Biogen BIIb037 (CLARITY)

Principal Investigator: Norman Foster
Keywords: Mild Cognitive Impairment , Mild Alzheimer's Disease , Memory Disturbance Department: Alzheimer's Center
IRB Number: 00083706 Co Investigator: Norman Foster
Specialty: Neurology, Neurology
Sub Specialties: Dementia, Cognitive Disorders
Recruitment Status: Not yet recruiting

Contact Information

Vivian Garcia
vivian.garcia@hsc.utah.edu
801-587-8385

Brief Summary

Primary Objective and Endpoint

The primary objective of the study is to evaluate the efficacy of monthly doses of aducanumab in slowing cognitive and functional impairment as measured by changes in the CDR-SB score as compared with placebo in subjects with early AD.

The primary endpoint that relates to this objective is change from baseline in CDR-SB score at Week 78.

Secondary Objectives and Endpoints

A secondary objective is to assess the effect of monthly doses of aducanumab as compared with placebo on clinical progression as measured by the MMSE.

  • The endpoint that relates to this objective is change from baseline in MMSE score at Week 78.

Another secondary objective is to assess the effect of monthly doses of aducanumab as compared with placebo on clinical progression as measured by ADAS-Cog 13.

  • The endpoint that relates to this objective is change from baseline in ADAS-Cog 13 score at Week 78.

Another secondary objective is to assess the effect of monthly doses of aducanumab as compared with placebo on clinical progression as measured by ADCS-ADL-MCI.

  • The endpoint that relates to this objective is change from baseline in ADCS-ADL-MCI score at Week 78.

Tertiary Objectives and Endpoints

Safety and Tolerability

  • To assess the safety and tolerability of monthly doses of aducanumab.
  • To assess the immunogenicity of aducanumab.

Biomarker

  • To assess the effect of aducanumab on cerebral amyloid plaque content as measured by amyloid PET imaging (in a subset of approximately 400 subjects).
  • To assess the effect of aducanumab on various morphometric measures in certain brain areas as measured by MRI.
  • To assess the effect of aducanumab on functional connectivity by task free functional (tf)-fMRI (where available).
  • To assess the effect of aducanumab on cerebral blood flow by arterial spin labeling (ASL)-MRI (where available).
  • To assess the effect of aducanumab on disease-related biomarkers in CSF which will include, but are not limited to, amyloid and tau proteins (in a subset of subjects).
  • To assess the effect of aducanumab on disease-related biomarkers in blood which may include, but are not limited to, amyloid and tau proteins.

Efficacy

  • To assess the effect of aducanumab on behavior as measured by the Neuropsychiatric Inventory (NPI-10).
  • To assess the effect of aducanumab on patient health status, measured by EuroQol health status measures (EQ-5D [informant-rated and patient self-reported]).
  • To assess the effect of aducanumab on the informant/study partner’s own health status, measured by the EQ-5D.
  • To assess the effect of aducanumab on patient self-reported cognitive function, measured by the modified Perceived Deficits Questionnaire-20 (mPDQ-20) [Lenderking 2014].
  • To assess the effect of aducanumab on caregiver burden measures.
  • To assess the correlation between primary endpoints and key biomarker endpoints.

Pharmacokinetics

  • To explore the potential relationships between PK or exposure and response (e.g., clinical and biomarker endpoints) including covariate analysis.
  • To explore the potential effect of co-medications on the PK of aducanumab using population PK.

Tertiary Endpoints

Safety and Tolerability:

  • Incidence of all AEs and SAEs.
  • Brain MRI findings including incidence of ARIA-E and ARIA-H.
  • Clinical laboratory shifts in reported values.
  • Clinically significant changes in vital sign measurements and electrocardiograms (ECGs).
  • Incidence of anti-aducanumab antibodies in serum.

Biomarkers:

  • Change from baseline in amyloid PET signal at Week 26 (in a subset of subjects).
  • Change from baseline in amyloid PET signal at Week 78 (in a subset of subjects).
  • Change from baseline in whole brain volume, hippocampal volume, ventricular volume, and cortical gray matter volume measured by MRI over time.
  • Change from baseline in functional connectivity as measured by tf-fMRI (where available) over time.
  • Change from baseline in cerebral blood flow as measured by ASL-MRI (where available) over time.
  • Change in disease-related biomarker levels in CSF, which will include, but are not limited to, amyloid or tau proteins at Week 78 (in a subset of subjects).
  • Change in disease-related biomarker levels in blood, which may include, but are not limited to, amyloid or tau proteins at Week 24.
  • Change in disease-related biomarker levels in blood, which may include, but are not limited to, amyloid or tau proteins at Week 78.

Efficacy

  • Change from baseline in NPI-10 score at Week 78.
  • Change from baseline in subject-self-reported EQ-5D index score at Week 78.
  • Change from baseline in informant-rated subject EQ-5D index score at Week 78.
  • Change from baseline in informant/care partner’s own EQ-5D index-score at Week 78.
  • Change from baseline in mPDQ-20 at Week 78.
  • Changes in caregiver burden questionnaire over time.
  • Correlation between clinical and biomarker endpoints over time.

Pharmacokinetics

  • Serum concentrations of aducanumab, population PK parameters of aducanumab including but not limited to clearance and volumes of central and peripheral compartments.

Long Term Extension Objectives and Endpoints

Objectives

  • To evaluate the long-term safety and tolerability profile of aducanumab in subjects with early AD.
  • To evaluate the long-term efficacy of aducanumab treatment as measured by clinical, radiological, and additional assessments reported by the subject and informant/care partner. Endpoints
  • The incidence of AEs and/SAEs; brain MRI findings (including the incidence of ARIA-E and ARIA-H); and the incidence of anti-aducanumab antibodies in serum over the placebo-controlled and LTE periods of the study.
  • Change in the following measures over the placebo-controlled and LTE periods of the study:
  • CDR-SB score.
  • MMSE score.
  • ADAS-Cog 13 score.
  • ADCS-ADL-MCI score.
  • Amyloid PET signal (in a subset of subjects).
  • Whole brain volume, hippocampal volume, ventricular volume, and cortical gray matter volume measured by MRI.
  • Functional connectivity as measured by tf-fMRI (where available).
  • Cerebral blood flow as measured by ASL-MRI (where available).
  • Disease-related biomarker levels in CSF which will include, but are not limited to, amyloid and tau proteins (in a subset of subjects).
  • Disease-related biomarker levels in blood which may include, but are not limited to, amyloid and tau proteins.
  • NPI-10 total score.
  • Informant-rated EQ-5D index score.
  • Informant/care partner’s own self-reported EQ-5D index score.
  • Caregiver burden measures. 

Inclusion Criteria

Inclusion Criteria

To be eligible to participate in this study, candidates must meet the following eligibility criteria at Screening or at the time point specified in the individual eligibility criterion listed:

1. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use confidential health information in accordance with national and local subject privacy regulations.

2. Aged 50 to 85 years old, inclusive, at the time of informed consent.

3. All women of childbearing potential and all men must practice effective contraception during the study and for 24 weeks after their last dose of study treatment. For further details of contraceptive requirements for this study, please refer to Section 15.5.

4. Must have at least 6 years of education or work experience to exclude mental deficits other than MCI or mild AD.

5. Must have a positive amyloid PET scan. Previously obtained PET scan (within 12 months of screening) is permissible for subjects not participating in the PET cohort. Previous PET scan images must be submitted to the central imaging vendor to confirm study inclusion criteria are met.

6. Must meet all of the following clinical criteria for MCI due to AD or mild AD according to NIA-AA criteria [Albert 2011; McKhann 2011], and must have:

  • A CDR-Global Score of 0.5.
  • An RBANS score of 85 or lower indicative of objective cognitive impairment.
  • An MMSE score between 24 and 30 (inclusive).

7. Apart from a clinical diagnosis of early AD, the subject must be in good health as determined by the Investigator, based on medical history and screening assessments.

8. Must consent to apolipoprotein E (ApoE) genotyping.

9. Has one informant/care partner who, in the Investigator’s judgment, has frequent and sufficient contact with the subject as to be able to provide accurate information about the subject’s cognitive and functional abilities. The informant/care partner must minimally be available by phone to provide information to the Investigator and study staff about the subject and agrees to attend in person clinic visits that require partner input for scale completion. An informant/care partner should be available for the duration of the study, and the use of the same informant/care partner for the duration of the study is encouraged. 

Inclusion Criteria for Long-Term Extension

To be eligible to participate in the LTE, subjects must meet the following eligibility criteria at Week 78:

1. Subject must have completed the placebo-controlled period of the study including the Week 78 Visit. Subject must have taken at least 14 doses and not have missed more than 4 consecutive doses. Subjects who do not meet these criteria can enter the LTE only with Sponsor’s approval.

2. MMSE score > 15 at the Week 78 Visit.

3. The subject (or the subject’s legally authorized representative) has the ability to understand the purpose and risks of the study and provide signed and dated informed consent (or assent) and authorization to use confidential health information in accordance with national and local subject privacy regulations.

4. Female subjects of childbearing potential and male subjects must practice effective contraception during the study and for 24 weeks after their last dose of study treatment.

5. Apart from a clinical diagnosis of AD, the subject must be in good health as determined by the Investigator, based on medical history.

6. Must have the ability to comply with procedures for protocol-related tests.

7. Has one informant/care partner who, in the Investigator’s judgment, has frequent and sufficient contact with the subject as to be able to provide accurate information about the subject’s cognitive and functional abilities. The informant/care partner must minimally be available by phone to provide information to the Investigator and study staff about the subject and agrees to attend in person clinic visits that require partner input for scale completion. An informant/care partner should be available for the duration of the study, and the use of the same informant/care partner for the duration of the study is encouraged.

 

AMENDMENT 3 UPDATES:

INCLUSION CRITERIA #6

  1. Must meet all of the following clinical criteria for MCI due to AD or mild AD according to NIA-AA criteria [Albert 2011; McKhann 2011], and must have:
    • A CDR-Global Score of 0.5.
    • An RBANS score of 85 or lower indicative of objective cognitive impairment (based upon the Delayed Memory Index [DMI] score).
    • An MMSE score between 24 and 30 (inclusive).

 

AMENDMENT 4 UPDATES: 

Inclusion Criteria for Long-Term Extension Period: Subjects with an MMSE score >10 at the time of LTE entry can now participate.

 

Exclusion Criteria

Exclusion Criteria

Candidates will be excluded from study entry if any of the following exclusion criteria exist at Screening, or at the time point specified in the individual criterion listed:

Medical History

1. Any uncontrolled medical or neurological/neurodegenerative condition (other than AD) that, in the opinion of the Investigator, might be a contributing cause of the subject’s cognitive impairment (e.g., substance abuse, vitamin B12 deficiency, abnormal thyroid function, stroke or other cerebrovascular condition, lewy body dementia, fronto-temporal dementia, head trauma)..

2. Clinically significant unstable psychiatric illness (e.g., uncontrolled major depression, uncontrolled schizophrenia, uncontrolled bipolar affective disorder) within 6 months prior to Screening.

3. Transient ischemic attack or stroke or any unexplained loss of consciousness within 1 year prior to Screening.

4. Brain MRI performed at Screening (per centrally read MRI) that shows evidence of any of the following:

  • Acute or sub-acute hemorrhage.
  • Prior macrohemorrhage (defined as 1 cm in diameter on T2* sequence) unless it can be documented that the finding is not due to an underlying structural or vascular abnormality (i.e., finding does not suggest subject is at risk of recurrent hemorrhage).
  • Greater than 4 microhemorrhages (defined as 1 cm in diameter on T2* sequence).
  • Cortical infarct (defined as > 1.5 cm in diameter).
  • 1 lacunar infarct (defined as  1.5 cm in diameter).
  • Superficial siderosis.
  • History of diffuse white matter disease as defined by a score of 3 on the age-related white matter changes scale [Wahlund 2001].
  • Any finding that, in the opinion of the Investigator, might be a contributing cause of subject’s dementia, might pose a risk to the subject, or might prevent a satisfactory MRI assessment for safety monitoring.

5. History of bleeding disorder or predisposing conditions, blood clotting or clinically significant abnormal results on coagulation profile at Screening, as determined by the Investigator.

6. Presence of diabetes mellitus that, in the judgment of the Investigator, cannot be controlled or adequately managed.

7. History of unstable angina, myocardial infarction, chronic heart failure (New York Heart Association Class III or IV), or clinically significant conduction abnormalities (e.g., unstable atrial fibrillation) within 1 year prior to Screening.

8. Clinically significant 12-lead ECG abnormalities, as determined by the Investigator.

9. Uncontrolled hypertension defined as: average of 3 systolic blood pressure [SBP]/diastolic blood pressure [DBP] readings > 165/100 mmHg at Screening (blood pressure measurements exceeding these limits may be repeated as warranted by the Investigator, but values must be within the specified limits for the subject to be eligible for the study), or persistent SBP/DBP readings > 180/100 mmHg 3 months prior to randomization (Day 1) that in the opinion of the Investigator are indicative of chronic uncontrolled hypertension.

10.History of malignancy or carcinoma. The following exceptions may be made after discussion with the Sponsor:

  • Subjects with cancers in remission more than 5 years prior to Screening.
  • Subjects with a history of excised or treated basal cell or squamous carcinoma of the skin.
  • Subjects with localized prostate cancer with treatment cycles that completed at least 6 months prior to Screening.

11. History of seizure within 10 years prior to Screening.

12. Indication of impaired liver function as shown by an abnormal liver function profile at Screening (e.g., repeated values of aspartate aminotransferase [AST] and alanine aminotransferase [ALT] ≥ 2 × the upper limit of normal).

13. History or evidence of an autoimmune disorder considered clinically significant by the Investigator or requiring chronic use of systemic corticosteroids or other immunosuppressants.

14. Recent history (within 1 year of Screening) of alcohol or substance abuse as determined by the Investigator, a positive urine drug (due to non-prescription drug) or alcohol test at Screening, or use of cannabinoids (prescription or recreational).

15. Clinically significant systemic illness or serious infection (e.g., pneumonia, septicemia) within 30 days prior to or during Screening.

16. History of or positive test result for human immunodeficiency virus (HIV).

17. History of or positive test result at Screening for hepatitis C virus antibody or hepatitis B virus (defined as positive for both hepatitis B surface antigen AND hepatitis B core antibody).

18. History of severe allergic or anaphylactic reactions, or history of hypersensitivity to any of the inactive ingredients in the drug product (refer to the IB for information on the clinical formulation).

19. Any other medical conditions (e.g., renal disease) that are not stable or controlled, or, which in the opinion of the Investigator, could affect the subject’s safety or interfere with the study assessments.

Medications

20. Any medications that, in the opinion of the Investigator, may contribute to cognitive impairment, put the subject at higher risk for AEs, or impair the subject’s ability to perform cognitive testing or complete study procedures.

21. Use of allowed chronic medications at doses that have not been stable for at least 4 weeks prior to Screening Visit 1 or use of AD medications (including but not limited to donepezil, rivastigmine, galantamine, tacrine, and memantine) at doses that have not been stable for at least 8 weeks prior to Screening Visit 1.

22. Use of medications with platelet anti-aggregant or anti-coagulant properties (the use of aspirin at a prophylactic dose [≤ 325 mg daily] is allowed).

23. Use of illicit narcotic medication.

24. Vaccinations within 10 days prior to randomization (Day 1).

25. Participation in any active immunotherapy study targeting Aβ unless documentation of receipt of placebo is available.

26. Participation in any passive immunotherapy study targeting Aβ within 12 months of Screening unless documentation of receipt of placebo is available.

27. Participation in any study with purported disease-modifying effect in AD within 12 months prior to Screening unless documentation of receipt of placebo is available. Subjects who developed ARIA-E during a previous disease-modifying trial should be excluded.

28. Participation in a previous study with aducanumab (subject is eligible if he/she did not receive active aducanumab).

Study Procedures

29. Contraindications to having a brain MRI (e.g., pacemaker; MRI-incompatible aneurysm clips, artificial heart valves, or other metal foreign body; claustrophobia that cannot be medically managed).

30. Contraindication to having a PET scan (e.g., inability to lie flat or still for the duration of the scan) or intolerance to previous PET scans (i.e., previous hypersensitivity reactions to any PET ligand or imaging agent, failure to participate in and comply with previous PET scans).

31. A negative PET scan result with any amyloid-targeting ligand within 6 months prior to Screening.

32. Have had or plan exposure to experimental radiation within 12 months prior to Screening such that radiodosimetry limits would be exceeded by participating in this study.

33. For subjects who consent to lumbar puncture (LP), any contraindications to having a LP (e.g., platelet count <100,000/μL, lumbar spine deformity). Any symptoms caused by or related to the optional LP during screening must be resolved prior to randomization. Subjects may still participate in the overall study even if participation in the optional LP portion is contraindicated.

Others

34. Female subjects who are pregnant or currently breastfeeding.

35. Previous participation in this study. Subjects who fail screening will be permitted to be rescreened once at the Sponsor’s discretion, except those who fail due to PET, MMSE, CDR, hepatitis B or C, or abnormal MRI findings.

36. Subject currently living in an organized care facility with extensive intervention and/or support of daily living activities.

37. Blood donation (≥ 1 unit) within 1 month prior to Screening.

38. Inability to comply with study requirements.

39. Other unspecified reasons that, in the opinion of the Investigator or Biogen, make the subject unsuitable for enrollment.

Exclusion Criteria for Long Term Extension

Subjects will be excluded from entering the LTE if at Week 78 they have:

  • any medical or psychiatric contraindication or clinically significant abnormality that, in the opinion of the Investigator, will substantially increase the risk associated with the subject's participation in and completion of the study.