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

NCT01835665 | Completed Phase 1

• 1 other identifier: CHR12-09098
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

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.

Conditions

Progranulin Mutation Carriers

Outcome Measures

Primary Outcomes (1)

• Maximum dose tolerated of nimodipine

  Nimodipine dose will be increased weekly for four weeks then maintained for 4 weeks at highest tolerated dose, followed by a 1-week taper.

  up to 10 weeks

Secondary Outcomes (5)

• Plasma progranulin levels

  up to 10 weeks post initial dosing

• Inflammatory marker levels (ESR, CRP, cytokines)

  up to 10 weeks post initial dosing

• CSF progranulin

  baseline (week 1) and 8 weeks after initial dosing

• CSF cytokines

  baseline (week 1) and 8 weeks post dosing

• Brain MRI scan

  Screening and week 8

Study Arms (1)

Nimodipine

EXPERIMENTAL

Drug: Nimodipine

Interventions

Nimodipine DRUG

Nimodipine is an FDA-approved drug for subarachnoid hemorrhage indication

Also known as: Nimotop

Nimodipine

Eligibility Criteria

• Age: 30 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed and dated written informed consent obtained from the subject and/or the subject's caregiver in accordance with local IRB regulations
• Symptomatic GRN mutation carrier as defined by presence of known disease-associated GRN mutation confirmed by genetic testing and meeting international (2011) criteria for FTD (Rascovsky et al., 2011), Boeve (2003) criteria (B. F. Boeve, Lang, \& Litvan, 2003) for CBS, or Gorno-Tempini criteria (2011) for primary progressive aphasia (Gorno-Tempini et al., 2011) (gene carrier status known) OR
• Asymptomatic GRN mutation carrier (gene carrier status known) from family with known disease-associated mutation;
• Age: \>30
• MMSE ≥ 10 at screening visit.
• Judged by investigator to be able to comply with all study procedures
• In the opinion of the investigator, the patient will be compliant with the protocol and have a high probability of completing the study
• Lack of other recent, severe medical conditions.

You may not qualify if:

• Hypersensitivity or other contra-indication to nimodipine use
• Systemic autoimmune disease (such as rheumatoid arthritis, thyroid disease, or diabetes) that might alter progranulin levels.
• Regular use of systemic corticosteroids or other anti-inflammatory medication. NSAID use acceptable if on a stable dose for 30 days prior to screening and agrees to remain on same dose for duration of trial.
• Subject is pregnant, plans to become pregnant during course of study or has a positive urine pregnancy test.
• Unwilling to use two forms of contraception if not surgically sterile for duration of study.
• History of cancer (other than basal cell CA of skin) within 5 years.
• History of myocardial infarction, cardiac conduction block, arrhythmia or other significant cardiac illness in the opinion of the investigator (in consultation with a board certified cardiologist).
• History of peptic ulcer.
• Metabolic disease such as gout or poorly controlled diabetes.
• History of alcohol or substance abuse within 1 year prior to screening, if deemed clinically significant by investigator.
• Any current malignancy, or any clinically significant hematological, endocrine, cardiovascular, renal, hepatic, gastrointestinal or neurological disease. If the condition has been stable for at least the past year and is judged by the investigator not to interfere with the patient's participation in the study, the patient may be included.
• CT or MRI evidence of any of the following: hydrocephalus, stroke, space-occupying lesion, cerebral infection or any clinically significant CNS disease other than FTD, CBS, or progressive aphasia.
• Systolic blood pressure greater than 180 or less than 90 mm Hg. Diastolic blood pressure greater than 105 or less than 50 mm Hg.
• Abnormal ECG at screening and judged to be clinically significant by the investigator and/or board certified cardiologist.
• Use of investigational drugs or participation in investigational drug study within 30 days of screening or 5 half lives of the previous investigational drug, whichever is longer.

Sponsors & Collaborators

• University of California, San Francisco: lead
• The Bluefield Project to Cure Frontotemporal Dementia: collaborator

Study Sites (1)

UCSF Memory and Aging Center

San Francisco, California, 94158, United States

Location

MeSH Terms

Interventions

Nimodipine

Intervention Hierarchy (Ancestors)

Dihydropyridines; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nicotinic Acids

Study Officials

• Adam Boxer, MD, PhD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 27, 2013
• First Posted: April 19, 2013
• Study Start: March 1, 2013
• Primary Completion: May 1, 2016
• Study Completion: May 1, 2016
• Last Updated: May 16, 2016

Record last verified: 2016-05

Locations

US (1)