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

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT01056965
• Date of registration: 21/01/2010
• Prospective Registration: No
• Primary sponsor: University of California, San Francisco
• Public title: Davunetide (AL-108) in Predicted Tauopathies - Pilot Study
• Scientific title: A 12 Week Randomized, Double Blind, Placebo-Controlled Pilot Study of Davunetide (NAP, AL-108) in Predicted Tauopathies
• Date of first enrolment: January 2010
• Target sample size: 12
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT01056965
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor).
• Phase: Phase 1

Countries of recruitment

United States

Contacts

• Name: Adam L. Boxer, M.D., Ph.D.
• Affiliation: UCSF Memory and Aging Center

Key inclusion & exclusion 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 sign


Age minimum: 40 Years
Age maximum: 85 Years
Gender: All

Health Condition(s) or Problem(s) studied

Predicted Tauopathies, Including

Progressive Supranuclear Palsy

Frontotemporal Dementia With Parkinsonism Linked to Chromosome 17

Corticobasal Degeneration Syndrome

Progressive Nonfluent Aphasia

Intervention(s)

Drug: Placebo nasal spray

Drug: davunetide (AL-108, NAP)

Primary Outcome(s)

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]

Secondary Outcome(s)

Clinical Dementia Rating (CDR) [Time Frame: 12 weeeks]

Geriatric Depression Scale (GDS) [Time Frame: 12 weeks]

Unified Parkinson's Disease Rating Scale (UPDRS) [Time Frame: 12 weeks]

Functional Activities Questionnaire (FAQ) [Time Frame: 12 weeks]

Clinician's Global Impression (CGI-ds) [Time Frame: 12 weeks]

Schwab and England Activities of Daily Living scale (SEADL) [Time Frame: 12 weeks]

CSF biomarkers will assess total tau, phosphorylated tau, and amyloid beta peptide (1-42) [Time Frame: 12 weeks]

PSP Rating Scale [Time Frame: 12 weeks]

MRI brain ventricular volume [Time Frame: 12 weeks]

Neuropsychiatric Inventory (NPI) [Time Frame: 12 weeks]

Saccadic Eye movements - vertical and horizontal total saccade time [Time Frame: 12 weeks]

Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) [Time Frame: 12 weeks]

Secondary ID(s)

AL-108 NAP Pilot

Source(s) of Monetary Support

Please refer to primary and secondary sponsors