Alzheimer Disease
Conditions
Brief summary
By doing this study researchers hope to learn if S-equol, a compound that acts like estrogen in the body, causes an increase in mitochondrial activity. Researchers also hope to determine the safety and tolerability of a therapeutic dose of S-equol and whether or not it influences cognition.
Detailed description
Enrolled participants with a diagnosis of Alzheimer's Disease (AD) will be randomized to receive either S-equol or placebo first, and then cross over to receive the opposite intervention. The study, therefore, consists of two treatment periods with randomly assigned treatment order. Specifically, subjects are randomized to either: (1) S-equol for one month, then placebo for one month; or (2) placebo for one month, then S-equol for one month.
Interventions
DRUGS-equol and Placebo
S-equol is an estrogen receptor β (ERβ) agonist. Provided in capsules. The placebo is a matched pill that cannot be distinguished from the active S-equol.
DRUGPlacebo and S-equol
S-equol is an estrogen receptor β (ERβ) agonist. Provided in capsules. The placebo is a matched pill that cannot be distinguished from the active S-equol.
Sponsors
Ausio Pharmaceuticals, LLC
Russell Swerdlow
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
* Have a diagnosis of Alzheimer's Disease (AD) * Have a study partner who has a close relationship with the participant and will attend study visits with the participant * Do not possess an Alkylphenol ethoxylates 4 (APOE4) variant of the APOE gene * Speak English as their primary language * Have not had any medication changes within the past 30 days
Exclusion criteria
* Reside in a nursing home or dementia special care unit * Have a potentially confounding, serious medical risk such as insulin-requiring diabetes, any history of cancer that required a chemotherapy or radiation therapy intervention within the past 5 years, or a recent cardiac event * Have any clinically significant abnormal safety laboratory values at the SEAD2 screening visit * Have any clinically significant abnormal findings on vital signs measurements, or on physical or neurological examination at the SEAD2 screening visit * Use any type of systemic estrogen or testosterone replacement therapy * Has participated in another clinical trial or received any investigational drug or investigational therapy within 30 days before the screening visit
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cytochrome Oxidase/Citrate Synthase (COX/CS) Activity | Column 1 is the value after completing S-equol minus the value after completing placebo. For S-equol then placebo, this is the Visit 3 minus the Visit 4 COX/CS value. For placebo then S-equol, this is the Visit 4 minus the Visit 3 COX/CS value. | Cytochrome oxidase (COX) was measured in platelet mitochondria as a pseudo-first order rate constant (sec-1/mg protein), which was determined as a Vmax, spectrophotometrically, by tracking the change in absorbance as reduced cytochrome c is oxidized to oxidized cytochrome C. Citrate synthase (CS) is a soluble mitochondrial matrix enzyme whose activity was determined spectrophotometrically as a Vmax (micromoles/mg protein). Reporting the COX activity as a ratio to CS activity takes mitochondrial mass into account, and normalizes the COX activity per the amount of mitochondria present in the assay sample, with units 1/(seconds multiplied by micromoles). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Montreal Cognitive Assessment (MoCA) | Score after completion of S-equol minus score after completion of placebo. For S-equol then placebo, this is the Visit 3 minus the Visit 4 MoCA score. For placebo then S-equol, this is the Visit 4 minus the Visit 3 MoCA score. | Scale range: 0-30. A higher score indicates better global cognitive performance. |
| Alzheimer's Disease Assessment Scale-Cognitive Portion (ADASCog-11) | Score after completion of S-equol minus score after completion of placebo. For S-equol then placebo, this is the Visit 3 minus the Visit 4 ADASCog score. For placebo then S-equol, this is the Visit 4 minus the Visit 3 ADASCog score. | Scale range: 0-70. A lower score indicates better global cognitive performance. |
| Logical Memory Test 1 (LMT1) - Immediate Recall | Score after completion of S-equol minus score after completion of placebo. For S-equol then placebo, this is the Visit 3 minus the Visit 4 LMT1 score. For placebo then S-equol, this is the Visit 4 minus the Visit 3 LMT1 score. | Scale range: 0-25. A higher score indicates better memory function. |
| Logical Memory Test 2 (LMT2) - Delayed Recall | Score after completion of S-equol minus score after completion of placebo. For S-equol then placebo, this is the Visit 3 minus the Visit 4 LMT2 score. For placebo then S-equol, this is the Visit 4 minus the Visit 3 LMT2 score. | Scale range: 0-25. A higher score indicates better memory performance. |
| Pattern of COX Activity Changes While on the Active Treatment Versus Placebo Arms of This Crossover Study. | Visits 2, 3, 4 | Participants are defined as responders or non-responders depending on the slope of COX/CS activity change. Those in the Responder group have a greater slope of COX/CS activity change going from off- to on-S-equol as compared to going from on- to off-S-equol. |
| Stroop Word Test | Score after completion of S-equol minus score after completion of placebo. For S-equol then placebo, this is the Visit 3 minus the Visit 4 Stroop Word Test score. For placebo then S-equol, this is the Visit 4 minus the Visit 3 Stroop Word Test score. | Scale range: 0-unlimited. A higher score indicates better executive function. |
| Stroop Interference Test | Score after completing S-equol minus score after completing placebo. For S-equol then placebo, this is the Visit 3 minus the Visit 4 Stroop Interference score. For placebo then S-equol, this is the Visit 4 minus the Visit 3 Stroop Interference score. | Scale range: 0-unlimited. A higher score indicates better executive function. |
| Number of Participants With Adverse Events | 4 Months: From Visit 1 (Day 0) through Visit 1 (end of month 1, +/- 7 days), Visit 2 (end of month 2, +/- 7 days), Visit 3 (end of month 3, +/- 7days), and Post-Interventions Phone Call (end of month 4, +/- 7 days) | List of adverse events as reported over the course of the study (safety labs, physical and neurological exams, vital signs, signs and symptoms). |
| Stroop Color Test Score | Score after completion of S-equol minus score after completion of placebo. For S-equol then placebo, this is the Visit 3 minus the Visit 4 Stroop Color Test score. For placebo then S-equol, this is the Visit 4 minus the Visit 3 Stroop Color Test score. | Scale range: 0-unlimited. A higher score indicates better executive function. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| S-equol First, Then Placebo This group received S-equol for one month, and then crossed over to receive placebo for one month. There was no washout period. | 20 |
| Placebo First, Then S-Equol This group received placebo for one month, then crossed over to receive S-equol for one month. There was no washout period. | 20 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo First, Then S-Equol | Total | S-equol First, Then Placebo |
|---|---|---|---|
| Age, Continuous | 71.7 years STANDARD_DEVIATION 8.4 | 74.2 years STANDARD_DEVIATION 8.2 | 76.7 years STANDARD_DEVIATION 7.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 40 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 20 Participants | 38 Participants | 18 Participants |
| Sex: Female, Male Female | 12 Participants | 21 Participants | 9 Participants |
| Sex: Female, Male Male | 8 Participants | 19 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 40 | 0 / 40 | 0 / 40 | 0 / 40 |
| other Total, other adverse events | 1 / 40 | 8 / 40 | 8 / 40 | 4 / 40 |
| serious Total, serious adverse events | 0 / 40 | 0 / 40 | 0 / 40 | 0 / 40 |
Outcome results
Primary
Cytochrome Oxidase/Citrate Synthase (COX/CS) Activity
Cytochrome oxidase (COX) was measured in platelet mitochondria as a pseudo-first order rate constant (sec-1/mg protein), which was determined as a Vmax, spectrophotometrically, by tracking the change in absorbance as reduced cytochrome c is oxidized to oxidized cytochrome C. Citrate synthase (CS) is a soluble mitochondrial matrix enzyme whose activity was determined spectrophotometrically as a Vmax (micromoles/mg protein). Reporting the COX activity as a ratio to CS activity takes mitochondrial mass into account, and normalizes the COX activity per the amount of mitochondria present in the assay sample, with units 1/(seconds multiplied by micromoles).
Time frame: Column 1 is the value after completing S-equol minus the value after completing placebo. For S-equol then placebo, this is the Visit 3 minus the Visit 4 COX/CS value. For placebo then S-equol, this is the Visit 4 minus the Visit 3 COX/CS value.
Population: Due to the pandemic, 1 participant in the Placebo, Then S-equol group did not complete the analysis. This subject was excluded from this primary analysis, and all secondary analyses except for the safety analysis. As the order of the intervention does not matter, all 39 participants who contributed COX/CS data to the final analysis are included. The mean (SD) value reflects the mean of values obtained when the COX/CS value while on placebo was subtracted from the COX/CS score while on S-equol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Difference (on S-equol Minus on Placebo) | Cytochrome Oxidase/Citrate Synthase (COX/CS) Activity | -0.0000049 1/(seconds multiplied by micromoles) | Standard Deviation 0.000024 |
| S-equol | Cytochrome Oxidase/Citrate Synthase (COX/CS) Activity | 0.0000195 1/(seconds multiplied by micromoles) | Standard Deviation 0.0000081 |
| Placebo | Cytochrome Oxidase/Citrate Synthase (COX/CS) Activity | 0.0000245 1/(seconds multiplied by micromoles) | Standard Deviation 0.0000258 |
Comparison: As the order of the intervention does not matter, all 39 participants who contributed data to the final analysis are included together.p-value: >0.05Paired T-test
Secondary
Alzheimer's Disease Assessment Scale-Cognitive Portion (ADASCog-11)
Scale range: 0-70. A lower score indicates better global cognitive performance.
Time frame: Score after completion of S-equol minus score after completion of placebo. For S-equol then placebo, this is the Visit 3 minus the Visit 4 ADASCog score. For placebo then S-equol, this is the Visit 4 minus the Visit 3 ADASCog score.
Population: The one subject missing the COX/CS difference score was excluded from this analysis. The key measure is the difference score. Participants unable to contribute both S-equol and placebo scores were not included in the difference score analysis, but do contribute to the S-equol or placebo scores as available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Difference (on S-equol Minus on Placebo) | Alzheimer's Disease Assessment Scale-Cognitive Portion (ADASCog-11) | 1.1 score on a scale | Standard Deviation 5.5 |
| S-equol | Alzheimer's Disease Assessment Scale-Cognitive Portion (ADASCog-11) | 24.6 score on a scale | Standard Deviation 11.3 |
| Placebo | Alzheimer's Disease Assessment Scale-Cognitive Portion (ADASCog-11) | 23.5 score on a scale | Standard Deviation 10.6 |
Secondary
Logical Memory Test 1 (LMT1) - Immediate Recall
Scale range: 0-25. A higher score indicates better memory function.
Time frame: Score after completion of S-equol minus score after completion of placebo. For S-equol then placebo, this is the Visit 3 minus the Visit 4 LMT1 score. For placebo then S-equol, this is the Visit 4 minus the Visit 3 LMT1 score.
Population: The one subject missing the COX/CS difference score was excluded from this analysis. The key measure is the difference score. Participants unable to contribute both S-equol and placebo scores were not included in the difference score analysis, but do contribute to the S-equol or placebo scores as available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Difference (on S-equol Minus on Placebo) | Logical Memory Test 1 (LMT1) - Immediate Recall | 0.2 score on a scale | Standard Deviation 2.9 |
| S-equol | Logical Memory Test 1 (LMT1) - Immediate Recall | 4.1 score on a scale | Standard Deviation 4.2 |
| Placebo | Logical Memory Test 1 (LMT1) - Immediate Recall | 3.9 score on a scale | Standard Deviation 3.3 |
Secondary
Logical Memory Test 2 (LMT2) - Delayed Recall
Scale range: 0-25. A higher score indicates better memory performance.
Time frame: Score after completion of S-equol minus score after completion of placebo. For S-equol then placebo, this is the Visit 3 minus the Visit 4 LMT2 score. For placebo then S-equol, this is the Visit 4 minus the Visit 3 LMT2 score.
Population: The one subject missing the COX/CS difference score was excluded from this analysis. The key measure is the difference score. Participants unable to contribute both S-equol and placebo scores were not included in the difference score analysis, but do contribute to the S-equol or placebo scores as available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Difference (on S-equol Minus on Placebo) | Logical Memory Test 2 (LMT2) - Delayed Recall | 0.2 score on a scale | Standard Deviation 2 |
| S-equol | Logical Memory Test 2 (LMT2) - Delayed Recall | 1.9 score on a scale | Standard Deviation 3.4 |
| Placebo | Logical Memory Test 2 (LMT2) - Delayed Recall | 1.8 score on a scale | Standard Deviation 2.7 |
Secondary
Montreal Cognitive Assessment (MoCA)
Scale range: 0-30. A higher score indicates better global cognitive performance.
Time frame: Score after completion of S-equol minus score after completion of placebo. For S-equol then placebo, this is the Visit 3 minus the Visit 4 MoCA score. For placebo then S-equol, this is the Visit 4 minus the Visit 3 MoCA score.
Population: The one subject missing the COX/CS difference score was excluded from this analysis. The key measure is the difference score. Participants unable to contribute both S-equol and placebo scores were not included in the difference score analysis, but do contribute to the S-equol or placebo scores as available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Difference (on S-equol Minus on Placebo) | Montreal Cognitive Assessment (MoCA) | 0.2 score on a scale | Standard Deviation 2.4 |
| S-equol | Montreal Cognitive Assessment (MoCA) | 12.3 score on a scale | Standard Deviation 6.3 |
| Placebo | Montreal Cognitive Assessment (MoCA) | 12.0 score on a scale | Standard Deviation 6.1 |
Secondary
Number of Participants With Adverse Events
List of adverse events as reported over the course of the study (safety labs, physical and neurological exams, vital signs, signs and symptoms).
Time frame: 4 Months: From Visit 1 (Day 0) through Visit 1 (end of month 1, +/- 7 days), Visit 2 (end of month 2, +/- 7 days), Visit 3 (end of month 3, +/- 7days), and Post-Interventions Phone Call (end of month 4, +/- 7 days)
Population: All 40 enrolled participants contributed to the safety data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Difference (on S-equol Minus on Placebo) | Number of Participants With Adverse Events | 1 participants |
| S-equol | Number of Participants With Adverse Events | 8 participants |
| Placebo | Number of Participants With Adverse Events | 8 participants |
| After Completing Both Drug and Placebo | Number of Participants With Adverse Events | 4 participants |
Secondary
Pattern of COX Activity Changes While on the Active Treatment Versus Placebo Arms of This Crossover Study.
Participants are defined as responders or non-responders depending on the slope of COX/CS activity change. Those in the Responder group have a greater slope of COX/CS activity change going from off- to on-S-equol as compared to going from on- to off-S-equol.
Time frame: Visits 2, 3, 4
Population: Only the 20 participants who had baseline then S-equol then placebo values contributed to this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Difference (on S-equol Minus on Placebo) | Pattern of COX Activity Changes While on the Active Treatment Versus Placebo Arms of This Crossover Study. | 7 participants |
Secondary
Stroop Color Test Score
Scale range: 0-unlimited. A higher score indicates better executive function.
Time frame: Score after completion of S-equol minus score after completion of placebo. For S-equol then placebo, this is the Visit 3 minus the Visit 4 Stroop Color Test score. For placebo then S-equol, this is the Visit 4 minus the Visit 3 Stroop Color Test score.
Population: The one subject missing the COX/CS difference score was excluded from this analysis. The key measure is the difference score. Participants unable to contribute both S-equol and placebo scores were not included in the difference score analysis, but do contribute to the S-equol or placebo scores as available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Difference (on S-equol Minus on Placebo) | Stroop Color Test Score | -0.1 score on a scale | Standard Deviation 5.8 |
| S-equol | Stroop Color Test Score | 40.0 score on a scale | Standard Deviation 20.9 |
| Placebo | Stroop Color Test Score | 39.3 score on a scale | Standard Deviation 18.5 |
Secondary
Stroop Interference Test
Scale range: 0-unlimited. A higher score indicates better executive function.
Time frame: Score after completing S-equol minus score after completing placebo. For S-equol then placebo, this is the Visit 3 minus the Visit 4 Stroop Interference score. For placebo then S-equol, this is the Visit 4 minus the Visit 3 Stroop Interference score.
Population: The one subject missing the COX/CS difference score was excluded from this analysis. The key measure is the difference score. Participants unable to contribute both S-equol and placebo scores were not included in the difference score analysis, but do contribute to the S-equol or placebo scores as available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Difference (on S-equol Minus on Placebo) | Stroop Interference Test | -1.2 score on a scale | Standard Deviation 6.8 |
| S-equol | Stroop Interference Test | 14.5 score on a scale | Standard Deviation 7.4 |
| Placebo | Stroop Interference Test | 15.3 score on a scale | Standard Deviation 8.2 |
Secondary
Stroop Word Test
Scale range: 0-unlimited. A higher score indicates better executive function.
Time frame: Score after completion of S-equol minus score after completion of placebo. For S-equol then placebo, this is the Visit 3 minus the Visit 4 Stroop Word Test score. For placebo then S-equol, this is the Visit 4 minus the Visit 3 Stroop Word Test score.
Population: The one subject missing the COX/CS difference score was excluded from this analysis. The key measure is the difference score. Participants unable to contribute both S-equol and placebo scores were not included in the difference score analysis, but do contribute to the S-equol or placebo scores as available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Difference (on S-equol Minus on Placebo) | Stroop Word Test | -0.1 score on a scale | Standard Deviation 9.5 |
| S-equol | Stroop Word Test | 56.1 score on a scale | Standard Deviation 23.1 |
| Placebo | Stroop Word Test | 56.3 score on a scale | Standard Deviation 21.9 |