Alzheimer's Disease
Conditions
Keywords
hypertension, prevention, family history, inflammation, blood brain barrier, amyloid
Brief summary
The purpose of this study is to determine if telmisartan, an FDA approved blood pressure medication, may also have beneficial effects on Alzheimer's disease prevention in African Americans, who are at high risk for Alzheimer's disease.
Detailed description
This study will assess if telmisartan, an FDA approved blood pressure medication, may also have beneficial effects on Alzheimer's disease (AD) prevention in African Americans, who are at high risk for Alzheimer's disease. Blood pressure medications known as angiotensin-receptor blockers have been associated with reduced risk of Alzheimer's in Caucasians because they act on the renin-angiotensin system (RAS), a key regulator of blood pressure in the body and the brain. The drugs appear to slow the progression of the disease by affecting flow of blood and the amount of plaque in the brain, but these benefits have not been tested in African Americans. The investigator will evaluate if telmisartan is able to influence the renin-angiotensin system in the brain and produce favorable effects on brain blood flow and enzymes that cause the brain plaques in Alzheimer's disease.The investigator will assess the mechanism by which telmisartan modifies the brain renin angiotensin system, cerebrospinal fluid amyloid-β, cerebral blood flow (CBF) and inflammatory markers in hypertensive African Americans.
Interventions
DRUGTelmisartan 20mg
Participants will be given 20 mg of telmisartan to be taken orally once a day before bedtime, for a duration of 8 months.
DRUGTelmisartan 40mg
Participants will be given 40 mg of telmisartan to be taken orally once a day before bedtime, for a duration of 8 months.
DRUGPlacebo
Participants will be given placebo to be taken orally once a day before bedtime, for a duration of 8 months.
Sponsors
National Institute on Aging (NIA)
Emory University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
30 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Mean resting systolic blood pressure ≥ 110 mmHg and ≤ 170 mmHg * Family history of Alzheimer's disease * African American
Exclusion criteria
* Currently in another investigational drug study * Potassium \>5.0 meq/dL at baseline * Creatinine \>1.99 mg/dL at baseline * History of stroke or transient ischemic attack (TIA) * Dementia * Current use of a RAS acting medication * Contraindication for lumbar puncture or magnetic resonance imaging * Heart failure * Diabetes Types I and II * Pregnant or nursing women
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Levels of Cerebrospinal Fluid P-tau | Baseline, Month 8 | Levels of P-tau in the cerebrospinal fluid were measured using LUMIPULSE® technology. Increases in concentrations of P-tau are indicative of a decrease in cognitive function. |
| Levels of Cerebrospinal Fluid T-tau | Baseline, Month 8 | Levels of T-tau in the cerebrospinal fluid were measured using LUMIPULSE® technology. Increases in concentrations of T-tau are indicative of a decrease in cognitive function. |
| Concentration of Angiotensin Converting Enzyme (ACE 1) | Baseline, Month 8 | The cerebrospinal fluid renin-angiotensin system (RAS) was assessed by measuring levels of angiotensin metabolites in a 1 milliliter (mL) sample of cerebrospinal fluid (CSF). ACE 1 helps to regulate blood pressure by converting angiotensin I to angiotensin II. |
| Concentration of Angiotensin Converting Enzyme 2 (ACE 2) | Baseline, Month 8 | The cerebrospinal fluid renin-angiotensin system (RAS) was assessed by measuring levels of angiotensin metabolites in a 1 milliliter (mL) sample of cerebrospinal fluid (CSF). ACE 2 regulates levels of circulating angiotensin II. ACE 2 increases during illness and with Alzheimer's disease. |
| Cerebrospinal Fluid Amyloid β40 | Baseline, Month 8 | Levels of amyloid β40 (Aβ40) in the cerebrospinal fluid were measured using LUMIPULSE® technology. The relationship between Aβ40 is non-linear with moderate levels showing the highest risk of future cognitive decline in some studies. |
| Levels of Cerebrospinal Fluid Amyloid β42 | Baseline, Month 8 | Levels of amyloid β42 (Aβ42) in the cerebrospinal fluid were measured using LUMIPULSE® technology. Decreases in concentrations of amyloid β42 are indicative of a decrease in cognitive function. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Monocyte Chemoattractant Protein 1 (MCP-1) Frequency | Baseline, Month 8 | Monocyte chemoattractant protein 1 inflammatory markers in CSF were examined. |
| Macrophage Derived Protein 1 (MDC-1) Frequency | Baseline, Month 8 | Macrophage derived protein 1 inflammatory markers in CSF were examined. |
| Transforming Growth Factor Alpha (TGF-α) Frequency | Baseline, Month 8 | Transforming growth factor alpha inflammatory markers in CSF were examined. |
| Tumor Necrosis Factor Alpha (TNF-α) Frequency | Baseline, Month 8 | Tumor necrosis factor alpha inflammatory markers in CSF were examined. |
| Vascular Cell Adhesion Molecule 1 (VCAM-1) Frequency | Baseline, Month 8 | Vascular cell adhesion molecule 1 inflammatory markers in CSF were examined. |
| Matrix Metalloproteinase (MMP) Frequency | Baseline, Month 8 | Matrix metalloproteinase inflammatory markers will be examined in CSF. |
| Tissue Inhibitor of Metalloproteinase (TIMP) Frequency | Baseline, Month 8 | Tissue inhibitor of metalloproteinase inflammatory markers will be examined in CSF. |
| CSF-Soluble Platelet-Derived Growth Factor Receptor Beta (sPDGFRβ) | Baseline, Month 8 | Soluble Platelet-Derived Growth Factor Receptor Beta (sPDGFRβ) is a marker of breakdown in the blood brain barrier. Increased levels of sPDGFRβ indicate cognitive dysfunction. |
| Intercellular Adhesion Molecule 1 (ICAM-1) Frequency | Baseline, Month 8 | Intercellular adhesion molecule 1 inflammatory markers in CSF were examined. |
| Interleukin-6 (IL-6) Frequency | Baseline, Month 8 | The inflammatory marker IL-6 in CSF was examined. |
| Interleukin-7 (IL-7) Frequency | Baseline, Month 8 | The inflammatory marker IL-7 in CSF was examined. |
| Interleukin-8 (IL-8) Frequency | Baseline, Month 8 | The inflammatory marker IL-8 in CSF was examined. |
| Interleukin-9 (IL-9) Frequency | Baseline, Month 8 | The inflammatory marker IL-9 in CSF was examined. |
| Interleukin-10 (IL-10) Frequency | Baseline, Month 8 | The inflammatory marker IL-10 in CSF was examined. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Structural Magnetic Resonance Imaging and White Matter Hyperintensities | Baseline, Month 8 | High-resolution anatomical images will be acquired using a 3D-Fast Spoiled Gradient Recalled Echo (FSPGR) Sequence. White Matter Hyperintensities (WMH) will be identified by a 3D T2 Fluid Attenuated Inversion Recovery (FLAIR) Fast Spin Echo sequence. The images will be co-registered using a within-subject inter-modal alignment between structural and perfusion images. T1-weighted Spoiled Gradient Recalled (SPGR) images will be used to identify cerebrospinal fluid and white and gray matter. Increased volumes of white matter hyperintensities indicate impaired cognitive function. |
| Change in Arterial Spin Labeling-Magnetic Resonance Imaging | Baseline, Month 8 | Echoplanar T1 mapping scans will be used for image registration and a scout image of the head will be obtained in order to choose the appropriate location for spin labeling and flow imaging. Arterial Spin Labeling images will be acquired using a custom 3D stack of interleaved spirals fast spin echo sequences and will be averaged in order to improve the signal-to-noise ratio. Images will be interpolated and smoothed in a panel by using a 0.5-pixel, full-width, half-maximum Gaussian kernel. Regional perfusion will be quantified in each hemisphere and maps of cerebral vasoreactivity will be obtained by co-registration of perfusion and anatomical images. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from the Wesley Woods Health Center, Emory Alzheimer's Clinical Research Unit (ACRU), and the Emory Brain Health Center in Atlanta, Georgia, USA. Participant enrollment began April 2015 and all follow-up assessments were completed by April 15, 2022.
Participants by arm
| Arm | Count |
|---|---|
| Telmisartan 20mg African American participants with untreated or treated hypertension and at high risk for Alzheimer's disease who were randomly assigned to receive 20 mg of telmisartan to be taken orally once a day before bedtime, for a duration of 8 months. | 19 |
| Telmisartan 40mg African American participants with untreated or treated hypertension and at high risk for Alzheimer's disease who were randomly assigned to receive 40 mg of telmisartan to be taken orally once a day before bedtime, for a duration of 8 months. | 18 |
| Placebo African American participants with untreated or treated hypertension and at high risk for Alzheimer's disease who were randomly assigned to receive a placebo to match telmisartan to be taken orally once a day before bedtime, for a duration of 8 months. | 24 |
| Total | 61 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 5 |
Baseline characteristics
| Characteristic | Telmisartan 20mg | Total | Placebo | Telmisartan 40mg |
|---|---|---|---|---|
| Age, Continuous | 57.79 years STANDARD_DEVIATION 8.85 | 59.66 years STANDARD_DEVIATION 8.48 | 60.54 years STANDARD_DEVIATION 8.65 | 60.44 years STANDARD_DEVIATION 7.48 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants | 61 Participants | 24 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 19 Participants | 61 Participants | 24 Participants | 18 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 19 Participants | 61 Participants | 24 Participants | 18 Participants |
| Sex: Female, Male Female | 16 Participants | 51 Participants | 19. Participants | 16 Participants |
| Sex: Female, Male Male | 3 Participants | 10 Participants | 5 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 18 | 0 / 24 |
| other Total, other adverse events | 13 / 19 | 13 / 18 | 15 / 24 |
| serious Total, serious adverse events | 0 / 19 | 0 / 18 | 0 / 24 |
Outcome results
Primary
Cerebrospinal Fluid Amyloid β40
Levels of amyloid β40 (Aβ40) in the cerebrospinal fluid were measured using LUMIPULSE® technology. The relationship between Aβ40 is non-linear with moderate levels showing the highest risk of future cognitive decline in some studies.
Time frame: Baseline, Month 8
Population: This analysis includes participants who completed 8 months of study treatment, attended the Month 8 study visit, and had a sufficient sample of CSF collected. The amount of CSF collected fluctuated and some samples were not of adequate quantity to be used for every lab measurement. In some cases, participants had an unsuccessful or inadequate lumbar puncture at Baseline and then had a successful lumbar puncture at the Month 8 visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Telmisartan 20mg | Cerebrospinal Fluid Amyloid β40 | Baseline | 7704.82 picograms per milliliter (pg/mL) | Standard Deviation 2237.94 |
| Telmisartan 20mg | Cerebrospinal Fluid Amyloid β40 | Month 8 | 8011.44 picograms per milliliter (pg/mL) | Standard Deviation 2688.34 |
| Telmisartan 40mg | Cerebrospinal Fluid Amyloid β40 | Baseline | 9121.62 picograms per milliliter (pg/mL) | Standard Deviation 3174.21 |
| Telmisartan 40mg | Cerebrospinal Fluid Amyloid β40 | Month 8 | 8820.08 picograms per milliliter (pg/mL) | Standard Deviation 2514.47 |
| Placebo | Cerebrospinal Fluid Amyloid β40 | Baseline | 8259.13 picograms per milliliter (pg/mL) | Standard Deviation 2176.62 |
| Placebo | Cerebrospinal Fluid Amyloid β40 | Month 8 | 8300.67 picograms per milliliter (pg/mL) | Standard Deviation 2623.31 |
Primary
Concentration of Angiotensin Converting Enzyme 2 (ACE 2)
The cerebrospinal fluid renin-angiotensin system (RAS) was assessed by measuring levels of angiotensin metabolites in a 1 milliliter (mL) sample of cerebrospinal fluid (CSF). ACE 2 regulates levels of circulating angiotensin II. ACE 2 increases during illness and with Alzheimer's disease.
Time frame: Baseline, Month 8
Population: This analysis includes participants who completed 8 months of study treatment, attended the Month 8 study visit, and had a sufficient sample of CSF collected. The amount of CSF collected fluctuated and some samples were not of adequate quantity to be used for every lab measurement. In some cases, participants had an unsuccessful or inadequate lumbar puncture at Baseline and then had a successful lumbar puncture at the Month 8 visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Telmisartan 20mg | Concentration of Angiotensin Converting Enzyme 2 (ACE 2) | Baseline | 889.06 ng/mL | Standard Deviation 870.83 |
| Telmisartan 20mg | Concentration of Angiotensin Converting Enzyme 2 (ACE 2) | Month 8 | 231.86 ng/mL | Standard Deviation 47.66 |
| Telmisartan 40mg | Concentration of Angiotensin Converting Enzyme 2 (ACE 2) | Baseline | 566.43 ng/mL | Standard Deviation 700.13 |
| Telmisartan 40mg | Concentration of Angiotensin Converting Enzyme 2 (ACE 2) | Month 8 | 274.17 ng/mL | Standard Deviation 84.74 |
| Placebo | Concentration of Angiotensin Converting Enzyme 2 (ACE 2) | Baseline | 783.72 ng/mL | Standard Deviation 998.95 |
| Placebo | Concentration of Angiotensin Converting Enzyme 2 (ACE 2) | Month 8 | 264.83 ng/mL | Standard Deviation 109.4 |
Primary
Concentration of Angiotensin Converting Enzyme (ACE 1)
The cerebrospinal fluid renin-angiotensin system (RAS) was assessed by measuring levels of angiotensin metabolites in a 1 milliliter (mL) sample of cerebrospinal fluid (CSF). ACE 1 helps to regulate blood pressure by converting angiotensin I to angiotensin II.
Time frame: Baseline, Month 8
Population: This analysis includes participants who completed 8 months of study treatment, attended the Month 8 study visit, and had a sufficient sample of CSF collected. The amount of CSF collected fluctuated and some samples were not of adequate quantity to be used for every lab measurement. In some cases, participants had an unsuccessful or inadequate lumbar puncture at Baseline and then had a successful lumbar puncture at the Month 8 visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Telmisartan 20mg | Concentration of Angiotensin Converting Enzyme (ACE 1) | Baseline | 4043.15 ng/mL | Standard Deviation 1425.34 |
| Telmisartan 20mg | Concentration of Angiotensin Converting Enzyme (ACE 1) | Month 8 | 3305.21 ng/mL | Standard Deviation 764.54 |
| Telmisartan 40mg | Concentration of Angiotensin Converting Enzyme (ACE 1) | Baseline | 4028.17 ng/mL | Standard Deviation 1509.02 |
| Telmisartan 40mg | Concentration of Angiotensin Converting Enzyme (ACE 1) | Month 8 | 4102.96 ng/mL | Standard Deviation 1498.07 |
| Placebo | Concentration of Angiotensin Converting Enzyme (ACE 1) | Baseline | 3836.31 ng/mL | Standard Deviation 1627.5 |
| Placebo | Concentration of Angiotensin Converting Enzyme (ACE 1) | Month 8 | 3696.71 ng/mL | Standard Deviation 1309.61 |
Primary
Levels of Cerebrospinal Fluid Amyloid β42
Levels of amyloid β42 (Aβ42) in the cerebrospinal fluid were measured using LUMIPULSE® technology. Decreases in concentrations of amyloid β42 are indicative of a decrease in cognitive function.
Time frame: Baseline, Month 8
Population: This analysis includes participants who completed 8 months of study treatment, attended the Month 8 study visit, and had a sufficient sample of CSF collected. The amount of CSF collected fluctuated and some samples were not of adequate quantity to be used for every lab measurement. In some cases, participants had an unsuccessful or inadequate lumbar puncture at Baseline and then had a successful lumbar puncture at the Month 8 visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Telmisartan 20mg | Levels of Cerebrospinal Fluid Amyloid β42 | Baseline | 611.91 pg/mL | Standard Deviation 138.51 |
| Telmisartan 20mg | Levels of Cerebrospinal Fluid Amyloid β42 | Month 8 | 620.89 pg/mL | Standard Deviation 256.43 |
| Telmisartan 40mg | Levels of Cerebrospinal Fluid Amyloid β42 | Baseline | 614.54 pg/mL | Standard Deviation 193.54 |
| Telmisartan 40mg | Levels of Cerebrospinal Fluid Amyloid β42 | Month 8 | 665.42 pg/mL | Standard Deviation 278 |
| Placebo | Levels of Cerebrospinal Fluid Amyloid β42 | Baseline | 578.31 pg/mL | Standard Deviation 190.75 |
| Placebo | Levels of Cerebrospinal Fluid Amyloid β42 | Month 8 | 599.25 pg/mL | Standard Deviation 204.17 |
Primary
Levels of Cerebrospinal Fluid P-tau
Levels of P-tau in the cerebrospinal fluid were measured using LUMIPULSE® technology. Increases in concentrations of P-tau are indicative of a decrease in cognitive function.
Time frame: Baseline, Month 8
Population: This analysis includes participants who completed 8 months of study treatment, attended the Month 8 study visit, and had a sufficient sample of CSF collected. The amount of CSF collected fluctuated and some samples were not of adequate quantity to be used for every lab measurement. In some cases, participants had an unsuccessful or inadequate lumbar puncture at Baseline and then had a successful lumbar puncture at the Month 8 visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Telmisartan 20mg | Levels of Cerebrospinal Fluid P-tau | Baseline | 29.75 pg/mL | Standard Deviation 12.88 |
| Telmisartan 20mg | Levels of Cerebrospinal Fluid P-tau | Month 8 | 30.48 pg/mL | Standard Deviation 10.16 |
| Telmisartan 40mg | Levels of Cerebrospinal Fluid P-tau | Baseline | 36.55 pg/mL | Standard Deviation 11.24 |
| Telmisartan 40mg | Levels of Cerebrospinal Fluid P-tau | Month 8 | 35.68 pg/mL | Standard Deviation 13.67 |
| Placebo | Levels of Cerebrospinal Fluid P-tau | Baseline | 31.58 pg/mL | Standard Deviation 13.24 |
| Placebo | Levels of Cerebrospinal Fluid P-tau | Month 8 | 30.48 pg/mL | Standard Deviation 10.3 |
Primary
Levels of Cerebrospinal Fluid T-tau
Levels of T-tau in the cerebrospinal fluid were measured using LUMIPULSE® technology. Increases in concentrations of T-tau are indicative of a decrease in cognitive function.
Time frame: Baseline, Month 8
Population: This analysis includes participants who completed 8 months of study treatment, attended the Month 8 study visit, and had a sufficient sample of CSF collected. The amount of CSF collected fluctuated and some samples were not of adequate quantity to be used for every lab measurement. In some cases, participants had an unsuccessful or inadequate lumbar puncture at Baseline and then had a successful lumbar puncture at the Month 8 visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Telmisartan 20mg | Levels of Cerebrospinal Fluid T-tau | Baseline | 347.73 pg/mL | Standard Deviation 371.85 |
| Telmisartan 20mg | Levels of Cerebrospinal Fluid T-tau | Month 8 | 393.11 pg/mL | Standard Deviation 404.35 |
| Telmisartan 40mg | Levels of Cerebrospinal Fluid T-tau | Baseline | 281.23 pg/mL | Standard Deviation 89.72 |
| Telmisartan 40mg | Levels of Cerebrospinal Fluid T-tau | Month 8 | 266.58 pg/mL | Standard Deviation 83.23 |
| Placebo | Levels of Cerebrospinal Fluid T-tau | Baseline | 248.94 pg/mL | Standard Deviation 107.67 |
| Placebo | Levels of Cerebrospinal Fluid T-tau | Month 8 | 244.58 pg/mL | Standard Deviation 67.04 |
Secondary
CSF-Soluble Platelet-Derived Growth Factor Receptor Beta (sPDGFRβ)
Soluble Platelet-Derived Growth Factor Receptor Beta (sPDGFRβ) is a marker of breakdown in the blood brain barrier. Increased levels of sPDGFRβ indicate cognitive dysfunction.
Time frame: Baseline, Month 8
Population: This analysis includes participants who completed 8 months of study treatment, attended the Month 8 study visit, and had a sufficient sample of CSF collected. The amount of CSF collected fluctuated and some samples were not of adequate quantity to be used for every lab measurement. In some cases, participants had an unsuccessful or inadequate lumbar puncture at Baseline and then had a successful lumbar puncture at the Month 8 visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Telmisartan 20mg | CSF-Soluble Platelet-Derived Growth Factor Receptor Beta (sPDGFRβ) | Baseline | 600.30 pg/mL | Standard Deviation 299.6 |
| Telmisartan 20mg | CSF-Soluble Platelet-Derived Growth Factor Receptor Beta (sPDGFRβ) | Month 8 | 470.93 pg/mL | Standard Deviation 104.5 |
| Telmisartan 40mg | CSF-Soluble Platelet-Derived Growth Factor Receptor Beta (sPDGFRβ) | Baseline | 432.02 pg/mL | Standard Deviation 210.85 |
| Telmisartan 40mg | CSF-Soluble Platelet-Derived Growth Factor Receptor Beta (sPDGFRβ) | Month 8 | 391.10 pg/mL | Standard Deviation 151.23 |
| Placebo | CSF-Soluble Platelet-Derived Growth Factor Receptor Beta (sPDGFRβ) | Baseline | 403.74 pg/mL | Standard Deviation 156.44 |
| Placebo | CSF-Soluble Platelet-Derived Growth Factor Receptor Beta (sPDGFRβ) | Month 8 | 471.60 pg/mL | Standard Deviation 190.34 |
Secondary
Intercellular Adhesion Molecule 1 (ICAM-1) Frequency
Intercellular adhesion molecule 1 inflammatory markers in CSF were examined.
Time frame: Baseline, Month 8
Population: This analysis includes participants who completed 8 months of study treatment, attended the Month 8 study visit, and had a sufficient sample of CSF collected. The amount of CSF collected fluctuated and some samples were not of adequate quantity to be used for every lab measurement. In some cases, participants had an unsuccessful or inadequate lumbar puncture at Baseline and then had a successful lumbar puncture at the Month 8 visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Telmisartan 20mg | Intercellular Adhesion Molecule 1 (ICAM-1) Frequency | Baseline | 207.81 ng/mL | Standard Deviation 107.74 |
| Telmisartan 20mg | Intercellular Adhesion Molecule 1 (ICAM-1) Frequency | Month 8 | 472.01 ng/mL | Standard Deviation 385.47 |
| Telmisartan 40mg | Intercellular Adhesion Molecule 1 (ICAM-1) Frequency | Baseline | 310.55 ng/mL | Standard Deviation 258.73 |
| Telmisartan 40mg | Intercellular Adhesion Molecule 1 (ICAM-1) Frequency | Month 8 | 461.41 ng/mL | Standard Deviation 290.66 |
| Placebo | Intercellular Adhesion Molecule 1 (ICAM-1) Frequency | Baseline | 205.18 ng/mL | Standard Deviation 179.56 |
| Placebo | Intercellular Adhesion Molecule 1 (ICAM-1) Frequency | Month 8 | 591.69 ng/mL | Standard Deviation 494.44 |
Secondary
Interleukin-10 (IL-10) Frequency
The inflammatory marker IL-10 in CSF was examined.
Time frame: Baseline, Month 8
Population: This analysis includes participants who completed 8 months of study treatment, attended the Month 8 study visit, and had a sufficient sample of CSF collected. The amount of CSF collected fluctuated and some samples were not of adequate quantity to be used for every lab measurement. In some cases, participants had an unsuccessful or inadequate lumbar puncture at Baseline and then had a successful lumbar puncture at the Month 8 visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Telmisartan 20mg | Interleukin-10 (IL-10) Frequency | Baseline | 9.70 pg/mL | Standard Deviation 3.31 |
| Telmisartan 20mg | Interleukin-10 (IL-10) Frequency | Month 8 | 8.83 pg/mL | Standard Deviation 2.31 |
| Telmisartan 40mg | Interleukin-10 (IL-10) Frequency | Baseline | 11.93 pg/mL | Standard Deviation 3.32 |
| Telmisartan 40mg | Interleukin-10 (IL-10) Frequency | Month 8 | 10.15 pg/mL | Standard Deviation 2.85 |
| Placebo | Interleukin-10 (IL-10) Frequency | Baseline | 10.92 pg/mL | Standard Deviation 3.09 |
| Placebo | Interleukin-10 (IL-10) Frequency | Month 8 | 10.60 pg/mL | Standard Deviation 2.26 |
Secondary
Interleukin-6 (IL-6) Frequency
The inflammatory marker IL-6 in CSF was examined.
Time frame: Baseline, Month 8
Population: This analysis includes participants who completed 8 months of study treatment, attended the Month 8 study visit, and had a sufficient sample of CSF collected. The amount of CSF collected fluctuated and some samples were not of adequate quantity to be used for every lab measurement. In some cases, participants had an unsuccessful or inadequate lumbar puncture at Baseline and then had a successful lumbar puncture at the Month 8 visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Telmisartan 20mg | Interleukin-6 (IL-6) Frequency | Baseline | 9.41 pg/mL | Standard Deviation 3.25 |
| Telmisartan 20mg | Interleukin-6 (IL-6) Frequency | Month 8 | 8.51 pg/mL | Standard Deviation 4.73 |
| Telmisartan 40mg | Interleukin-6 (IL-6) Frequency | Baseline | 10.65 pg/mL | Standard Deviation 6.77 |
| Telmisartan 40mg | Interleukin-6 (IL-6) Frequency | Month 8 | 8.69 pg/mL | Standard Deviation 4.14 |
| Placebo | Interleukin-6 (IL-6) Frequency | Baseline | 8.62 pg/mL | Standard Deviation 3.08 |
| Placebo | Interleukin-6 (IL-6) Frequency | Month 8 | 8.19 pg/mL | Standard Deviation 3.23 |
Secondary
Interleukin-7 (IL-7) Frequency
The inflammatory marker IL-7 in CSF was examined.
Time frame: Baseline, Month 8
Population: This analysis includes participants who completed 8 months of study treatment, attended the Month 8 study visit, and had a sufficient sample of CSF collected. The amount of CSF collected fluctuated and some samples were not of adequate quantity to be used for every lab measurement. In some cases, participants had an unsuccessful or inadequate lumbar puncture at Baseline and then had a successful lumbar puncture at the Month 8 visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Telmisartan 20mg | Interleukin-7 (IL-7) Frequency | Baseline | 1.88 pg/mL | Standard Deviation 1.77 |
| Telmisartan 20mg | Interleukin-7 (IL-7) Frequency | Month 8 | 2.06 pg/mL | Standard Deviation 1.84 |
| Telmisartan 40mg | Interleukin-7 (IL-7) Frequency | Baseline | 1.70 pg/mL | Standard Deviation 1.57 |
| Telmisartan 40mg | Interleukin-7 (IL-7) Frequency | Month 8 | 1.16 pg/mL | Standard Deviation 0.66 |
| Placebo | Interleukin-7 (IL-7) Frequency | Baseline | 1.77 pg/mL | Standard Deviation 1.17 |
| Placebo | Interleukin-7 (IL-7) Frequency | Month 8 | 1.03 pg/mL | Standard Deviation 1.01 |
Secondary
Interleukin-8 (IL-8) Frequency
The inflammatory marker IL-8 in CSF was examined.
Time frame: Baseline, Month 8
Population: This analysis includes participants who completed 8 months of study treatment, attended the Month 8 study visit, and had a sufficient sample of CSF collected. The amount of CSF collected fluctuated and some samples were not of adequate quantity to be used for every lab measurement. In some cases, participants had an unsuccessful or inadequate lumbar puncture at Baseline and then had a successful lumbar puncture at the Month 8 visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Telmisartan 20mg | Interleukin-8 (IL-8) Frequency | Baseline | 123.77 pg/mL | Standard Deviation 64.31 |
| Telmisartan 20mg | Interleukin-8 (IL-8) Frequency | Month 8 | 103.31 pg/mL | Standard Deviation 42.88 |
| Telmisartan 40mg | Interleukin-8 (IL-8) Frequency | Baseline | 156.99 pg/mL | Standard Deviation 49.1 |
| Telmisartan 40mg | Interleukin-8 (IL-8) Frequency | Month 8 | 102.11 pg/mL | Standard Deviation 25.84 |
| Placebo | Interleukin-8 (IL-8) Frequency | Baseline | 165.40 pg/mL | Standard Deviation 100.25 |
| Placebo | Interleukin-8 (IL-8) Frequency | Month 8 | 122.99 pg/mL | Standard Deviation 51.36 |
Secondary
Interleukin-9 (IL-9) Frequency
The inflammatory marker IL-9 in CSF was examined.
Time frame: Baseline, Month 8
Population: This analysis includes participants who completed 8 months of study treatment, attended the Month 8 study visit, and had a sufficient sample of CSF collected. The amount of CSF collected fluctuated and some samples were not of adequate quantity to be used for every lab measurement. In some cases, participants had an unsuccessful or inadequate lumbar puncture at Baseline and then had a successful lumbar puncture at the Month 8 visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Telmisartan 20mg | Interleukin-9 (IL-9) Frequency | Baseline | 96.55 pg/mL | Standard Deviation 64.31 |
| Telmisartan 20mg | Interleukin-9 (IL-9) Frequency | Month 8 | 81.24 pg/mL | Standard Deviation 34.06 |
| Telmisartan 40mg | Interleukin-9 (IL-9) Frequency | Baseline | 153.65 pg/mL | Standard Deviation 71.26 |
| Telmisartan 40mg | Interleukin-9 (IL-9) Frequency | Month 8 | 98.32 pg/mL | Standard Deviation 28.48 |
| Placebo | Interleukin-9 (IL-9) Frequency | Baseline | 119.18 pg/mL | Standard Deviation 79.53 |
| Placebo | Interleukin-9 (IL-9) Frequency | Month 8 | 88.22 pg/mL | Standard Deviation 39.96 |
Secondary
Macrophage Derived Protein 1 (MDC-1) Frequency
Macrophage derived protein 1 inflammatory markers in CSF were examined.
Time frame: Baseline, Month 8
Population: This analysis includes participants who completed 8 months of study treatment, attended the Month 8 study visit, and had a sufficient sample of CSF collected. The amount of CSF collected fluctuated and some samples were not of adequate quantity to be used for every lab measurement. In some cases, participants had an unsuccessful or inadequate lumbar puncture at Baseline and then had a successful lumbar puncture at the Month 8 visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Telmisartan 20mg | Macrophage Derived Protein 1 (MDC-1) Frequency | Baseline | 23.68 pg/mL | Standard Deviation 30.61 |
| Telmisartan 20mg | Macrophage Derived Protein 1 (MDC-1) Frequency | Month 8 | 6.70 pg/mL | Standard Deviation 4.84 |
| Telmisartan 40mg | Macrophage Derived Protein 1 (MDC-1) Frequency | Baseline | 13.12 pg/mL | Standard Deviation 22.27 |
| Telmisartan 40mg | Macrophage Derived Protein 1 (MDC-1) Frequency | Month 8 | 9.47 pg/mL | Standard Deviation 5.46 |
| Placebo | Macrophage Derived Protein 1 (MDC-1) Frequency | Baseline | 30.88 pg/mL | Standard Deviation 67.71 |
| Placebo | Macrophage Derived Protein 1 (MDC-1) Frequency | Month 8 | 10.40 pg/mL | Standard Deviation 4.41 |
Secondary
Matrix Metalloproteinase (MMP) Frequency
Matrix metalloproteinase inflammatory markers will be examined in CSF.
Time frame: Baseline, Month 8
Population: MMP was not analyzed because since developing the protocol for this study much has been learned about inflammatory cytokines and chemokines as AD preclinical biomarkers. The biological assay menu options for group analyses changed to include only those that have been shown to be related to disease state and likelihood of progression. The marker MMP was removed from the preplanned menu of inflammatory markers by the manufacturer and having MMP analyzed independently was cost prohibitive.
Secondary
Monocyte Chemoattractant Protein 1 (MCP-1) Frequency
Monocyte chemoattractant protein 1 inflammatory markers in CSF were examined.
Time frame: Baseline, Month 8
Population: This analysis includes participants who completed 8 months of study treatment, attended the Month 8 study visit, and had a sufficient sample of CSF collected. The amount of CSF collected fluctuated and some samples were not of adequate quantity to be used for every lab measurement. In some cases, participants had an unsuccessful or inadequate lumbar puncture at Baseline and then had a successful lumbar puncture at the Month 8 visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Telmisartan 20mg | Monocyte Chemoattractant Protein 1 (MCP-1) Frequency | Month 8 | 2069.32 pg/mL | Standard Deviation 735.75 |
| Telmisartan 20mg | Monocyte Chemoattractant Protein 1 (MCP-1) Frequency | Baseline | 3369.30 pg/mL | Standard Deviation 1180.22 |
| Telmisartan 40mg | Monocyte Chemoattractant Protein 1 (MCP-1) Frequency | Baseline | 3347.26 pg/mL | Standard Deviation 786.79 |
| Telmisartan 40mg | Monocyte Chemoattractant Protein 1 (MCP-1) Frequency | Month 8 | 2343.98 pg/mL | Standard Deviation 487.36 |
| Placebo | Monocyte Chemoattractant Protein 1 (MCP-1) Frequency | Baseline | 3606.96 pg/mL | Standard Deviation 1077.71 |
| Placebo | Monocyte Chemoattractant Protein 1 (MCP-1) Frequency | Month 8 | 2548.37 pg/mL | Standard Deviation 872.88 |
Secondary
Tissue Inhibitor of Metalloproteinase (TIMP) Frequency
Tissue inhibitor of metalloproteinase inflammatory markers will be examined in CSF.
Time frame: Baseline, Month 8
Population: TIMP was not analyzed because since developing the protocol for this study much has been learned about inflammatory cytokines and chemokines as AD preclinical biomarkers. The biological assay menu options for group analyses changed to include only those that have been shown to be related to disease state and likelihood of progression. The marker TIMP was removed from the preplanned menu of inflammatory markers by the manufacturer and having TIMP analyzed independently was cost prohibitive.
Secondary
Transforming Growth Factor Alpha (TGF-α) Frequency
Transforming growth factor alpha inflammatory markers in CSF were examined.
Time frame: Baseline, Month 8
Population: This analysis includes participants who completed 8 months of study treatment, attended the Month 8 study visit, and had a sufficient sample of CSF collected. The amount of CSF collected fluctuated and some samples were not of adequate quantity to be used for every lab measurement. In some cases, participants had an unsuccessful or inadequate lumbar puncture at Baseline and then had a successful lumbar puncture at the Month 8 visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Telmisartan 20mg | Transforming Growth Factor Alpha (TGF-α) Frequency | Baseline | 9.42 pg/mL | Standard Deviation 2.29 |
| Telmisartan 20mg | Transforming Growth Factor Alpha (TGF-α) Frequency | Month 8 | 7.56 pg/mL | Standard Deviation 2.08 |
| Telmisartan 40mg | Transforming Growth Factor Alpha (TGF-α) Frequency | Baseline | 9.58 pg/mL | Standard Deviation 1.65 |
| Telmisartan 40mg | Transforming Growth Factor Alpha (TGF-α) Frequency | Month 8 | 7.07 pg/mL | Standard Deviation 1.61 |
| Placebo | Transforming Growth Factor Alpha (TGF-α) Frequency | Baseline | 9.05 pg/mL | Standard Deviation 1.71 |
| Placebo | Transforming Growth Factor Alpha (TGF-α) Frequency | Month 8 | 7.25 pg/mL | Standard Deviation 1.25 |
Secondary
Tumor Necrosis Factor Alpha (TNF-α) Frequency
Tumor necrosis factor alpha inflammatory markers in CSF were examined.
Time frame: Baseline, Month 8
Population: This analysis includes participants who completed 8 months of study treatment, attended the Month 8 study visit, and had a sufficient sample of CSF collected. The amount of CSF collected fluctuated and some samples were not of adequate quantity to be used for every lab measurement. In some cases, participants had an unsuccessful or inadequate lumbar puncture at Baseline and then had a successful lumbar puncture at the Month 8 visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Telmisartan 20mg | Tumor Necrosis Factor Alpha (TNF-α) Frequency | Baseline | 4.54 pg/mL | Standard Deviation 4.12 |
| Telmisartan 20mg | Tumor Necrosis Factor Alpha (TNF-α) Frequency | Month 8 | 2.96 pg/mL | Standard Deviation 0.94 |
| Telmisartan 40mg | Tumor Necrosis Factor Alpha (TNF-α) Frequency | Baseline | 6.72 pg/mL | Standard Deviation 4.68 |
| Telmisartan 40mg | Tumor Necrosis Factor Alpha (TNF-α) Frequency | Month 8 | 3.12 pg/mL | Standard Deviation 0.98 |
| Placebo | Tumor Necrosis Factor Alpha (TNF-α) Frequency | Baseline | 5.17 pg/mL | Standard Deviation 3.28 |
| Placebo | Tumor Necrosis Factor Alpha (TNF-α) Frequency | Month 8 | 4.71 pg/mL | Standard Deviation 8.63 |
Secondary
Vascular Cell Adhesion Molecule 1 (VCAM-1) Frequency
Vascular cell adhesion molecule 1 inflammatory markers in CSF were examined.
Time frame: Baseline, Month 8
Population: This analysis includes participants who completed 8 months of study treatment, attended the Month 8 study visit, and had a sufficient sample of CSF collected. The amount of CSF collected fluctuated and some samples were not of adequate quantity to be used for every lab measurement. In some cases, participants had an unsuccessful or inadequate lumbar puncture at Baseline and then had a successful lumbar puncture at the Month 8 visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Telmisartan 20mg | Vascular Cell Adhesion Molecule 1 (VCAM-1) Frequency | Baseline | 12585.04 ng/mL | Standard Deviation 10891.2 |
| Telmisartan 20mg | Vascular Cell Adhesion Molecule 1 (VCAM-1) Frequency | Month 8 | 12964.43 ng/mL | Standard Deviation 2893.44 |
| Telmisartan 40mg | Vascular Cell Adhesion Molecule 1 (VCAM-1) Frequency | Baseline | 16838.79 ng/mL | Standard Deviation 9151.95 |
| Telmisartan 40mg | Vascular Cell Adhesion Molecule 1 (VCAM-1) Frequency | Month 8 | 172781.50 ng/mL | Standard Deviation 4513.46 |
| Placebo | Vascular Cell Adhesion Molecule 1 (VCAM-1) Frequency | Baseline | 13807.56 ng/mL | Standard Deviation 8991.6 |
| Placebo | Vascular Cell Adhesion Molecule 1 (VCAM-1) Frequency | Month 8 | 19212.32 ng/mL | Standard Deviation 8557.18 |
Other Pre-specified
Change in Arterial Spin Labeling-Magnetic Resonance Imaging
Echoplanar T1 mapping scans will be used for image registration and a scout image of the head will be obtained in order to choose the appropriate location for spin labeling and flow imaging. Arterial Spin Labeling images will be acquired using a custom 3D stack of interleaved spirals fast spin echo sequences and will be averaged in order to improve the signal-to-noise ratio. Images will be interpolated and smoothed in a panel by using a 0.5-pixel, full-width, half-maximum Gaussian kernel. Regional perfusion will be quantified in each hemisphere and maps of cerebral vasoreactivity will be obtained by co-registration of perfusion and anatomical images.
Time frame: Baseline, Month 8
Other Pre-specified
Change in Structural Magnetic Resonance Imaging and White Matter Hyperintensities
High-resolution anatomical images will be acquired using a 3D-Fast Spoiled Gradient Recalled Echo (FSPGR) Sequence. White Matter Hyperintensities (WMH) will be identified by a 3D T2 Fluid Attenuated Inversion Recovery (FLAIR) Fast Spin Echo sequence. The images will be co-registered using a within-subject inter-modal alignment between structural and perfusion images. T1-weighted Spoiled Gradient Recalled (SPGR) images will be used to identify cerebrospinal fluid and white and gray matter. Increased volumes of white matter hyperintensities indicate impaired cognitive function.
Time frame: Baseline, Month 8