ischemic attack [TIA] in the last 12 months). Low dose aspirin (= 325 mg
daily) is not exclusionary.

4. Alcohol or substance use sufficient to meet DSM-V criteria currently or within the
past year.

5. History of or Baseline visit brain MRI scan indicative of any other significant
abnormality, including but not limited to > 5 definite microhemorrhages, history or
evidence of a single prior hemorrhage > 1 cm3, 2 or more subcortical infarcts,
evidence of a single prior cortical infarct > 1 cm3, evidence of a cerebral contusion,
encephalomalacia, aneurysms, vascular malformations, subdural hematoma, or
space-occupying lesions (e.g., arachnoid cysts or brain tumors, such as meningioma),
hydrocephalus (other than hydrocephalus ex vacuo). Minor or clinically insignificant
imaging findings are not exclusionary. Participants with > 5 definite microhemorrhages
or > 1 area of leptomeningeal hemosiderosis will be evaluated on a case-by-case basis
by the site PI or designated sub-investigator and the PAL and medical director or
designee.

6. 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.

7. Uncontrolled hypertension within 6 months prior to screening (e.g., sustained systolic
blood pressure [BP] >160 mm Hg or diastolic blood pressure > 95 mm Hg).

8. Myocardial infarction or other myocardial ischemic events within the last 2 years.

9. Heart failure that results in limitation of physical activity (e.g., New York Heart
Association [NYHA] functional classification stage 2 or higher).

10. History of atrial fibrillation unless more than 1 year ago, and no structural lesions
(e.g., atrial enlargement or cardiomyopathy) that would increase risk of stroke.

11. 12-lead ECG: Clinically significant abnormalities including Bazett's corrected QT
(QTc) interval greater than 450 msec for males and 470 msec for females; in
participants above 65 years of age: 470 msec (atrioventricular [AV]-block I° allowed;
right bundle branch block [RBBB] allowed).

12. Alanine aminotransferase (ALT) = 2 times the upper limit of normal or aspartate
aminotransferase (AST) = 3 times the upper limit of normal or Baseline total bilirubin
= 2 times the upper limit of normal.

13. Creatinine clearance lower than 30 mL/min according to Cockcroft-Gault formula (if
confirmed at re-test).

14. Clinically significant abnormalities in urinalysis.

15. History of Human Immunodeficiency Virus (HIV) infection, history of Hepatitis B
infection within the past year, history of Hepatitis C infection which has not been
adequately treated or history of spirochete infection of the CNS, (e.g., syphilis,
Lyme or borreliosis).

16. Known allergies, hypersensitivity, or intolerance to study drug or its excipients (see
current investigator's brochures [IB]) or sensitivity to study-drug specific PET
imaging agents.

17. Treatment with immunosuppressive medications (e.g., systemic corticosteroids) within
90 days prior to the CRI Entry and Baseline (V2) visit (topical and nasal
corticosteroids and inhaled corticosteroids for asthma are permitted) or
chemotherapeutic agents for malignancy within the last 3 years.

18. Current clinically significant abnormalities of thyroid function, or clinically
significant deficiency in vitamin B12.

19. Screening hemoglobin A1c (HbA1c) > 8% (retesting is permitted if slightly elevated) or
poorly controlled insulin-dependent diabetes (including hypoglycemic episodes).
Participants may be rescreened after 3 months to allow optimization of diabetic
control.

20. Morbid obesity with significant comorbidities or that would preclude MRI imaging.

21. Current use of anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, or apixaban).
Daily use of low dose (< 325 mg) aspirin is not exclusionary.

22. Have been exposed to a monoclonal antibody targeting Aß peptide within the past 6
months or 5 half-lives from screening, whichever is longer.

23. Received any other investigational pharmacological treatment within 3 months of
Screening or 5 half-lives, whichever is longer.

24. Lack of sufficient venous access.

25. Clinically relevant abnormalities in hematology, coagulation, or clinical chemistry.

26. History of cancer within the last 3 years, except basal cell carcinoma, non-squamous
skin carcinoma, prostate cancer, or carcinoma in situ with no significant progression
over the past 2 years.

27. Any other medical condition that could be expected to progress, recur, or change to
such an extent that it could bias the assessment of the clinical or mental status of
the participant to a significant degree or put the participant at special risk.

28. Currently, or within the last month prior to screening, participated in a clinical
study, including a nonpharmacological study, without prior approval.

29. Positive urine or serum pregnancy test or plans to become pregnant during the study.

30. Currently breastfeeding. Participants must agree to refrain from breastfeeding from
the time of signed ICF until 16 weeks after the last dose of study drug.

31. Participants with the "Dutch" APP E693Q mutation.

32. Unable to fully complete CRI Entry visit and baseline visit (V2) procedures with
appropriate cognitive and clinical scores for eligibility (e.g., mild dementia).

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2/Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Suspended
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
2/12/2022
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/03/2034
Actual
Sample size
Target
220
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 0 0
Neuroscience Research Australia - Randwick
Recruitment hospital [2] 0 0
Mental Health Research Institute - Melbourne
Recruitment postcode(s) [1] 0 0
2031 - Randwick
Recruitment postcode(s) [2] 0 0
3010 - Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Connecticut
Country [4] 0 0
United States of America
State/province [4] 0 0
Georgia
Country [5] 0 0
United States of America
State/province [5] 0 0
Illinois
Country [6] 0 0
United States of America
State/province [6] 0 0
Indiana
Country [7] 0 0
United States of America
State/province [7] 0 0
Missouri
Country [8] 0 0
United States of America
State/province [8] 0 0
Pennsylvania
Country [9] 0 0
United States of America
State/province [9] 0 0
Rhode Island
Country [10] 0 0
United States of America
State/province [10] 0 0
Texas
Country [11] 0 0
United States of America
State/province [11] 0 0
Washington
Country [12] 0 0
Argentina
State/province [12] 0 0
Ciudad Autonoma de Buenos Aire
Country [13] 0 0
Canada
State/province [13] 0 0
British Columbia
Country [14] 0 0
Canada
State/province [14] 0 0
Ontario
Country [15] 0 0
Canada
State/province [15] 0 0
Quebec
Country [16] 0 0
Canada
State/province [16] 0 0
Québec
Country [17] 0 0
Colombia
State/province [17] 0 0
Medellín
Country [18] 0 0
France
State/province [18] 0 0
Haute Garonne
Country [19] 0 0
France
State/province [19] 0 0
Nord
Country [20] 0 0
France
State/province [20] 0 0
Paris
Country [21] 0 0
France
State/province [21] 0 0
Rhone
Country [22] 0 0
France
State/province [22] 0 0
Seine Maritime
Country [23] 0 0
Germany
State/province [23] 0 0
Baden Wuerttemberg
Country [24] 0 0
Germany
State/province [24] 0 0
Bayern
Country [25] 0 0
Ireland
State/province [25] 0 0
Dublin
Country [26] 0 0
Italy
State/province [26] 0 0
Brescia
Country [27] 0 0
Italy
State/province [27] 0 0
Firenze
Country [28] 0 0
Mexico
State/province [28] 0 0
Distrito Federal
Country [29] 0 0
Netherlands
State/province [29] 0 0
Amsterdam
Country [30] 0 0
Puerto Rico
State/province [30] 0 0
San Juan
Country [31] 0 0
Spain
State/province [31] 0 0
Barcelona
Country [32] 0 0
United Kingdom
State/province [32] 0 0
Greater London

Funding & Sponsors
Primary sponsor type
Other
Name
Washington University School of Medicine
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Hoffmann-La Roche
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Other
Name [2] 0 0
Alzheimer's Association
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Government body
Name [3] 0 0
National Institute on Aging (NIA)
Address [3] 0 0
Country [3] 0 0
Other collaborator category [4] 0 0
Commercial sector/Industry
Name [4] 0 0
Genentech, Inc.
Address [4] 0 0
Country [4] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
The purpose is to evaluate the biomarker effect, safety, and tolerability of investigational
study drugs in participants who are known to have an Alzheimer's disease (AD)-causing
mutation. Part 1 will determine if treatment with the study drug prevents or slows the rate
of amyloid beta (Aß) pathological disease accumulation demonstrated by Aß positron emission
tomography (PET) imaging. Part 2 will evaluate the effect of early Aß plaque
reduction/prevention on disease progression by assessing downstream non-Aß biomarkers of AD
(e.g., CSF total tau, p-tau, NfL) compared to an external control group from the DIAN-OBS
natural history study and the DIAN-TU-001 placebo-treated participants.
Trial website
https://clinicaltrials.gov/ct2/show/NCT05552157
Trial related presentations / publications
Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ, Xie X, Blazey TM, Holtzman DM, Santacruz A, Buckles V, Oliver A, Moulder K, Aisen PS, Ghetti B, Klunk WE, McDade E, Martins RN, Masters CL, Mayeux R, Ringman JM, Rossor MN, Schofield PR, Sperling RA, Salloway S, Morris JC; Dominantly Inherited Alzheimer Network. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med. 2012 Aug 30;367(9):795-804. doi: 10.1056/NEJMoa1202753. Epub 2012 Jul 11. Erratum In: N Engl J Med. 2012 Aug 23;367(8):780.
Mills SM, Mallmann J, Santacruz AM, Fuqua A, Carril M, Aisen PS, Althage MC, Belyew S, Benzinger TL, Brooks WS, Buckles VD, Cairns NJ, Clifford D, Danek A, Fagan AM, Farlow M, Fox N, Ghetti B, Goate AM, Heinrichs D, Hornbeck R, Jack C, Jucker M, Klunk WE, Marcus DS, Martins RN, Masters CM, Mayeux R, McDade E, Morris JC, Oliver A, Ringman JM, Rossor MN, Salloway S, Schofield PR, Snider J, Snyder P, Sperling RA, Stewart C, Thomas RG, Xiong C, Bateman RJ. Preclinical trials in autosomal dominant AD: implementation of the DIAN-TU trial. Rev Neurol (Paris). 2013 Oct;169(10):737-43. doi: 10.1016/j.neurol.2013.07.017. Epub 2013 Sep 6.
Wang G, Berry S, Xiong C, Hassenstab J, Quintana M, McDade EM, Delmar P, Vestrucci M, Sethuraman G, Bateman RJ; Dominantly Inherited Alzheimer Network Trials Unit. A novel cognitive disease progression model for clinical trials in autosomal-dominant Alzheimer's disease. Stat Med. 2018 Sep 20;37(21):3047-3055. doi: 10.1002/sim.7811. Epub 2018 May 14.
Weninger S, Carrillo MC, Dunn B, Aisen PS, Bateman RJ, Kotz JD, Langbaum JB, Mills SL, Reiman EM, Sperling R, Santacruz AM, Tariot PN, Welsh-Bohmer KA. Collaboration for Alzheimer's Prevention: Principles to guide data and sample sharing in preclinical Alzheimer's disease trials. Alzheimers Dement. 2016 May;12(5):631-2. doi: 10.1016/j.jalz.2016.04.001. No abstract available.
Grill JD, Bateman RJ, Buckles V, Oliver A, Morris JC, Masters CL, Klunk WE, Ringman JM; Dominantly Inherited Alzheimer's Network. A survey of attitudes toward clinical trials and genetic disclosure in autosomal dominant Alzheimer's disease. Alzheimers Res Ther. 2015 Jul 22;7(1):50. doi: 10.1186/s13195-015-0135-0. eCollection 2015.
McDade E, Bateman RJ. Stop Alzheimer's before it starts. Nature. 2017 Jul 12;547(7662):153-155. doi: 10.1038/547153a. No abstract available.
McDade E, Wang G, Gordon BA, Hassenstab J, Benzinger TLS, Buckles V, Fagan AM, Holtzman DM, Cairns NJ, Goate AM, Marcus DS, Morris JC, Paumier K, Xiong C, Allegri R, Berman SB, Klunk W, Noble J, Ringman J, Ghetti B, Farlow M, Sperling RA, Chhatwal J, Salloway S, Graff-Radford NR, Schofield PR, Masters C, Rossor MN, Fox NC, Levin J, Jucker M, Bateman RJ; Dominantly Inherited Alzheimer Network. Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease. Neurology. 2018 Oct 2;91(14):e1295-e1306. doi: 10.1212/WNL.0000000000006277. Epub 2018 Sep 14.
Ryman DC, Acosta-Baena N, Aisen PS, Bird T, Danek A, Fox NC, Goate A, Frommelt P, Ghetti B, Langbaum JB, Lopera F, Martins R, Masters CL, Mayeux RP, McDade E, Moreno S, Reiman EM, Ringman JM, Salloway S, Schofield PR, Sperling R, Tariot PN, Xiong C, Morris JC, Bateman RJ; Dominantly Inherited Alzheimer Network. Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology. 2014 Jul 15;83(3):253-60. doi: 10.1212/WNL.0000000000000596. Epub 2014 Jun 13.
Weng H, Bateman R, Morris JC, Xiong C. Validity and power of minimization algorithm in longitudinal analysis of clinical trials. Biostat Epidemiol. 2017;1(1):59-77. doi: 10.1080/24709360.2017.1331822. Epub 2017 Jun 13.
Public notes

Contacts
Principal investigator
Name 0 0
Eric M McDade, DO
Address 0 0
Washington University School of Medicine
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT05552157