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

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Brief Title

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

Official Title

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

Brief Summary

      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 Phase

Phase 1

Study Type

Interventional


Primary Outcome

Safety evaluations will be performed by recording clinical adverse events at each study visit. Clinical laboratory, ECGs, physical examinations will be conducted.

Secondary Outcome

 PSP Rating Scale

Condition

Predicted Tauopathies, Including

Intervention

davunetide (AL-108, NAP)

Study Arms / Comparison Groups

 davunetide (Al-108, NAP) nasal spray
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

12

Start Date

January 2010

Completion Date

December 2012

Primary Completion Date

December 2012

Eligibility Criteria

        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.
      

Gender

All

Ages

40 Years - 85 Years

Accepts Healthy Volunteers

No

Contacts

Adam L. Boxer, M.D., Ph.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01056965

Organization ID

AL-108 NAP Pilot


Responsible Party

Principal Investigator

Study Sponsor

University of California, San Francisco


Study Sponsor

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


Verification Date

April 2019