Dose Finding Study of Nimodipine for the Treatment of Progranulin Insufficiency From GRN Gene Mutations

Phase 1

Completed

• Conditions: Progranulin Mutation Carriers
• Interventions: Drug: Nimodipine

• Registration Number: NCT01835665
• Lead Sponsor: University of California, San Francisco

Brief Summary

The purpose of this study is to determine the maximum tolerated dose of nimodipine as well as the safety and tolerability of oral nimodipine in progranulin mutation carriers in preparation for longer term efficacy studies in patients with frontotemporal dementia due to progranulin gene mutations.

Detailed Description

8 people with a GRN gene mutation will be given escalating doses of oral nimodipine for four weeks, followed by the maximally tolerated dose for four weeks. To maximize enrollment, the trial will enroll both symptomatic and asymptomatic GRN mutation carriers. The trial will include a four week, dose-escalation phase followed by 1-month maintenance phase, and a 1-week taper. Assessments at the study site will take place prior to starting nimodipine, each week the dose is increased (weeks 1-5), after 4 weeks of maintenance dose, and 2 weeks after completion of the study. These will include blood chemistry tests, ECGs, and blood pressure. Both dose escalation and maintenance will focus on safety and tolerability of nimodipine treatment in this population as well as plasma progranulin levels as a biomarker outcome. The trial will incorporate a variety of other fluid biomarker (blood and CSF) and imaging assessments to determine which will be most sensitive to nimodipine pharmacodynamic effects in this population.

Study Timeline

• Study Start: 2013-03
• Study First Submitted: 2013-03-27
• Study First Submitted QC: 2013-04-16
• Study First Posted: 2013-04-19
• Status Verified: 2016-05
• Primary Completion: 2016-05
• Study Completion: 2016-05
• Last Update Submitted: 2016-05-12
• Last Update Posted: 2016-05-16

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 8

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Nimodipine	Nimodipine	-

Primary Outcome Measures

Name	Time	Method
Maximum dose tolerated of nimodipine	up to 10 weeks	Nimodipine dose will be increased weekly for four weeks then maintained for 4 weeks at highest tolerated dose, followed by a 1-week taper.

Secondary Outcome Measures

Name	Time	Method
Plasma progranulin levels	up to 10 weeks post initial dosing	Plasma progranulin levels will be obtained at screening, baseline, and at each week dose is increased, after the 4 week maintenance phase, and 2 weeks after the taper. Due to the small sample size, inferential statistics will not be calculated to assess the endpoints of interest. However, descriptive statistics will be presented for the primary and secondary outcome measures (such as plasma and CSF progranulin levels) summarized by treatment group and visit. For these continuous variables, the following information will be presented by visit: n, mean, standard deviation and order statistics (minimum, 25th percentile, median, 75th percentile and maximum). These statistics will be presented using the actual value at baseline and the change from baseline for later data.
Brain MRI scan	Screening and week 8	To acquire preliminary data on the sensitivity of functional and brain MR imaging (resting-state functional connectivity and arterial spin label perfusion) to progranulin elevating therapies.
Inflammatory marker levels (ESR, CRP, cytokines)	up to 10 weeks post initial dosing	Markers of inflammation will be obtained from the blood at screening, baseline, each week dose is increased, after 4 weeks of stable dose, and 2 weeks after the taper. Due to the small sample size, inferential statistics will not be calculated to assess the endpoints of interest. However, descriptive statistics will be presented for the primary and secondary outcome measures (such as plasma and CSF progranulin levels) summarized by treatment group and visit. For these continuous variables, the following information will be presented by visit: n, mean, standard deviation and order statistics (minimum, 25th percentile, median, 75th percentile and maximum). These statistics will be presented using the actual value at baseline and the change from baseline for later data.
CSF cytokines	baseline (week 1) and 8 weeks post dosing	CSF cytokines will be obtained at baseline and after 8 weeks of taking nimodipine
CSF progranulin	baseline (week 1) and 8 weeks after initial dosing	CSF progranulin levels will be obtained at baseline and week 8

Trial Locations

Locations (1)

UCSF Memory and Aging Center; 🇺🇸 San Francisco, California, United States