DementiaPhase 4PoNDNCT03221751
Prazosin and Cerebrospinal Fluid (CSF) Biomarkers in Mild Traumatic Brain Injury (mTBI)
A Phase 4 study testing prazosin hydrochloride in people with Dementia, run by VA Office of Research and Development at 1 site in United States.
Trial summary
Mild traumatic brain injury (mTBI) from explosions is the "signature injury" of Veterans who have deployed to the wars in Afghanistan and Iraq. Although the immediate effects of a single mTBI usually resolve over days or weeks, multiple mTBIs can lead to both persistent symptoms and, years later, to two fatal… Read more about this study
- Who is it for?
- Ages 21 years and older
- Conditions the study is for
- Dementia
- What is being tested?
- prazosin hydrochloride
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 9 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Dec 2016to 5 Dec 2023
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age 21 years of age or older
- Ability to complete psychometric and other clinical assessments in English
- No clinically significant laboratory abnormalities at screen
- Platelet count >100,000/mm2 within two weeks of lumbar puncture (LP)
- Body mass index (BMI) between 18 and 36 inclusive (BMIs outside this range affect CSF biomarker measurements and/or make LPs for CSF collection difficult to perform).
- Women of childbearing potential must agree to abstain from sexual relations that could result in pregnancy or use an effective method of birth control acceptable to both participant and the study clinician during the study. Men are not required to use contraception during the study
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- Meeting criteria for at least one of the following:
- 1. History of mild or moderate TBI:
- Exposure to at least one blast or experiencing at least one collision of the head associated with acute symptoms that meet VA/DoD criteria for mild or moderate TBI (loss of consciousness, if present, <24 hours; posttraumatic amnesia, if present, <1 week; Glasgow Coma Scale (if available) 9-15) ->6 months since last TBI. 2. Documented diagnosis of PTSD related to combat trauma (from any conflict)
Who cannot join
- Medical
- History of severe TBI (Glasgow Coma Scale (if available) <9, loss of consciousness >24 hours, posttraumatic amnesia >1 week)
- Acute or unstable chronic medical illness, including unstable angina, recent myocardial infarction (within 6 months), congestive heart failure, preexisting hypotension (systolic <110) or orthostatic hypotension (systolic drop > 20mmHg after two minutes standing or any drop accompanied by dizziness), autoimmune disorders; insulin-dependent diabetes
- Chronic renal or hepatic failure, acute pancreatitis, Meniere's disease, benign positional vertigo, narcolepsy, or diagnosed untreated sleep apnea (sleep apnea currently being treated is not exclusionary).
- Contraindications to LP (e.g., spinal cord injury; deformity, severe disease or infection in the region of the lumbosacral spine; bleeding tendency, clotting abnormalities, use of anticoagulant medications, or platelet count <100,000/mm2); trauma or infection in the 4 weeks before LP
- Current pregnancy or lactation. Women of childbearing potential must agree to abstain from sexual relations that could result in pregnancy or use an effective method of birth control acceptable to both participant and the study clinician during the study. Men are not required to use contraception during the study.
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- Psychiatric/Behavioral
- Meets DSM(IV or 5, depending on what evaluative method was used in this subject) criteria for current schizophrenia, schizoaffective disorder, other specified or unspecified psychotic disorder, delirium, or any DSM cognitive disorder
- Current substance use disorder (except caffeine-related disorders, tobacco-related disorders, or cannabis intoxication) other than in remission for at least 3 months. The use of cannabis other than that meeting criteria for cannabis use disorder is not exclusionary. Use of cannabis will be documented.
- Current use of any stimulant, including prescribed stimulant medications
- Current use (within the past 1 month, ongoing, or expected during the study period) of any drugs that are illegal under Washington state law.
- Severe psychiatric instability or severe situational life crises, including evidence of being actively suicidal or homicidal, or any behavior which poses an immediate danger to participant or others.
- Medications/Therapies
- Current use of prazosin or other alpha-1 antagonist or trazodone, or use of such agent within the 3 month period prior to when the baseline 2 visit would be scheduled (a 3-month washout is required due to the potential effects it may have on the biomarker measurements).
- Allergy or previous adverse reaction to prazosin or other alpha-1 antagonist
- Use of exclusionary medications in the 4 weeks prior to screening: selected CNS-acting medications; antipsychotics, anti-Parkinson's disease medications and CNS stimulants; Coumadin or other medications affecting coagulation and/or inflammation (low-dose aspirin and use of NSAIDs for pain will not be exclusionary); potent immune-modulating medications, such as hydrocortisone or methotrexate; anti-HIV medications.
- Use of avanafil (Stendra), sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra) will be not be permitted during the study dose titration period because of increased risk of hypotension in combination with alpha-1 blockers, but will be allowed at 1/2 the usual starting dose following dose titration
- Current use of stimulants or nitrates, or of alternative medications or supplements with stimulant properties (e.g., ephedra) or vasodilatory properties (e.g., nitrate containing supplements)
- Recent evidence based trauma- or sleep-focused psychotherapy, such as Prolonged Exposure therapy (PE), Cognitive Processing Therapy (CPT), Eye Movement Desensitization and Reprogramming (EMDR), Cognitive Behavioral Therapy for Insomnia (CBTi) or Image Rehearsal and Rescripting therapy for nightmares. These therapies must have been completed > 4 weeks before first baseline assessment visit (study visit 2).
- Other
- Allergy or previous adverse reaction to prazosin or other alpha-1 antagonist
- Receiving another medication in another interventional study
Trial locations and contacts
1 site in 1 country.
United States1 site
VA Puget Sound Health Care System Seattle Division, Seattle, WA
Seattle, Washington, 98108-1532
About this study
Official title: Prazosin and CSF Biomarkers in mTBI
Mild traumatic brain injury (mTBI) from explosions is the "signature injury" of Veterans who have deployed to the wars in Afghanistan and Iraq. Although the immediate effects of a single mTBI usually resolve over days or weeks, multiple mTBIs can lead to both persistent symptoms and, years later, to two fatal progressive brain diseases, chronic traumatic encephalopathy (CTE) and Alzheimer's disease (AD). It is believed that CTE and AD are caused by nerve damaging chemicals called tau and beta amyloid produced by the brain but which are not removed from the brain in a normal manner in persons with mTBIs. The investigators will determine in Veterans who experienced mTBIs whether a clinically available drug called prazosin increases removal of tau and beta amyloid from the brain. This will be accomplished by seeing if prazosin reduces the amount of tau and beta amyloid in the spinal fluid that surrounds the brain. If the investigators find such reductions, prazosin will be evaluated as a preventative treatment for CTE and AD in future studies.
Read the detailed description
A majority of neurodegenerative dementing disorders, including Alzheimer's disease, (AD), dementia with Lewy bodies (DLB) and chronic traumatic encephalopathy (CTE), now appear to be caused by the accumulation and aggregation of proteins that cause progressive damage to the brain. Recent preclinical results suggest that clearance of such neurotoxic proteins from the brain may be greatly increased during states where noradrenergic (NA) tone is decreased or blocked, such as anesthesia and normal sleep, but impaired in animal models of mild Traumatic Brain Injury (mTBI). These results also suggest that clearance through this mechanism, which has been termed the 'glymphatic' system, is likely to be decreased in conditions where NA signaling is inappropriately maintained during sleep, such as posttraumatic stress disorder (PTSD). Importantly, the rate at which toxins are cleared through the glymphatic system has been found to be under alpha-1 adrenergic receptor (AR) control, and the application of noradrenergic blockers such as the alpha-1 AR antagonist drug, prazosin, has been shown to increase waking clearance of these proteins to levels normally found during sleep or anesthesia. This suggests two important possibilities: first, that conditions in which the brain NA signaling is increased and sleep is impaired, such as posttraumatic stress disorder (PTSD) and mTBI, may predispose people to decreased clearance of neurotoxic proteins associated with the development and progression of dementia; and second, that the use of prazosin may be able to prevent such effects.
- Conditions
- Dementia
- Being tested
- prazosin hydrochloride, placebo
- Keywords
- randomized controlled trial
- Medical subject headings
- Dementia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
prazosin hydrochlorideDrug
Also called Minipress
Prazosin is an oral capsule. It is an alpha-1 antagonists.
placeboDrug
Also called inactive drug, sugar pill
Placebo is an inert oral capsule identical in appearance to prazosin capsules.
| Study group | Role | What they receive |
|---|---|---|
| Prazosin | Experimental | Subjects will be titrated up to the maximum dose or the maximum tolerated dose based on a dosing algorithm. The maximum dose is 5 mg in the morning, 5 mg in the afternoon and 15 mg at bedtime. Receives: Drug: prazosin hydrochloride |
| Placebo | Placebo comparator | Subjects will be titrated up to the maximum dose or the maximum tolerated dose based on a dosing algorithm. The maximum dose is 5 mg in the morning, 5 mg in the afternoon and 15 mg at bedtime. Receives: Drug: placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in CSF Total-tau From Baseline to End of Study (pg/mL)
an established biomarker of neurodegeneration in Alzheimer's disease.
Measured: 10 weeks
Change in p-tau181 From Baseline to End of Study (pg/mL)
an established biomarker of neurodegeneration in Alzheimer's disease.
Measured: 10 weeks
Change in Amyloid Beta 42 From Baseline to End of Study (pg/mL)
an established biomarker of neurodegeneration in Alzheimer's disease.
Measured: 10 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Jul 2017
- Study start1 Dec 2016
- Primary completion3 Jan 2023
- Study completion5 Dec 2023
Why it stopped: staffing issues and COVID
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for DementiaStudies of the same condition, open and under way.
- More trials run by VA Office of Research and DevelopmentThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 9 participants (actual)
Sponsor and investigators
- Lead sponsor
- VA Office of Research and Development
- Sponsor type
- US federal agency
- Responsible party
- Sponsor
- Investigators
- Murray A. Raskind, MD, Principal investigator, VA Puget Sound Health Care System Seattle Division, Seattle, WA
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03221751
- Sponsor's protocol ID
- B2180-P
- Other IDs
- 1I21RX002180-01
- Acronym
- PoND
- Status last verified
- Feb 2024
- First submitted
- 13 Jul 2017
- Last updated
- 26 Feb 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 26 Feb 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Prazosin and CSF Biomarkers in mTBI
- ClinicalTrials.gov ID
- NCT03221751
- Acronym / sponsor ID
- PoND / B2180-P
- Conditions
- Dementia
- Keywords
- randomized controlled trial
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: staffing issues and COVID
- Enrolment
- 9 participants (actual)
- Lead sponsor
- VA Office of Research and DevelopmentUS federal agency
- Study start
- 1 Dec 2016 (actual)
- Primary completion
- 3 Jan 2023 (actual)
- Study completion
- 5 Dec 2023 (actual)
- First posted
- 19 Jul 2017 (actual)
- Results
- Posted 26 Feb 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Mild traumatic brain injury (mTBI) from explosions is the "signature injury" of Veterans who have deployed to the wars in Afghanistan and Iraq. Although the immediate effects of a single mTBI usually resolve over days or weeks, multiple mTBIs can lead to both persistent symptoms and, years later, to two fatal progressive brain diseases, chronic traumatic encephalopathy (CTE) and Alzheimer's disease (AD). It is believed that CTE and AD are caused by nerve damaging chemicals called tau and beta amyloid produced by the brain but which are not removed from the brain in a normal manner in persons with mTBIs. The investigators will determine in Veterans who experienced mTBIs whether a clinically available drug called prazosin increases removal of tau and beta amyloid from the brain. This will be accomplished by seeing if prazosin reduces the amount of tau and beta amyloid in the spinal fluid that surrounds the brain. If the investigators find such reductions, prazosin will be evaluated as a preventative treatment for CTE and AD in future studies.
Detailed description
A majority of neurodegenerative dementing disorders, including Alzheimer's disease, (AD), dementia with Lewy bodies (DLB) and chronic traumatic encephalopathy (CTE), now appear to be caused by the accumulation and aggregation of proteins that cause progressive damage to the brain. Recent preclinical results suggest that clearance of such neurotoxic proteins from the brain may be greatly increased during states where noradrenergic (NA) tone is decreased or blocked, such as anesthesia and normal sleep, but impaired in animal models of mild Traumatic Brain Injury (mTBI). These results also suggest that clearance through this mechanism, which has been termed the 'glymphatic' system, is likely to be decreased in conditions where NA signaling is inappropriately maintained during sleep, such as posttraumatic stress disorder (PTSD). Importantly, the rate at which toxins are cleared through the glymphatic system has been found to be under alpha-1 adrenergic receptor (AR) control, and the application of noradrenergic blockers such as the alpha-1 AR antagonist drug, prazosin, has been shown to increase waking clearance of these proteins to levels normally found during sleep or anesthesia. This suggests two important possibilities: first, that conditions in which the brain NA signaling is increased and sleep is impaired, such as posttraumatic stress disorder (PTSD) and mTBI, may predispose people to decreased clearance of neurotoxic proteins associated with the development and progression of dementia; and second, that the use of prazosin may be able to prevent such effects.
Study design
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Prazosin | Experimental | Drug: prazosin hydrochlorideSubjects will be titrated up to the maximum dose or the maximum tolerated dose based on a dosing algorithm. The maximum dose is 5 mg in the morning, 5 mg in the afternoon and 15 mg at bedtime. |
| Placebo | Placebo comparator | Drug: placeboSubjects will be titrated up to the maximum dose or the maximum tolerated dose based on a dosing algorithm. The maximum dose is 5 mg in the morning, 5 mg in the afternoon and 15 mg at bedtime. |
Who may qualify
- Ages
- 21 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- Age 21 years of age or older
- Ability to complete psychometric and other clinical assessments in English
- No clinically significant laboratory abnormalities at screen
- Platelet count >100,000/mm2 within two weeks of lumbar puncture (LP)
- Body mass index (BMI) between 18 and 36 inclusive (BMIs outside this range affect CSF biomarker measurements and/or make LPs for CSF collection difficult to perform).
Key exclusion criteria (22 listed)
- Medical
- History of severe TBI (Glasgow Coma Scale (if available) <9, loss of consciousness >24 hours, posttraumatic amnesia >1 week)
- Acute or unstable chronic medical illness, including unstable angina, recent myocardial infarction (within 6 months), congestive heart failure, preexisting hypotension (systolic <110) or orthostatic hypotension (systolic drop > 20mmHg after two minutes standing or any drop accompanied by dizziness), autoimmune disorders; insulin-dependent diabetes
- Chronic renal or hepatic failure, acute pancreatitis, Meniere's disease, benign positional vertigo, narcolepsy, or diagnosed untreated sleep apnea (sleep apnea currently being treated is not exclusionary).
- Contraindications to LP (e.g., spinal cord injury; deformity, severe disease or infection in the region of the lumbosacral spine; bleeding tendency, clotting abnormalities, use of anticoagulant medications, or platelet count <100,000/mm2); trauma or infection in the 4 weeks before LP
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| prazosin hydrochlorideAlso: MinipressPrazosin is an oral capsule. It is an alpha-1 antagonists. | Drug | Prazosin |
| placeboAlso: inactive drug, sugar pillPlacebo is an inert oral capsule identical in appearance to prazosin capsules. | Drug | Placebo |
Primary outcome
Change in CSF Total-tau From Baseline to End of Study (pg/mL)
Time frame: 10 weeks
an established biomarker of neurodegeneration in Alzheimer's disease.
Change in p-tau181 From Baseline to End of Study (pg/mL)
Time frame: 10 weeks
an established biomarker of neurodegeneration in Alzheimer's disease.
Change in Amyloid Beta 42 From Baseline to End of Study (pg/mL)
Time frame: 10 weeks
an established biomarker of neurodegeneration in Alzheimer's disease.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Feb 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Murray A. Raskind, MD principal investigator
VA Puget Sound Health Care System Seattle Division, Seattle, WA
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing prazosin hydrochloride in people with Dementia, run by VA Office of Research and Development at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 26 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 26 Feb 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in CSF Total-tau From Baseline to End of Study (pg/mL) (time frame: 10 weeks). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Feb 2024.