A Phase 2/3, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Davunetide for the Treatment of Progressive Supranuclear Palsy.

• Register: EUCTR
• Last refreshed on: 22 April 2013
• Main ID: EUCTR2010-019159-23-DE
• Date of registration: 27/08/2010
• Prospective Registration: Yes
• Primary sponsor: Allon Therapeutics Inc
• Public title: A Phase 2/3, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Davunetide for the Treatment of Progressive Supranuclear Palsy.
• Scientific title: A Phase 2/3, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Davunetide for the Treatment of Progressive Supranuclear Palsy.
• Date of first enrolment: 08/11/2010
• Target sample size: 300
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2010-019159-23
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2

Countries of recruitment

Australia, Canada, France, Germany, United Kingdom, United States

Key inclusion & exclusion criteria

Inclusion criteria:
1. Probable or possible PSP defined as:
1) at least a 12-month history of
a) postural instability or falls during the first 3 years that symptoms are present and
b) at screening (Visit 1) decreased downward saccade velocity defined as observable eye movement (deviation from the “main sequence” linear relationship between saccade amplitude and saccade velocity), or supranuclear ophthalmoplegia defined as 50% reduction in upward gaze or 30% reduction in downward gaze.
2) age at symptom onset of 40 to 85 years by history; and
3) an akinetic-rigid syndrome with prominent axial rigidity.
2. Aged 41 to 85 years at the time of screening.
3. Judged by investigator to be able to comply with neuropsychological evaluation at
baseline and throughout the study.
4. Must have reliable caregiver accompany subject to all study visits. Caregiver must read, understand, and speak local language fluently to ensure comprehension of informed consent form and informant-based assessments of subject. Caregiver must
also have frequent contact with subject (at least 3 hours per week at one time or at different times) and be willing to monitor study medication compliance and the subject’s health and concomitant medications throughout the study.
5. Modified Hachinski score = 3 (Appendix 7). This modified Hachinski will not include the focal neurological signs, symptoms or pseudobulbar affect questions, given the prominence of all 3 in PSP.
6. Score = 15 on the mini-mental state examination (MMSE) at screening (Visit 1).
7. Written informed consent provided by subject (or legally-appointed representative, as appropriate) and caregiver (if not the legally-appointed representative) who are both fluent local language speakers.
8. Subject resides outside a skilled nursing facility or dementia care facility at the time of screening, and admission to such a facility is not planned. Residence in an assisted living facility is allowed.
9. If the subject is receiving levodopa/carbidopa, levodopa/benserazide, a dopamine
agonist, catechol-o-methyltransferase (COMT) inhibitor, or other Parkinson’s medication with the exeption of Azilect (rasagiline), the dose must have been stable for at least 60 days prior to the screening visit (Visit 1) and must remain stable for the duration of the study. No such medication can be initiated during the study. Subjects receiving rasagiline or CoQ10 must be on a stable dose for at least 90 days prior to the screening visit (Visit 1).
10. Able to tolerate the MRI scan during screening with either no sedation or low dose lorazepam.
11. Able to ambulate independently or with assistance defined as the ability to take at least 5 steps with a walker (guarding is allowed provided there is no contact) or the ability to take at least 5 steps with the assistance of another person who can only have contact with one upper extremity.
12. Presence of symptoms for less than 5 years or the presence of symptoms for more than 5 years with a PSPRS baseline score = 40.
13. Stable on all other chronic medications for at least 30 days prior to the screening visit (Visit 1).
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. Insufficient fluency in local language to complete neuropsychological and functional assessments
2. A diagnosis of ALS or other motor neuron disease
3. Any of
a. Abrupt onset of symptoms defined in IC1 associated with ictal events
b. Head trauma related to onset of symptoms defined in IC1
c. Severe amnesia within 6 m of the symptoms defined in IC1
d. Cerebellar ataxia
e. Choreoathetosis
f. Early symptomatic autonomic dysfunction
g. Tremor while at rest
4. Presence of other significant neurological or psychiatric disorders including Alzheimer’s disease; dementia with Lewy bodies; prion disease; Parkinson’s disease; any psychotic disorder; severe bipolar or unipolar depression; seizure disorder; tumor or other spaceoccupying lesion; or history of stroke or head injury with loss of consciousness for at least 15 min within the past 20 y
5. Within 4 w of screening or during the course of the study, concurrent treatment with memantine; acetylcholinesterase inhibitors; antipsychotic agents or mood stabilizers; or benzodiazepines
a. Low dose lorazepam (NMT 2 mg) may be used for sedation prior to MRI scans for those subjects requiring sedation Neuropsychological testing may not be performed after lorazepam admin
b. Subjects who take short acting benzodiazepines for sleep may continue to do so if they have been on a stable dose for 30 d prior to screening.
c. Clonazepam may be used for treatment of dystonia or painful rigidity associated with PSP if the dose has been stable for 90 d prior to screening and is not expected to change during
the course of the study.
6. Treatment with lithium, methylene blue, tramiprosate, ketone bodies, latrepirdine or any putative disease-modifying agent directed at tau within 90 days of screening
7. A history of alcohol or substance abuse within 1 y prior to screening and deemed to be clinically significant by the site investigator
8. Any malignancy within 5 years of the screening visit (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 one year before the screening visit and is judged by the site investigator not to interfere with the subject’s participation in the study, the subject may be included
9. Clinically significant laboratory abnormalities at screening, including creatinine = 2.5 mg/dL, ALT or AST = 3 times the upper limit of the normal reference range, vit B12 below the laboratory normal reference range, or TSH above laboratory normal reference range.
10. The systolic blood pressure measurement is >190 or <85 mm Hg. The diastolic blood pressure measurement is >105 or <50 mm Hg at screening.
11. Abnormal ECG tracing at screening and judged to be clinically significant by the site investigator.
12. Treatment with any IMP or device within 90 d of screening.
13. Known history of serum or plasma progranulin level less than one standard deviation below the normal subject mean for the laboratory performing the assay.
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 (e.g Chromosome 9 ass FTD).
15. History of DBS surgery other than sham surgery for DBS
clinical trial
16. History of early prominent REM sleep behavior disorder
17. Women who are pregnant or lactating and women of childbearing

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Progressive Supranuclear Palsy
MedDRA version: 14.1 Level: PT Classification code 10036813 Term: Progressive supranuclear palsy System Organ Class: 10029205 - Nervous system disorders

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Intervention(s)

Product Name: Davunetide
Product Code: AL-108
Pharmaceutical Form: Nasal spray
INN or Proposed INN: Davunetide
CAS Number: 211439-12-2
Current Sponsor code: AL-108
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 75-
Pharmaceutical form of the placebo: Nasal spray
Route of administration of the placebo: Intranasal use (Noncurrent)

Primary Outcome(s)

Main Objective: To evaluate davunetide 30 mg BID relative to placebo, when both are administered IN for 52 weeks, to subjects with PSP, with respect to:
- Efficacy, as measured by change from baseline scores of the Progressive Supranuclear Palsy Rating Scale (PSPRS) at 52 weeks.
- Efficacy, as measured by the change from baseline of the Schwab and England Activities of Daily Living Scale (SEADL) at 52 weeks.
- Safety, as measured by reported adverse events (AEs), electrocardiograms (ECGs), nasal examination and clinical laboratory measures.

Primary end point(s): - Efficacy will be assessed as the change from baseline using the PSPRS (Appendix 1)
at 52 weeks (Visit 7).
- Efficacy will be assessed as the change from baseline of the SEADL (Appendix 3) at
52 weeks (Visit 7).
- Safety evaluations will be performed by recording clinical AEs and a nasal
examination at each study visit. Additionally, samples will be collected for
laboratory analysis at regular intervals. The 12-lead ECGs will be evaluated at the
screening visit (Visit 1) and 52 weeks (Visit 7). Physical examinations will be
performed at the screening visit (Visit 1), 6 and 52 weeks (Visits 3 and 7). Vital
signs including blood pressure and heart rate will be obtained at screening (Visit 1)
and 0, 3, 6, 13, 26, 39, and 52 weeks (Visits 2 through 7, inclusive), and clinical
laboratory tests will be obtained at screening (Visit 1) and weeks 6, 13, 26, 39, and
52 (Visits 3-7). Nasal examinations will be conducted at baseline (Week 0) and all
follow-up visits (Weeks 3 to 52, inclusive).

Secondary Objective: To evaluate davunetide 30 mg BID relative to placebo, when both are administered IN to subjects with PSP, with respect to:
• Efficacy, as measured by the Clinical Global Impression of Change (CGI-C) at 52
weeks.
• Brain atrophy, as measured by change from baseline of ventricular volumes measured by volumetric brain MRI at 52 weeks.

Timepoint(s) of evaluation of this end point: 52 weeks (visit 7) for all these end points and additionally visit 1 and visits 1-7 depending on the case.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: 52 weeks (visit 7)

Secondary end point(s): - Efficacy will be assessed by the CGI-C (Appendix 2) at 52 weeks (Visit 7).
- Brain atrophy will be assessed as the change from baseline of ventricular volumes measured by volumetric brain MRI at 52 weeks (Visit 7).

Secondary ID(s)

AL-108-231