Clinical trial NCT03748303: Allopregnanolone Regenerative Therapeutic for Early Alzheimer's Disease: Intramuscular Study
Official title: Allopregnanolone Regenerative Therapeutic for Early Alzheimer's Disease: IV to IM Bridging Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: Alzheimer Dementia
Keywords: Alzheimer's disease
Mild cognitive impairment
Dementia
Regenerative therapeutic
Drug development
Lead sponsor: University of Arizona
Sponsor class: OTHER
Collaborators: name: University of Southern California
name: Alzheimer's Association
First posted: 2018-11-20
Enrollment: 12
Sex: ALL
Minimum age (years): 55
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Single-arm, open-label study
Primary purpose: TREATMENT

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.

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).

Eligibility 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.

Primary outcomes:
measure: Safety - Adverse events
timeFrame: From baseline to visit 16 (14 weeks)
measure: Safety - clinical laboratory measures
timeFrame: From Baseline to visit 16 (14 weeks)
measure: Safety - clinical assessment
timeFrame: From Baseline to visit 16 (14 weeks)
Secondary outcomes:
measure: Pharmacokinetic parameter - Cmax
timeFrame: Visits 3 - 6 (up to 4 weeks)
measure: Pharmacokinetic parameter - AUC
timeFrame: Visits 3 - 6 (up to 4 weeks)
measure: Pharmacokinetic parameter - Tmax
timeFrame: Visits 3 - 6 (up to 4 weeks)
measure: Pharmacokinetic parameter - Clearance
timeFrame: Visits 3 - 6 (up to 4 weeks)
measure: Pharmacokinetic parameter - Volume of distribution
timeFrame: Visits 3 - 6 (up to 4 weeks)
measure: Satisfaction and feasibility of home nurse survey
timeFrame: Visits 8-9 and 11-15 (up to 8 weeks)
Other outcomes:
measure: MRI brain volumes
timeFrame: Baseline to visit 16 (14 weeks)
measure: Cambridge Neuropsychological Test Automated Battery (CANTAB) Paired Associates Learning (PAL)
timeFrame: Baseline to visit 16 (14 weeks)
measure: Mini-Mental State Exam (MMSE)
timeFrame: Baseline to visit 16 (14 weeks)
measure: Alzheimer's Disease Assessment Scale Cognitive Subscale 14 (ADAS-Cog14)
timeFrame: Baseline to visit 16 (14 weeks)
measure: Clinical Dementia Rating Scale Sum of Boxes (CDR-SB)
timeFrame: Baseline to visit 16 (14 weeks)
measure: Cogstate Alzheimer's battery
timeFrame: Baseline to visit 16 (14 weeks)
measure: Activities of daily living
timeFrame: Baseline to visit 16 (14 weeks)
measure: Caregiver burden survey
timeFrame: Baseline to visit 16 (14 weeks)
measure: Actigraphy sleep assessment - Total sleep time
timeFrame: Screen to visit 16 (16 weeks)
measure: Actigraphy sleep assessment - Wake after sleep onset
timeFrame: Screen to visit 16 (16 weeks)
measure: Actigraphy sleep assessment - Sleep efficiency
timeFrame: Screen to visit 16 (16 weeks)
measure: Physical activity
timeFrame: Screen to visit 16 (16 weeks)
Locations:
city: Los Angeles
country: United States
facility: University of Southern California - Alzheimer Disease Research Center - Healthcare Consultation Center II
state: California
Study officials:
affiliation: University of Arizona
name: Roberta D Brinton, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Southern California
name: Lon S Schneider, MD, MS
role: PRINCIPAL_INVESTIGATOR
References: