Allopregnanolone for Mild Cognitive Impairment Due to Alzheimer's Disease or Mild AD (Allo)

• ClinicalTrials.gov Identifier: NCT02221622
• Recruitment Status: Completed
• First Posted: August 20, 2014
• Last Update Posted: July 5, 2019
• Sponsor: University of Southern California
• Collaborator: National Institute on Aging (NIA)
• Information provided by (Responsible Party): University of Southern California

Tracking Information

• First Submitted Date: July 2, 2014
• First Posted Date: August 20, 2014
• Last Update Posted Date: July 5, 2019
• Study Start Date: August 2014
• Actual Primary Completion Date: February 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 31, 2018)

• Safety profile: Adverse events [ Time Frame: From Baseline to week 16 ]
  Incidence and severity of treatment emergent adverse events assessed weekly per treatment arm.
• Safety profile: Clinical laboratory measurements [ Time Frame: From Baseline to week 13 ]
  Evaluating the proportion of subjects exceeding pre-established critical values per treatment arm: Alanine aminotransferase (ALT, U/L) > 5 times upper normal limit Aspartate aminotransferase (AST, U/L) > 5 times upper normal limit Total serum bilirubin (mg/dl) > 2 times upper normal limit Serum creatinine (mg/dl) > 2 times upper normal limit Serum creatine phosphokinase (U/L) > 5 times upper normal limit
• Safety profile: ARIA [ Time Frame: From Baseline to week 13 ]
  MRI based assessment of amyloid related imaging abnormalities (ARIA); proportion of subjects with ARIA
• Safety profile: Physical and neurological examination [ Time Frame: From Baseline to week 16 ]
  To evaluate the proportion of abnormal examination findings of subjects in each treatment arm.
• Tolerability - Maximum tolerated dose (MTD) [ Time Frame: From Baseline to week 12 ]
  Onset of sedation will define the upper most limit of drug dose

• Original Primary Outcome Measures (submitted: August 18, 2014): Safety and tolerability as measured by vital signs, clinical laboratory measurements, adverse events, brain MRI, clinical assessment and examination. [ Time Frame: From Baseline to week 16 ]

Current Secondary Outcome Measures (submitted: May 31, 2018)

• Pharmacokinetic profile after single and multiple doses: Maximum Concentration (Cmax) [ Time Frame: Weeks: 1 and 12 ]
  Measurement of maximum concentration
• Pharmacokinetic profile after single and multiple doses: time attain to Cmax (Tmax) [ Time Frame: Weeks: 1 and 12 ]
  Time to attain maximum concentration.
• Pharmacokinetic profile after single and multiple doses: Area under the curve (AUC) [ Time Frame: Weeks: 1 and 12 ]
  Pharmacokinetic parameter.
• Pharmacokinetic profile after single and multiple doses: Drug Clearance (CL) [ Time Frame: Weeks: 1 and 12 ]
  Pharmacokinetic parameter.
• Pharmacokinetic profile after single and multiple doses: apparent volume of distribution at steady state (Vss) [ Time Frame: Weeks: 1 and 12 ]
  Pharmacokinetic parameter.
• Cognitive tests (ADAS-Cog; MMSE/MoCA; ADCS-CGIC; CogState) [ Time Frame: Baseline to Week 13 ]
  Alzheimer's disease Assessment Scale Cognitive Subscale 14 (ADAS-Cog); Mini-Mental State Exam (MMSE); Montreal Cognitive Assessment (MoCA); Alzheimer's disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC); CogState 12-min battery (CogState)
• Brain MRI volumetrics [ Time Frame: Baseline and Week 13 ]
  Gray matter, white matter and hippocampal volume measurements, including subfield analysis.

Original Secondary Outcome Measures (submitted: August 18, 2014)

• Pharmacokinetic profile after single and multiple doses: Maximum Concentration (Cmax) [ Time Frame: Weeks: 1 and 12 ]
• Pharmacokinetic profile after single and multiple doses: time attain to Cmax (Tmax) [ Time Frame: Weeks: 1 and 12 ]
• Pharmacokinetic profile after single and multiple doses: Area under the curve (AUC) [ Time Frame: Weeks: 1 and 12 ]
• Pharmacokinetic profile after single and multiple doses: Drug Clearance (CL) [ Time Frame: Weeks: 1 and 12 ]
• Pharmacokinetic profile after single and multiple doses: apparent volume of distribution at steady state (Vss) [ Time Frame: Weeks: 1 and 12 ]
• Cognitive tests (ADAS-Cog; MMSE/MoCA; ADCS-CGIC; CogState) [ Time Frame: Baseline to Week 13 ]
  Alzheimer's disease Assessment Scale Cognitive Subscale 14 (ADAS-Cog); Mini-Mental State Exam (MMSE); Montreal Cognitive Assessment (MoCA); Alzheimer's disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC); CogState 12-min battery (CogState)
• Structural and functional brain MRI [ Time Frame: Baseline and Week 13 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Allopregnanolone for Mild Cognitive Impairment Due to Alzheimer's Disease or Mild AD
• Official Title: Allopregnanolone Regenerative Therapeutic for MCI/AD: Dose Finding Phase 1
• Brief Summary: The purpose of this study is to evaluate the safety and tolerability of allopregnanolone, a naturally occurring brain steroid, in mild cognitive impairment and early Alzheimer's disease participants. The primary goal is to determine the maximally tolerated dose.
• Detailed Description: 1) Each dose group will be comprised of 8 participants (6 randomized to allopregnanolone; 2 randomized to placebo) administered one dose of allopregnanolone or placebo once per week for 12 weeks. A higher dose will be administered to the next group of participants when the lower dose is shown to be safe and tolerable. 2) Pharmacokinetic analyses will be conducted on blood samples taken from participants at the beginning and end of the trial. 3) The trial will assess safety including via MRI brain imaging.
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Mild Cognitive Impairment
• Alzheimer Disease

Intervention

• Drug: Allopregnanolone injection (intravenous solution)
  Allopregnanolone intravenous infusion
  Other Names:

  • 3α,5α-tetrahydroprogesterone
  • 3α-hydroxy-5α-pregnan-20-one
• Drug: Placebo injection (intravenous solution)
  Placebo intravenous infusion

Study Arms

• Experimental: Allopregnanolone 2 mg
  Drug: Allopregnanolone injection (intravenous solution) once per week for 12 weeks
  Intervention: Drug: Allopregnanolone injection (intravenous solution)
• Experimental: Allopregnanolone 4 mg
  Drug: Allopregnanolone injection (intravenous solution) once per week for 12 weeks
  Intervention: Drug: Allopregnanolone injection (intravenous solution)
• Experimental: Allopregnanolone 6-18 mg
  Drug: Allopregnanolone injection (intravenous solution) once per week for 12 weeks
  Intervention: Drug: Allopregnanolone injection (intravenous solution)
• Placebo Comparator: Placebo
  Drug: Placebo injection (intravenous solution) once per week for 12 weeks
  Intervention: Drug: Placebo injection (intravenous solution)

• Publications *: Hernandez GD, Solinsky CM, Mack WJ, Kono N, Rodgers KE, Wu CY, Mollo AR, Lopez CM, Pawluczyk S, Bauer G, Matthews D, Shi Y, Law M, Rogawski MA, Schneider LS, Brinton RD. Safety, tolerability, and pharmacokinetics of allopregnanolone as a regenerative therapeutic for Alzheimer's disease: A single and multiple ascending dose phase 1b/2a clinical trial. Alzheimers Dement (N Y). 2020 Dec 16;6(1):e12107. doi: 10.1002/trc2.12107. eCollection 2020.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 26, 2015): 24
• Original Estimated Enrollment (submitted: August 18, 2014): 32
• Actual Study Completion Date: February 2018
• Actual Primary Completion Date: February 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Men or postmenopausal women
• 55 years of age or older
• Diagnosis of MCI due to AD or mild AD
• MMSE > 20 at screen
• Capacity to provide informed consent
• Residing in the community with a caregiver able to accompany the patient to clinic visits
• No medical contraindications to participation
• Willingness to comply with study procedures

Exclusion Criteria:

• 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
• MRI indicative of any other significant abnormality, including but not limited to evidence of a cerebral contusion, encephalomalacia, aneurysms, vascular malformations, subdural hematoma, or space occupying lesions
• Any condition that would contraindicate an MRI such as the presence of metallic objects in the eyes, skin, heart, or body

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 55 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02221622
• Other Study ID Numbers: AlloPhase1; 1UF1AG046148 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: University of Southern California
• Study Sponsor: University of Southern California
• Collaborators: National Institute on Aging (NIA)

Investigators

• Principal Investigator: Roberta D Brinton, Ph.D.; University of Southern California
• Principal Investigator: Lon S Schneider, M.D.; University of Southern California

• PRS Account: University of Southern California
• Verification Date: May 2018