Allopregnanolone Regenerative Therapeutic for Early Alzheimer's Disease: Intramuscular Study

Study Overview
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Brief Summary
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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
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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).

Official Title
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Allopregnanolone Regenerative Therapeutic for Early Alzheimer's Disease: IV to IM Bridging Study

Conditions
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Alzheimer Dementia

Intervention / Treatment
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* Drug: Allopregnanolone


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Single-arm, open-label study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Allo IM cohort<br>Allopregnanolone 4-18mg IM, weekly, for 12 weeks. | Drug: Allopregnanolone<br>* Administration of weekly IM injections of Allopregnanolone.<br>* Other names: Allo;|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic parameter - Cmax | Determine maximum serum concentration of Allo after IM administration of each dose. | Visits 3 - 6 (up to 4 weeks) | 
| Pharmacokinetic parameter - AUC | Determine the area under the curve after each IM administration of Allo. | Visits 3 - 6 (up to 4 weeks) | 
| Pharmacokinetic parameter - Tmax | Determine the time at which Cmax is attained. | Visits 3 - 6 (up to 4 weeks) | 
| Pharmacokinetic parameter - Clearance | Pharmacokinetic measurement of the volume of plasma from which Allo is completely removed per unit time. | Visits 3 - 6 (up to 4 weeks) | 
| Pharmacokinetic parameter - Volume of distribution | Determine the volume of distribution at steady state of Allo. | Visits 3 - 6 (up to 4 weeks) | 
| Satisfaction and feasibility of home nurse survey | 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). | Visits 8-9 and 11-15 (up to 8 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer's disease, Mild cognitive impairment, Dementia, Regenerative therapeutic, Drug development