Fasudil fOr redUcing elopemeNt and Spatial Disorientation (FOUND)

• ClinicalTrials.gov Identifier: NCT04793659
• Recruitment Status: Completed
• First Posted: March 11, 2021
• Last Update Posted: July 11, 2022
• Sponsor: Woolsey Pharmaceuticals
• Information provided by (Responsible Party): Woolsey Pharmaceuticals

Study Description

Brief Summary:

Fasudil, a Rho kinase inhibitor, is believed to reduce wandering behaviors of elopement and getting lost by improving spatial memory and navigation through improvements in hippocampal blood flow. Fasudil is non-sedating.

The aim of the study is to assess the effectiveness of oral fasudil in reducing wandering behaviors of elopement and/or getting lost in subjects with dementia. In addition, effects on wandering behaviors of excess movement and pacing, cognition, memory, neuropsychiatric symptomatology, caregiver/nursing staff burden, and the safety and tolerability of fasudil treatment will be assessed.

Condition or disease	Intervention/treatment	Phase
Dementia	Drug: Oral Fasudil 90 mg/day; Drug: Oral Fasudil 180 mg/day; Drug: Oral Placebo	Phase 2

Detailed Description:

The study population will consist of subjects with dementia and wandering behaviors of elopement and/or getting lost. While it is anticipated that most participants will be residing at home (with caregiver support), subjects may live in another setting such as a group home, an assisted living unit, or in a long-term care facility, provided that a caregiver, formal or informal, has sufficient contact with the subject to permit accurate completion of the necessary assessments.

Enrolled subjects will enter the Open-Label Phase and receive treatment with fasudil 90 mg/day (30 mg three times daily [tid]) for 6 weeks in Open-Label Period 1. Responders (i.e., subjects who improve 2 points or more on the GIW) will proceed to the Double-Blind Phase. Subjects in whom fasudil is well-tolerated (i.e. subjects with ≤ 2 drug-related AEs of mild intensity, no drug-related AEs of greater than mild intensity, and creatinine level of < 1.5 mg/dL at all times during the period) and who do not respond will enter Open-Label Period 2, and be dosed with fasudil 180 mg/day (60 mg tid) for 6 weeks. Responders will proceed to the Double-Blind Phase and non-responders will move to the final post-treatment visit. In the Double-Blind Phase, subjects will receive treatment with either placebo or the dose they responded to in the Open-Label Phase (90 mg/day or 180 mg/day) for 6 weeks (Double-Blind Period 1), following which treatment assignment will be crossed over for 6 weeks (Double-Blind Period 2). A final post-treatment visit will occur 14 days after the last dose of study drug. Visits may be performed by qualified healthcare professionals at home or other care setting, or at a doctor's office/clinic. Interviews may be performed by telephone and/or telemedicine as appropriate.

Study Endpoints:

Primary:

• The Global Impression of Wandering (GIW)

Secondary:

• Weekly Wandering Report - Community Version (WWR-C)
• The Revised Algase Wandering Scale - Community Version (RAWS-CV)
• The Mini Mental State Examination (MMSE)
• The Neuropsychiatric Inventory-Questionnaire (NPI-Q)
• The Cohen-Mansfield Agitation Inventory - Community Version (CMAI-C)
• The Center for Neurological Study-Lability Scale (CNS-LS)
• The Zarit Burden Interview (ZBI)
• Safety
• Tolerability

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: Combined Open-Label and Double-Blind, Placebo-Controlled Crossover
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description

Periods 1 and 2 of the open-label phase will be unblinded.

Periods 3 and 4 are double-blind crossover phases.

• Primary Purpose: Treatment
• Official Title: A Phase 2a Combined Open-Label and Double-Blind, Placebo-Controlled Crossover Study Assessing the Effectiveness, Safety, and Tolerability of Oral Fasudil in Subjects With Dementia and Wandering Behaviors of Elopement and/or Getting Lost
• Actual Study Start Date: December 15, 2020
• Actual Primary Completion Date: December 8, 2021
• Actual Study Completion Date: February 11, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Oral Fasudil 90 mg/day; Subjects will receive a daily dose of 90 mg Fasudil for 42 days (open-label period 1). After Period 1 is complete, if the subject is a responder to Fasudil 90 mg/day, they will be randomized to either Fasudil 90 mg/day or a placebo for 6 weeks (double-blind period 1), then crossover to the other arm for 6 weeks (double-blind period 2).	Drug: Oral Fasudil 90 mg/day; Oral tablet; Drug: Oral Placebo; Oral tablet
Experimental: Oral Fasudil 180 mg/day; If the subject is a not a responder in the open-label period 1 but tolerated Fasudil 90 mg/day, they will be escalated to Fasudil 180 mg/day (open-label period 2) for 42 days. If the subject is a responder to Fasudil 180 mg/day, they are randomized to either Fasudil 180 mg/day for 42 days or a placebo (double-blind period 1), then crossover to the other arm for 6 weeks (double-blind period 2).	Drug: Oral Fasudil 180 mg/day; Oral tablet; Drug: Oral Placebo; Oral tablet
Placebo Comparator: Oral Placebo; Placebo comparator arm to investigational drug (Fasudil 90 mg/day or 180 mg/day).	Drug: Oral Fasudil 90 mg/day; Oral tablet; Drug: Oral Fasudil 180 mg/day; Oral tablet; Drug: Oral Placebo; Oral tablet

Outcome Measures

Primary Outcome Measures :

1. Change in Global Impression of Wandering (GIW) after oral Fasudil vs placebo in the Double-Blind Phase [ Time Frame: Week 6 and Week 12 of the Double-Blind period ]
   The GIW is a variant of the 7-point Clinical Global Impression-Severity (CGI-S) scale and is used in FOUND specifically to obtain the investigator's overall assessment of severity of the subject's wandering behavior.

Secondary Outcome Measures :

1. Change in Weekly Wandering Report - Community Version (WWR-C) [ Time Frame: Weekly during the 12 weeks of the Double-Blind period ]
   The WWR-C is composed of targeted questions related to excess walking, spontaneous pacing, elopement, and wayfinding; it is designed to be assessed on a weekly basis by caregivers about subjects for whom they care. The WWR-C asks the caregiver to rate the subject's behavior for the previous week.
2. Change in the Revised Algase Wandering Scale - Community Version (RAWS-CV) [ Time Frame: Week 6 and Week 12 of the Double-Blind period ]
   The RAWS-CV is a 40-item tool with 6 subscales to assess wandering behaviors (eloping behaviors, negative outcomes, mealtime impulsivity, persistent walking, repetitive walking, and spatial disorientation), and a total score scale.
3. Change in Mini Mental State Examination (MMSE) [ Time Frame: Week 6 and Week 12 of the Double-Blind period ]
   The MMSE is a 30-point questionnaire that is used to measure cognitive impairment.
4. Change in Neuropsychiatric Inventory-Questionnaire (NPI-Q) [ Time Frame: Week 6 and Week 12 of the Double-Blind period ]

   The NPI-Q provides an assessment of dementia-related emotional behavioral symptomatology in routine clinical practice settings. Caregiver distress is also assessed.

   The NPI-Q asks the assessor to rate the previous 30 days. At the Final Visit, the assessor will rate the NPI-Q for the 2-week period following the final dose. The scale is completed by the caregiver without input from the subject. All reasonable efforts should be made to ensure each NPI-Q for an individual subject is completed by the same caregiver to minimize inter-rater variability.

5. Cohen-Mansfield Agitation Inventory - Community Version (CMAI-C) [ Time Frame: Week 6 and Week 12 of the Double-Blind period ]
   The CMAI-C is a 37-item scale to systematically assess agitation.
6. Center for Neurological Study-Lability Scale (CNS-LS) [ Time Frame: Week 6 and Week 12 of the Double-Blind period ]
   The CNS-LS is a 7-item questionnaire to assess perceived frequency of pseudobulbar affect episodes.
7. Zarit Burden Interview (ZBI) [ Time Frame: Week 6 and Week 12 of the Double-Blind period ]
   The ZBI is a 22-item scale to assess caregiver burden.
8. Adverse Events (AEs) [ Time Frame: Through study completion, up to 26 weeks ]
9. Serious Adverse Events (SAEs) [ Time Frame: Through study completion, up to 26 weeks ]
10. Change in blood pressure [ Time Frame: Through study completion, up to 26 weeks ]
11. Change in blood parameters [ Time Frame: Through study completion, up to 26 weeks ]
    Hematology: white blood cell count, hemoglobin, hematocrit, platelet count
12. Change in blood chemistry [ Time Frame: Through study completion, up to 26 weeks ]
    Blood chemistry: glucose, sodium, potassium, bicarbonate, blood urea nitrogen, creatinine, cystatin c
13. Change in liver function [ Time Frame: Through study completion, up to 26 weeks ]
    Liver function tests: albumin, total bilirubin, direct bilirubin, ALP, AST, ALT, gamma glutamyl transferase, lactate dehydrogenase
14. Change in urine contents [ Time Frame: Through study completion, up to 26 weeks ]
    Urinalysis (occult blood, protein)
15. Change in heart rhythm [ Time Frame: Through study completion, up to 26 weeks ]
    12-lead Electrocardiogram (ECG) will be used to obtain a record of cardiac activity
16. Change in body weight [ Time Frame: Through study completion, up to 26 weeks ]
17. Change in body temperature [ Time Frame: Through study completion, up to 26 weeks ]
18. Change in respiratory rate [ Time Frame: Through study completion, up to 26 weeks ]
19. Columbia Suicide Severity Rating Scale (C-SSRS) [ Time Frame: Through study completion, up to 26 weeks ]

    The C-SSRS is an assessment used to identify immediate risk of suicide, and is completed following the patient interview, review of medical record(s) and/or consultation with family members and/or other professionals. While the C-SSRS is a detailed interview, the full interview is needed only if the initial screening questions about suicidal ideation and behavior are positive.

    In subjects with severe cognitive impairment, i.e., so substantial as to interfere with an understanding of the concept of suicide, the C-SSRS may be omitted.

Eligibility Criteria

• Ages Eligible for Study: 50 Years to 90 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. 50 to 90 years of age (inclusive).
2. Diagnosis of dementia of any etiology.
3. MMSE 9-24 (inclusive).

4. Presence of one or both of the following wandering behaviors that in the opinion of the investigator, in consultation with caregiver, is at least of moderate severity (defined as clearly a wanderer, and this causes some distress or difficulty for both the subject and caregiver):

   1. Elopes or attempts to elope AND/OR
   2. Gets lost or is unable to locate a specific place.
5. Independently ambulatory with or without assistive devices (such as canes or walkers). Subjects must not require assistance to transfer out of bed or a chair.
6. Subject has a caregiver who has more than 10 hours/week of contact with the subject, is fluent and literate in English and is willing to accept responsibility for supervising the treatment (e.g., administering study drug) and assessing the condition of the subject throughout the study in accordance with all protocol requirements.
7. Consent obtained from the participant/legally authorized representative (LAR) in accordance with local regulations.

Exclusion Criteria:

1. Expected change in medication that could interfere with the study or free movement of the subject.
2. Serum creatinine ≥ 1.5 mg/dL.
3. ALT and/or alkaline aminotransferase (AST) ≥ 2 X and/or alkaline phosphatase (ALP) ≥ 1.5 upper limit of normal.
4. Blood pressure < 90/60.
5. On more than one of the following drug classes: long-acting nitrates, beta-blockers, or calcium channel blockers.
6. Any severe comorbidity that in the opinion of the Investigator would disallow safe participation in the trial.
7. Women of child-bearing potential; females must be postmenopausal or surgically sterilized.
8. Suicidal ideation per the Columbia-Suicide Severity Rating Scale (C-SSRS) that in the opinion of the PI would pose a safety risk or interfere with the appropriate interpretation of study data.
9. Planned change in the current living setting during the study.
10. History within the last year of either two or more falls leading to clinically significant injuries or one or more fall leading to hospitalization, and/or evidence of orthostatic hypotension.
11. Participation in another investigational drug study within 30 days before start of Open-Label period.
12. Subjects who, in the opinion of the investigator, are not suitable for the study.

Contacts and Locations

Locations

United States, Connecticut

New England Institute for Clinical Research

Stamford, Connecticut, United States, 06905

United States, Florida

Accel Research Sites

Lakeland, Florida, United States, 33803

Lakes Research, LLC.

Miami Lakes, Florida, United States, 33014

United States, New Jersey

Bio Behavioral Health

Toms River, New Jersey, United States, 08755

United States, New Mexico

Albuquerque Neuroscience Inc.

Albuquerque, New Mexico, United States, 87109

United States, Virginia

Re:Cognition Health

Fairfax, Virginia, United States, 22031

Australia, South Australia

Modbury Hospital

Modbury, South Australia, Australia, 5092

Australia, Victoria

Barwon Geriatrics

Geelong, Victoria, Australia, 3220

GV Health

Shepparton, Victoria, Australia, 3630

Northeast Health Wangaratta

Wangaratta, Victoria, Australia, 3677

Australia, Western Australia

Neurodegenerative Disorders Research

West Perth, Western Australia, Australia, 6005

Sponsors and Collaborators

Woolsey Pharmaceuticals

More Information

• Responsible Party: Woolsey Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT04793659
• Other Study ID Numbers: WP-0512-001
• First Posted: March 11, 2021
• Last Update Posted: July 11, 2022
• Last Verified: July 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Woolsey Pharmaceuticals:

Wandering Behavior; Dementia; Fasudil

Additional relevant MeSH terms:

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Mental Disorders; Fasudil; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Calcium Channel Blockers; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs; Vasodilator Agents; Protein Kinase Inhibitors; Enzyme Inhibitors