Prazosin and Cerebrospinal Fluid (CSF) Biomarkers in Mild Traumatic Brain Injury (mTBI)

NCT03221751 | Terminated Phase 4 Results FDA Drug

• 2 other identifiers: B2180-P1I21RX002180-01
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

Brief 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 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.

Conditions

Dementia

Keywords

randomized controlled trial

Outcome Measures

Primary Outcomes (3)

• Change in CSF Total-tau From Baseline to End of Study (pg/mL)

  an established biomarker of neurodegeneration in Alzheimer's disease.

  10 weeks

• Change in p-tau181 From Baseline to End of Study (pg/mL)

  an established biomarker of neurodegeneration in Alzheimer's disease.

  10 weeks

• Change in Amyloid Beta 42 From Baseline to End of Study (pg/mL)

  an established biomarker of neurodegeneration in Alzheimer's disease.

  10 weeks

Study Arms (2)

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.

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.

Drug: placebo

Interventions

prazosin hydrochloride DRUG

Prazosin is an oral capsule. It is an alpha-1 antagonists.

Also known as: Minipress

Prazosin

placebo DRUG

Placebo is an inert oral capsule identical in appearance to prazosin capsules.

Also known as: inactive drug, sugar pill

Placebo

Eligibility Criteria

• Age: 21 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• Meeting criteria for at least one of the following:
• \. 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)

You may not qualify if:

• 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
• 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.
• 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 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 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)

Sponsors & Collaborators

• VA Office of Research and Development: lead

Study Sites (1)

VA Puget Sound Health Care System Seattle Division, Seattle, WA

Seattle, Washington, 98108-1532, United States

Location

MeSH Terms

Conditions

Dementia

Interventions

Prazosin; Sugars

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Carbohydrates

Limitations and Caveats

These results are not generalizable due to the small sample size.

Results Point of Contact

• Title: Hollie Holmes
• Organization: VA Puget Sound Health Care System

Hollie.Holmes@va.gov

206-277-6207

Study Officials

• Murray A. Raskind, MD

  VA Puget Sound Health Care System Seattle Division, Seattle, WA

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 13, 2017
• First Posted: July 19, 2017
• Study Start: December 1, 2016
• Primary Completion: January 3, 2023
• Study Completion: December 5, 2023
• Last Updated: February 26, 2024
• Results First Posted: February 26, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)