Davunetide (AL-108) in Predicted Tauopathies - Pilot Study

April 3, 2019 updated by: Adam Boxer, University of California, San Francisco

A 12 Week Randomized, Double Blind, Placebo-Controlled Pilot Study of Davunetide (NAP, AL-108) in Predicted Tauopathies

The primary objective of the study is to obtain preliminary safety and tolerability data with davunetide (NAP, AL-108) in patients with a tauopathy (frontotemporal lobar degeneration [FTLD] with predicted tau pathology, corticobasal degeneration syndrome [CBS] or progressive supranuclear palsy [PSP]). The secondary objectives of this study are to obtain preliminary data on short term changes (at 12 weeks) in a variety of clinical, functional and biomarker measurements from baseline, including cerebrospinal fluid (CSF) tau levels, eye movements, and brain MRI measurements.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

12

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • San Francisco, California, United States, 94143-1207
        • University of California, San Francisco (UCSF)

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

38 years to 83 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. A probable tauopathy defined as:

    • Probable or possible progressive supranuclear palsy (PSP) defined as:

      1. at least a 12-month history of:

        • postural instability or falls during the first 3 years that symptoms are present and
        • prominent decreased saccade velocity or supranuclear ophthalmoplegia;
      2. age at symptom onset ≥ 40 years by history; and
      3. an akinetic-rigid syndrome with prominent axial rigidity.

    OR,

    • Progressive nonfluent aphasia (PNFA)defined as:

      1. at least a 6-month history of difficulty with expressive speech characterized by at least 3 of the following:

        • apraxia of speech,
        • speech hesitancy,
        • labored speech,
        • word finding difficulty, or
        • agrammatism; and
      2. the symptoms above are the subject's principal neurological deficit and the symptoms constituted the initial clinical presentation.

    OR,

    • Corticobasal Degeneration syndrome (CBS) defined as:

      1. at least a 6-month history of progressive cortical dysfunction evidenced by at least one of the following:

        • ideomotor apraxia,
        • alien limb phenomenon,
        • cortical sensory loss,
        • focal or asymmetric myoclonus, or
        • apraxia of speech /nonfluent aphasia; and

      2. at least a 6-month history of progressive extrapyramidal dysfunction evidenced by at least one of the following:

        • focal or asymmetrical rigidity (limb or axial) or asymmetrical dystonia (limb or axial); and
        • lacking prominent and sustained L-dopa response.

    OR

    • Frontotemporal Dementia with Parkinsonism linked to Chromosome 17 (FTDP-17): Motor, cognitive or behavioral dysfunction, as defined below associated with a previously demonstrated mutation of the MAPT gene, and meets criteria for PNFA, CBS or PSP as defined above, or CDR-FTLD ≥ 1.0.
  2. Documented age 40-85 years at the time of the onset of symptoms associated with the neurological deficits described in inclusion criterion 1.
  3. Judged by investigator to be able to comply with neuropsychological evaluation at baseline.
  4. Must have reliable caregiver accompany subject to all study visits. Caregiver must read, understand and speak local language fluently in order to ensure comprehension of informed consent form and informant-based assessments of subject. Caregiver must also have frequent contact with subject (at least 3 times per week for one hour) and be willing to monitor study medication compliance and the subject's health and concomitant medications throughout the study.
  5. FTLD Modified Hachinski score ≤ 3.(Knopman et al., 2008) This modified Hachinski will not include the focal neurological signs, symptoms or pseudobulbar affect questions, given the prominence of all three in CBS/PSP.
  6. MMSE ≥ 15 at Visit 1.
  7. Written informed consent provided by both subject and caregiver who are both fluent English speakers.
  8. Subject resides outside a skilled nursing facility or dementia care facility. Residence in an assisted living facility is allowed.
  9. If the subject is receiving levodopa/carbidopa, a dopamine agonist, COMT inhibitor or other Parkinson's medication the dose must have been stable for at least 120 days prior to Visit 1 and must remain stable for the duration of the study.
  10. Able to tolerate MRI scan during screening without use of sedation.
  11. Able to ambulate with or without assistance.

Exclusion Criteria:

  1. Insufficient fluency in local language to complete neuropsychological and functional assessments.
  2. A diagnosis of Amyotrophic Lateral Sclerosis or other motor neuron disease.

  3. Any of the following:

    • Abrupt onset of symptoms defined in inclusion criteria 1 associated with ictal events,
    • Head trauma related to onset of symptoms defined in inclusion criteria 1,
    • Severe amnesia within 6 months of the symptoms defined in inclusion criteria 1,
    • Cerebellar ataxia,
    • Choreoathetosis,
    • Early, symptomatic autonomic dysfunction, or
    • Tremor at rest.
  4. History of other significant neurological or psychiatric disorders including, but not limited to, Alzheimer's disease, dementia with Lewy bodies, Prion disease, stroke, Parkinson's disease, any psychotic disorder, severe bipolar or unipolar depression, seizure disorder, tumor or other space-occupying lesion, or head injury with loss of consciousness within past 20 years temporally related to onset of symptoms.
  5. Within 4 weeks of screening or during the course of the study, concurrent treatment with memantine (stable dose memantine, greater than 6 months is allowed), acetylcholinesterase inhibitors, antipsychotic agents or mood stabilizers (valproate, lithium, etc.) or benzodiazepines (other than temazepam or zolpidem).
  6. Treatment with lithium, methylene blue, tramiprosate, ketone bodies, Dimebon or any putative disease-modifying agent directed at tau within 90 days of screening.
  7. A history of alcohol or substance abuse within 1 year prior to screening and deemed to be clinically significant by the site investigator.
  8. Any malignancy (other than non-metastatic basal cell carcinoma of the skin) within 5 years of Visit 1 or current clinically significant hematological, endocrine, cardiovascular, renal, hepatic, gastrointestinal, or neurological disease. For the non-cancer conditions, if the condition has been stable for at least the past year and is judged by the site investigator not to interfere with the patient's participation in the study, the patient may be included.
  9. Clinically significant lab abnormalities at screening, including creatinine ≥ 2.5 mg/dL, vitamin B12 below laboratory normal reference range, or TSH above laboratory normal reference range.
  10. Systolic blood pressure greater than 180 or less than 90 mm Hg. Diastolic blood pressure greater than 105 or less than 50 mm Hg.
  11. ECG abnormal at screening and judged to be clinically significant by the site investigator.
  12. Treatment with any investigational drugs or device or participation in an investigational drug study within 60 days of screening.
  13. Known history of serum or plasma progranulin level < 110.9 ng/mL.
  14. Known presence of known disease-associated mutation in TDP-43, PGRN, CHMPB2 or VCP genes or any other FTLD causative genes not associated with underlying tau pathology (eg. Chr. 9 associated FTD).
  15. History of deep brain stimulator surgery other than sham surgery for DBS clinical trial.
  16. History of early, prominent REM behavior disorder.
  17. Women of childbearing potential who are not using at least two forms of medically recognized contraception.
  18. An employee or relative of an employee of Allon Therapeutics
  19. Significant anatomical nasal abnormality (e.g., septal deviation obstructing airflow to at least one nostril or septal perforation) or history of nasal turbinate surgery.
  20. History of a clinically significant medical condition that that would interfere with the subject's ability to comply with study instructions, would place the subject at increased risk, or might confound the interpretation of the study results.
  21. Contraindication to MRI examination for any reason (eg., severe claustrophobia, ferromagnetic metal in body, etc.).
  22. Structural abnormality on MRI within 2 years of baseline that precludes diagnosis of PSP, CBS or PNFA, such as cortical infarct in brain region that might account for subject's symptoms.
  23. In subjects receiving anti-Parkinson's Disease medication at the time of screening, in the opinion of the investigator substantial worsening of motor signs or symptoms compared to normal functioning following overnight withdrawal of the anti-Parkinson medication.
  24. Subject not willing to attempt LP.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Placebo nasal spray
Drug: Placebo nasal spray
Subjects will be randomized 2:1 (drug:placebo). Subjects will receive twice daily treatment with placebo administered intranasally.
Experimental: davunetide (Al-108, NAP) nasal spray
Subjects will be randomized 2:1 (drug:placebo). Subjects will receive twice daily treatment with either davunetide 15 mg or placebo. Davunetide and placebo will be administered intranasally with a multi-dispensing, metered nasal spray pump device.
Drug: davunetide (AL-108, NAP)
Subjects will be randomized 2:1 (drug:placebo). Subjects will receive twice daily treatment with davunetide 15 mg administered intranasally.
Other Names:
  • NAP
  • AL-108

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Safety evaluations will be performed by recording clinical adverse events at each study visit. Clinical laboratory, ECGs, physical examinations will be conducted.
Time Frame: 12 weeks
12 weeks

Secondary Outcome Measures

Outcome Measure
Time Frame
PSP Rating Scale
Time Frame: 12 weeks
12 weeks
Clinician's Global Impression (CGI-ds)
Time Frame: 12 weeks
12 weeks
Schwab and England Activities of Daily Living scale (SEADL)
Time Frame: 12 weeks
12 weeks
MRI brain ventricular volume
Time Frame: 12 weeks
12 weeks
Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)
Time Frame: 12 weeks
12 weeks
Unified Parkinson's Disease Rating Scale (UPDRS)
Time Frame: 12 weeks
12 weeks
Neuropsychiatric Inventory (NPI)
Time Frame: 12 weeks
12 weeks
Geriatric Depression Scale (GDS)
Time Frame: 12 weeks
12 weeks
CSF biomarkers will assess total tau, phosphorylated tau, and amyloid beta peptide (1-42)
Time Frame: 12 weeks
12 weeks
Saccadic Eye movements - vertical and horizontal total saccade time
Time Frame: 12 weeks
12 weeks
Clinical Dementia Rating (CDR)
Time Frame: 12 weeeks
12 weeeks
Functional Activities Questionnaire (FAQ)
Time Frame: 12 weeks
12 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of California, San Francisco

Investigators

  • Principal Investigator: Adam L. Boxer, M.D., Ph.D., UCSF Memory and Aging Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2010

Primary Completion (Actual)

December 1, 2012

Study Completion (Actual)

December 1, 2012

Study Registration Dates

First Submitted

January 21, 2010

First Submitted That Met QC Criteria

January 25, 2010

First Posted (Estimate)

January 26, 2010

Study Record Updates

Last Update Posted (Actual)

April 5, 2019

Last Update Submitted That Met QC Criteria

April 3, 2019

Last Verified

April 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • AL-108 NAP Pilot

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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