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NCT Number: NCT03462121

A Clinical Study Evaluating the Efficacy and Safety of RPh201 Treatment in Individuals With Alzheimer's Disease With or Without Coexisting Cerebrovascular Disease

This study is a randomized, double-blind, placebo-controlled, multicentre, Phase 2 study, with an optional open-label extension, to evaluate the safety, tolerability, and efficacy of RPh201 in subjects with mild to moderate AD who are eligible for enrollment in this study.

Subject participation will include a Screening Phase, Treatment Phase, and an Optional Open-Label Extension. The Screening Phase will be up to 4 weeks prior to randomization. Both the subject and their study partner(s) will sign an informed consent form (ICF). At Visit 2, Subjects will be randomized 2:1 to RPh201 or placebo. The Treatment Phase will last for 6 months post-randomization, or until subject withdrawal from the study, whichever comes first. The Optional Open-Label Extension will begin once a subject has completed the Treatment Phase and the subject and their study partner(s) have signed an ICF to continue on the study. The Optional Open-Label Extension will continue for 6 months, or until subject withdrawal from the study, whichever comes first. Subjects who do not participate in the Optional Open-Label Extension will be asked to return for an optional post-study visit 6 months after the end of the Treatment Phase.

Subjects may participate in an optional biomarker sub-study. Up to 15 subjects may also participate in an optional FDG-PET sub-study during their study participation. Separate informed consent will be required for both of these sub-studies.

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Key information

Conditions

Mild to Moderate Dementia Due to Alzheimer's Disease Alzheimer Disease Brain Diseases Central Nervous System Diseases Dementia Mental Disorders Nervous System Diseases Neurocognitive Disorders Neurodegenerative Diseases Tauopathies With or Without Coexisting Cerebrovascular Disease

Age range

65 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Kawartha Centre - Redefining Healthy Aging, Peterborough, Ontario, Canada

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Subjects must be ≥65 years of age at the time of consent.
  • Subjects 65-69 years old, inclusive, must have evidence of cerebrovascular disease.
  • Meet National Institute on Aging-Alzheimer's Association 2011 criteria for All-Cause Dementia and have evidence for probable AD or possible AD with coexisting cerebrovascular disease. Coexisting cerebrovascular disease includes evidence of any of the following: cortical infarcts, subcortical and lacunar infarcts, macro or micro-hemorrhage, and small vessel ischemic microangiopathy.
  • Willing and able to provide informed consent or, if incapable of informed consent, have a legally authorized representative willing to consent on their behalf.
  • MMSE at screen visit: 15-22, inclusive.
  • Cholinesterase inhibitors, memantine, and other background medications impacting cognition and mood, if used, are at stable doses for at least 6 weeks prior to screening.
  • A study partner is available who has adequate contact with the subject to administer study drug, oversee study drug compliance, report on adverse events (AEs), and provide meaningful input into scales and assessments.
  • Adequate hearing, vision, and fluency in the language of testing.
  • Magnetic resonance imaging (MRI) of the brain must reveal findings consistent with AD with or without coexisting cerebrovascular disease. In subjects for whom brain MRI is contraindicated (e.g., presence of a pacemaker), computed tomography (CT) of the brain is acceptable. Historic MRI or CT scans up to 18 months prior to screening may be used for inclusion unless there have been interval clinical events warranting an updated scan.
  • Male subjects who are sexually active must agree to use one of the following acceptable methods of birth control from Screening and for at least one month after the last dose of study drug: abstinence (no sexual intercourse), male condom, or vasectomy.
  • Subjects must be willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
  • Optional FDG-PET sub-study: no contraindications to PET imaging. Individuals participating in the FDG-PET sub-study will be capped at 15 volunteers and a further cap may be imposed on the number enrolling in this sub-study without evidence of cerebrovascular disease.

Exclusion criteria

  • Neurological or non-neurological conditions other than AD and cerebrovascular disease that, in the Investigator's opinion, contribute to, or provide alternative etiology for, the subject's dementia. Examples include, but are not limited to, brain tumors, clinically significant head injury, Parkinson's disease, current or prior excess use of alcohol that, in the investigator's judgment, has caused or significantly contributed to the subject's cognitive decline, or primary psychiatric disorders (e.g., schizophrenia or bipolar affective disorder).
  • Unstable medical conditions which are likely to impact subject's ability to complete the trial and which are likely to confound AE assessment. These include, but are not limited to, uncontrolled hypertension, uncontrolled diabetes, and cancer within past the 2 years. Exceptions include prostate cancer in-situ and local basal and squamous cell skin cancers.
  • Chronic use of systemic or inhaled steroids (use of topical steroids is acceptable).
  • Other concomitant medications that, in the Investigator's judgment, impair cognition and/or confound efficacy assessments.
  • Women of child-bearing potential are excluded (e.g., women who have not been post-menopausal for at least 2 years or are not surgically sterile).
  • Treatment with investigational product from a previous clinical drug trial within the last 30 days or five half-lives prior to Visit 2 (Baseline), whichever is longer.

Treatment and study plan

RPh201

Drug

RPh201 is a well-defined extract from a botanical source

Placebo

Other

Inactive placebo consisting of the therapeutic vehicle

Other names: Cottonseed oil

Primary outcomes

  1. Change in (Alzheimer disease assessment scale) ADAS-Cog score between Baseline and Month 6

    Time frame: Month 6

    The ADAS-Cog is an established general cognitive measure scaled used in clinical trials of AD. The ADAS-Cog assesses multiple performance and cognitive domains including memory, language, praxis, and orientation. Test responses are scored using summed error points where 0 represents no errors and 70 represents errors on all items; higher scores indicate greater cognitive impairment.

  2. Change in CDR-SB score between Baseline and Month 6

    Time frame: Month 6

    The CDR is a global clinical scale with established diagnostic and severity-ranking utility widely used in clinical trials yielding global and sum of boxes scores (CDR-SB). The CDR global score is used in AD trials as a global measure of disease severity. The CDR is rated based on subject and informant input. The CDR assess three domains of cognition (memory, orientation, judgment/problem solving) and three domains of function (community affairs, home/hobbies, personal care) using semi- structured interviews of both the study subject and a companion/informant carried out by a trained rater and scored using a standard methodology. Each domain is rated on a 5-point scale of functioning as follows: (0) no impairment; (0.5) questionable impairment; (1) mild impairment; (2) moderate impairment; (3) severe impairment (personal care is scored on a 4-point scale without a 0.5 rating available). Higher scores indicate greater impairment.

  3. AEs at Month 6

    Time frame: Month 6

  4. 12-lead ECG at Month 6

    Time frame: Month 6

  5. Clinical Laboratory Assessments - (blood and urine) at at Month 6

    Time frame: Month 6

    Chemistry: alkaline phosphatase, albumin, blood urea nitrogen, calcium, chloride, creatinine, glucose (random), inorganic phosphorus, potassium, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, lactate dehydrogenase, sodium, direct bilirubin, total bilirubin, total protein, amylase, uric acid Hematology: haemoglobin, hematocrit, red blood cell count, white blood cell (WBC) count, WBC differential (absolute counts), numerical platelet count Urinalysis: specific gravity, pH, ketones, glucose, nitrite, blood, leukocyte esterase, protein, urobilinogen, bilirubin If nitrite, blood, or protein tests are positive, a microscopic examination will be performed

  6. Vital Signs

    Time frame: Month 6

    Vital signs consist of tympanic temperature, respiratory rate, blood pressure (systolic and diastolic blood pressure, mmHg), and pulse (bpm) after at least 3 minutes rest. Blood pressure will be measured in a sitting or semi-reclined seated position. Weight and height will be captured at Screening and weight will be captured at all other visits where this assessment is performed.

Secondary outcomes

  1. Change from Baseline on ADAS-Cog total scores at Month 3

    Time frame: Months 3

    The ADAS-Cog is an established general cognitive measure scaled used in clinical trials of AD. The ADAS-Cog assesses multiple performance and cognitive domains including memory, language, praxis, and orientation. Test responses are scored using summed error points where 0 represents no errors and 70 represents errors on all items; higher scores indicate greater cognitive impairment.

  2. Change from Baseline on ADAS-Cog total scores at Month 5

    Time frame: Month 5

    The ADAS-Cog is an established general cognitive measure scaled used in clinical trials of AD. The ADAS-Cog assesses multiple performance and cognitive domains including memory, language, praxis, and orientation. Test responses are scored using summed error points where 0 represents no errors and 70 represents errors on all items; higher scores indicate greater cognitive impairment.

  3. Change from Baseline on ADAS-Cog total scores at Month 12

    Time frame: Month 12

    The ADAS-Cog is an established general cognitive measure scaled used in clinical trials of AD. The ADAS-Cog assesses multiple performance and cognitive domains including memory, language, praxis, and orientation. Test responses are scored using summed error points where 0 represents no errors and 70 represents errors on all items; higher scores indicate greater cognitive impairment.

  4. Change from Baseline on CDR-SB total scores at Month 3

    Time frame: Month 3

    The CDR is a global clinical scale with established diagnostic and severity-ranking utility widely used in clinical trials yielding global and sum of boxes scores (CDR-SB). The CDR global score is used in AD trials as a global measure of disease severity. The CDR is rated based on subject and informant input. The CDR assess three domains of cognition (memory, orientation, judgment/problem solving) and three domains of function (community affairs, home/hobbies, personal care) using semi- structured interviews of both the study subject and a companion/informant carried out by a trained rater and scored using a standard methodology. Each domain is rated on a 5-point scale of functioning as follows: (0) no impairment; (0.5) questionable impairment; (1) mild impairment; (2) moderate impairment; (3) severe impairment (personal care is scored on a 4-point scale without a 0.5 rating available). Higher scores indicate greater impairment.

  5. Change from Baseline on CDR-SB total scores at Month 5

    Time frame: Month 5

    The CDR is a global clinical scale with established diagnostic and severity-ranking utility widely used in clinical trials yielding global and sum of boxes scores (CDR-SB). The CDR global score is used in AD trials as a global measure of disease severity. The CDR is rated based on subject and informant input. The CDR assess three domains of cognition (memory, orientation, judgment/problem solving) and three domains of function (community affairs, home/hobbies, personal care) using semi- structured interviews of both the study subject and a companion/informant carried out by a trained rater and scored using a standard methodology. Each domain is rated on a 5-point scale of functioning as follows: (0) no impairment; (0.5) questionable impairment; (1) mild impairment; (2) moderate impairment; (3) severe impairment (personal care is scored on a 4-point scale without a 0.5 rating available). Higher scores indicate greater impairment.

  6. Change from Baseline on CDR-SB total scores at Month 12

    Time frame: Month 12

    The CDR is a global clinical scale with established diagnostic and severity-ranking utility widely used in clinical trials yielding global and sum of boxes scores (CDR-SB). The CDR global score is used in AD trials as a global measure of disease severity. The CDR is rated based on subject and informant input. The CDR assess three domains of cognition (memory, orientation, judgment/problem solving) and three domains of function (community affairs, home/hobbies, personal care) using semi- structured interviews of both the study subject and a companion/informant carried out by a trained rater and scored using a standard methodology. Each domain is rated on a 5-point scale of functioning as follows: (0) no impairment; (0.5) questionable impairment; (1) mild impairment; (2) moderate impairment; (3) severe impairment (personal care is scored on a 4-point scale without a 0.5 rating available). Higher scores indicate greater impairment.

  7. Change from Baseline in ADCS-ADL total score at Month 3

    Time frame: Month 3

    The ADCS-ADL is an assessment consisting of 23 basic and instrumental ADLs used in mild to moderate AD subjects.7 The scores of the informant-rated assessment are graded against a 78- point scale, with lower scores indicating greater impairment.

  8. Change from Baseline in ADCS-ADL total score at Months 12

    Time frame: Month 12

    The ADCS-ADL is an assessment consisting of 23 basic and instrumental ADLs used in mild to moderate AD subjects.7 The scores of the informant-rated assessment are graded against a 78- point scale, with lower scores indicating greater impairment.

  9. Change from Baseline in NPI total score at Month 3

    Time frame: Month 3

    The NPI is designed to detect, quantify, and track changes of psychiatric symptoms in a demented population.6 It uses a structured, caregiver-based interview format to assess 10 behavioral domains (delusions, hallucinations, agitation/aggression, dysphoria/depression, anxiety, apathy, irritability, euphoria, disinhibition, and aberrant motor behavior). The same behaviors are then rated on level of severity (1 = mild, 2 = moderate, 3 = severe). The domain total score is the product of the frequency score multiplied by the severity score for that behavioral domain. An NPI total score is obtained by summing all the individual domain total scores.

  10. Change from Baseline in NPI total score at Month 6

    Time frame: Month 6

    The NPI (Appendix 7) is designed to detect, quantify, and track changes of psychiatric symptoms in a demented population.6 It uses a structured, caregiver-based interview format to assess 10 behavioral domains (delusions, hallucinations, agitation/aggression, dysphoria/depression, anxiety, apathy, irritability, euphoria, disinhibition, and aberrant motor behavior). The same behaviors are then rated on level of severity (1 = mild, 2 = moderate, 3 = severe). The domain total score is the product of the frequency score multiplied by the severity score for that behavioral domain. An NPI total score is obtained by summing all the individual domain total scores.

  11. Change from Baseline in NPI total score at Month 12

    Time frame: Month 12

    The NPI (Appendix 7) is designed to detect, quantify, and track changes of psychiatric symptoms in a demented population.6 It uses a structured, caregiver-based interview format to assess 10 behavioral domains (delusions, hallucinations, agitation/aggression, dysphoria/depression, anxiety, apathy, irritability, euphoria, disinhibition, and aberrant motor behavior). The same behaviors are then rated on level of severity (1 = mild, 2 = moderate, 3 = severe). The domain total score is the product of the frequency score multiplied by the severity score for that behavioral domain. An NPI total score is obtained by summing all the individual domain total scores.

  12. Change from Baseline in the MMSE at Month 3

    Time frame: Month 3

    The MMSE is a brief 30-point examination consisting of 11 questions intended to evaluate an adult subject's level of cognition. The MMSE evaluates 6 areas of cognition: orientation, attention, immediate recall, short-term recall, language, and the ability to follow simple verbal and written commands. In addition, it provides a total score allowing the examiner to evaluate the severity of cognitive impairment.

    The MMSE will be scored using backward spelling (WORLD) and not serial subtractions. The scoring of WORLD will follow the original Folstein et al (1975)8 instructions for this assessment.

  13. Change from Baseline in the MMSE at Month 6

    Time frame: Month 6

    The MMSE is a brief 30-point examination consisting of 11 questions intended to evaluate an adult subject's level of cognition. The MMSE evaluates 6 areas of cognition: orientation, attention, immediate recall, short-term recall, language, and the ability to follow simple verbal and written commands. In addition, it provides a total score allowing the examiner to evaluate the severity of cognitive impairment.

    The MMSE will be scored using backward spelling (WORLD) and not serial subtractions. The scoring of WORLD will follow the original Folstein et al (1975)8 instructions for this assessment.

  14. Change from Baseline in the MMSE at Month 12

    Time frame: Month 12

    The MMSE is a brief 30-point examination consisting of 11 questions intended to evaluate an adult subject's level of cognition. The MMSE evaluates 6 areas of cognition: orientation, attention, immediate recall, short-term recall, language, and the ability to follow simple verbal and written commands. In addition, it provides a total score allowing the examiner to evaluate the severity of cognitive impairment.

    The MMSE will be scored using backward spelling (WORLD) and not serial subtractions. The scoring of WORLD will follow the original Folstein et al (1975)8 instructions for this assessment.

  15. AEs at Month 12

    Time frame: Month 12

  16. Clinically significant changes in vital signs at Month 12

    Time frame: Month 12

  17. 12-lead ECG at Month 12

    Time frame: Month 12

  18. Clinical Laboratory Assessments - (blood and urine) at Month 12

    Time frame: Month 12

    Chemistry: alkaline phosphatase, albumin, blood urea nitrogen, calcium, chloride, creatinine, glucose (random), inorganic phosphorus, potassium, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, lactate dehydrogenase, sodium, direct bilirubin, total bilirubin, total protein, amylase, uric acid Hematology: haemoglobin, hematocrit, red blood cell count, white blood cell (WBC) count, WBC differential (absolute counts), numerical platelet count Urinalysis: specific gravity, pH, ketones, glucose, nitrite, blood, leukocyte esterase, protein, urobilinogen, bilirubin If nitrite, blood, or protein tests are positive, a microscopic examination will be performed

  19. Vital Signs

    Time frame: Month 12

    Vital signs consist of tympanic temperature, respiratory rate, blood pressure (systolic and diastolic blood pressure, mmHg), and pulse (bpm) after at least 3 minutes rest. Blood pressure will be measured in a sitting or semi-reclined seated position. Weight and height will be captured at Screening and weight will be captured at all other visits where this assessment is performed.

Other outcomes

  1. AD blood biomarkers to assess change from Baseline at Month 6

    Time frame: Month 6

  2. AD blood biomarkers to assess change from Baseline at Month 12

    Time frame: Month 12

  3. Change in FDG-PET between Baseline and Month 6 in a subset of subjects (Optinal)

    Time frame: Month 6

    18-Fluoro-deoxyglucose positron emission tomography (FDG-PET) is a noninvasive, 3-dimensional imaging modality that has become widely used in the management of subjects with malignant lymphomas.9 Up to 15 subjects will participate in an optional FDG-PET sub-study to assess the effect of RPh201 on cerebral glucose metabolism at Baseline and after 6 months of treatment.

Sponsors and collaborators

Lead sponsor

Regenera Pharma Ltd

Industry

Registry information

Official study title

A 6-Month, Double-Blind, Phase 2 Study and 6-Month Open- Label Extension Evaluating the Safety, Tolerability, and Clinical Benefit of RPh201 in Individuals With Alzheimer's Disease With or Without Coexisting Cerebrovascular Disease

Important dates

Study start
2018
Primary completion
2019
Study completion
2020
First posted
Mar 12, 2018
Registry last updated
Apr 30, 2020

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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