Allopregnanolone Regenerative Therapeutic for Early Alzheimer's Disease: Intramuscular Study (Allo-IM)

• ClinicalTrials.gov Identifier: NCT03748303
• Recruitment Status: Recruiting
• First Posted: November 20, 2018
• Last Update Posted: January 29, 2020
• Sponsor: University of Arizona
• Collaborators: University of Southern California; Alzheimer's Association
• Information provided by (Responsible Party): Roberta Brinton, University of Arizona

Study Description

Brief Summary:

The purpose of this study is to identifying the intramuscular dose equivalent to the 4mg intravenous dose and assess its safety and tolerability as a weekly injection.

Condition or disease	Intervention/treatment	Phase
Alzheimer Dementia	Drug: Allopregnanolone	Phase 1

Detailed Description:

The purpose of this bridging study is to advance the therapeutic development of Allopregnanolone (Allo) by using the intramuscular (IM) route of administration as an alternative to the intravenous (IV) route. In order to identify the equivalent IM dose we will conduct pharmacokinetic (PK) analysis previously informed by simulations and modeling. We will recruit a total of 12 participants, both males and females equally distributed, into this single-arm, open-label study.

PK analysis and dose finding will take place for the initial 4 weeks; some participants may not require all 4 weeks of initial dosing to establish maintenance dose. Once maintenance dose is established all participants will receive weekly administration of Allo IM until they complete 12 weeks total of Allo exposure (5 or 6 clinic visits and 6 or 7 home-nurse visits).

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 12 participants
• Intervention Model: Single Group Assignment
• Intervention Model Description: Single-arm, open-label study
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Allopregnanolone Regenerative Therapeutic for Early Alzheimer's Disease: IV to IM Bridging Study
• Actual Study Start Date: October 1, 2019
• Estimated Primary Completion Date: August 2020
• Estimated Study Completion Date: October 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Allo IM cohort; Allopregnanolone 4-18mg IM, weekly, for 12 weeks.	Drug: Allopregnanolone; Administration of weekly IM injections of Allopregnanolone.; Other Name: Allo

Outcome Measures

Primary Outcome Measures :

1. Safety - Adverse events [ Time Frame: From baseline to visit 16 (14 weeks) ]
   Incidence and severity of treatment emergent adverse events assessed weekly.
2. Safety - clinical laboratory measures [ Time Frame: From Baseline to visit 16 (14 weeks) ]
   Proportion of subjects exceeding pre-established critical laboratory values.
3. Safety - clinical assessment [ Time Frame: From Baseline to visit 16 (14 weeks) ]
   Proportion of subjects with abnormal findings in physical/neurological exams, vital signs and electrocardiograms.

Secondary Outcome Measures :

1. Pharmacokinetic parameter - Cmax [ Time Frame: Visits 3 - 6 (up to 4 weeks) ]
   Determine maximum serum concentration of Allo after IM administration of each dose.
2. Pharmacokinetic parameter - AUC [ Time Frame: Visits 3 - 6 (up to 4 weeks) ]
   Determine the area under the curve after each IM administration of Allo.
3. Pharmacokinetic parameter - Tmax [ Time Frame: Visits 3 - 6 (up to 4 weeks) ]
   Determine the time at which Cmax is attained.
4. Pharmacokinetic parameter - Clearance [ Time Frame: Visits 3 - 6 (up to 4 weeks) ]
   Pharmacokinetic measurement of the volume of plasma from which Allo is completely removed per unit time.
5. Pharmacokinetic parameter - Volume of distribution [ Time Frame: Visits 3 - 6 (up to 4 weeks) ]
   Determine the volume of distribution at steady state of Allo.
6. Satisfaction and feasibility of home nurse survey [ Time Frame: Visits 8-9 and 11-15 (up to 8 weeks) ]
   Standardized patient satisfaction questionnaire to assess the feasibility of home-health care visits to administer the study medication and its desirability by participants and caregivers. Levels of satisfaction measured on a 5-point scale (1 = lowest satisfaction, 5 = greatest).

Other Outcome Measures:

1. MRI brain volumes [ Time Frame: Baseline to visit 16 (14 weeks) ]
   To evaluate MRI-based brain volumes 1-week before before and 1-week after the administration of Allo IM for 12 weeks (total assessment period of 14 weeks).
2. Cambridge Neuropsychological Test Automated Battery (CANTAB) Paired Associates Learning (PAL) [ Time Frame: Baseline to visit 16 (14 weeks) ]
   Test to evaluate changes in cognition
3. Mini-Mental State Exam (MMSE) [ Time Frame: Baseline to visit 16 (14 weeks) ]
   Test to evaluate changes in cognition.
4. Alzheimer's Disease Assessment Scale Cognitive Subscale 14 (ADAS-Cog14) [ Time Frame: Baseline to visit 16 (14 weeks) ]
   Well known test to evaluate changes in cognition. Scores on this 14 item test range from 0 (best) to 85 (worse); a positive change indicates cognitive worsening.
5. Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) [ Time Frame: Baseline to visit 16 (14 weeks) ]
   Clinical scale that rates the severity of dementia as absent, questionable, mild, moderate, or severe (CDR score of 0, 0.5, 1, 2, or 3, respectively).
6. Cogstate Alzheimer's battery [ Time Frame: Baseline to visit 16 (14 weeks) ]
   Test to evaluate changes in cognition.
7. Activities of daily living [ Time Frame: Baseline to visit 16 (14 weeks) ]
   To assess activities of daily living per the Alzheimer's Disease Cooperative Study - Activities of Daily Living Scale (ADCS-iADLS). In a structured interview format, informants are queried as to whether participants attempted each item in the inventory during the prior 4 weeks and their level of performance. Scores range from 0-56.
8. Caregiver burden survey [ Time Frame: Baseline to visit 16 (14 weeks) ]
   Assessed per Zarit's burden 22-item questionnaire. Burden measured on a 5-point scale (0 = never burdened, 4 = nearly always burdened). Max score = 88
9. Actigraphy sleep assessment - Total sleep time [ Time Frame: Screen to visit 16 (16 weeks) ]
   To assess standard sleep parameters using wearable devices (actigraph wristwatch): Total sleep time reported as time in minutes.
10. Actigraphy sleep assessment - Wake after sleep onset [ Time Frame: Screen to visit 16 (16 weeks) ]
    To assess standard sleep parameters using wearable devices (actigraph wristwatch): Wake after sleep onset (WASO) reported as time in minutes.
11. Actigraphy sleep assessment - Sleep efficiency [ Time Frame: Screen to visit 16 (16 weeks) ]
    To assess standard sleep parameters using wearable devices (actigraph wristwatch): Sleep efficiency reported as percentage.
12. Physical activity [ Time Frame: Screen to visit 16 (16 weeks) ]
    To assess daily activity using wearable devices: FitBit.

Eligibility Criteria

• Ages Eligible for Study: 55 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Provision of signed and dated informed consent form
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Men or postmenopausal women, aged 55 years or older
• Diagnosis of MCI due to AD or mild AD
• In good general health as evidenced by medical history and with no medical contraindications to participation
• MMSE > 20 at screen
• Caregiver willing and capable to accompany the patient to clinic visits

Exclusion Criteria:

• Daily use of benzodiazepines, sedative/hypnotics, anticonvulsants, antipsychotics, and other drugs that might interact with the GABA-A receptor complex.
• Seizure disorder, history of stroke, focal brain lesion, traumatic brain injury, substance abuse, malignancy.
• Clinically significant laboratory or ECG abnormality obtained at screening visit.
• MRI indicative of significant abnormality, including but not limited to evidence of a single prior hemorrhage or infarct >1 cm3, multiple lacunar infarcts (>1) or evidence of a single prior infarct >1cm3, evidence of a cerebral contusion, encephalomalacia, aneurysms, vascular malformations, subdural hematoma, or space occupying lesions (e.g. abscess or tumor).
• Has any contraindications for MRI studies, including claustrophobia, the presence of metal (ferromagnetic) implants, or a cardiac pacemaker that is not compatible with MRI.
• Is currently enrolled in a clinical trial involving an off-label use of an investigational drug or device, or concurrently enrolled in any other type of medical research or observational study judged not to be scientifically or medically compatible with this study.

Contacts and Locations

Contacts

Contact: Gerson Hernandez, MD, MPH; 520+626-5781; gersonhe@email.arizona.edu

Contact: Claudia M Lopez, BS; 520-626-6276; claudiml@email.arizona.edu

Locations

United States, California

University of Southern California - Alzheimer Disease Research Center - Healthcare Consultation Center II; Recruiting

Los Angeles, California, United States, 90033

Sponsors and Collaborators

University of Arizona

University of Southern California

Alzheimer's Association

Investigators

• Principal Investigator: Roberta D Brinton, PhD; University of Arizona
• Principal Investigator: Lon S Schneider, MD, MS; University of Southern California

More Information

• Responsible Party: Roberta Brinton, Professor, University of Arizona
• ClinicalTrials.gov Identifier: NCT03748303
• Other Study ID Numbers: AlloPhase1-IM
• First Posted: November 20, 2018
• Last Update Posted: January 29, 2020
• Last Verified: January 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

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

Keywords provided by Roberta Brinton, University of Arizona:

Alzheimer's disease; Mild cognitive impairment; Dementia; Regenerative therapeutic; Drug development

Additional relevant MeSH terms:

Alzheimer Disease; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Pregnanolone; Anesthetics; Central Nervous System Depressants; Physiological Effects of Drugs