| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Progressive Supranuclear Palsy |
|
| E.1.1.1 | Medical condition in easily understood language |
Progressive Supranuclear Palsy
PSP |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10036813 |
| E.1.2 | Term | Progressive supranuclear palsy |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To evaluate divunetide 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 ofthe Progressive
Supranuclear Palsy Rating Scale (PSPRS) at 52 weeks.
• Safety, as measured by reported AEs, electrocardiograms (ECG), and clinical laboratory measures. |
|
| E.2.2 | Secondary objectives of the trial |
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 change from baseline ofthe Schwab and England Activities of Daily Living Scale (SEADL) at 52 weeks.
• Efficacy, as measured by the change from baseline ofthe Clinical Global Impression ofDisease Severity (CGI-ds) at 52 weeks.
• Brain atrophy, as measured by change from baseline of ventricular volumes measured by volumetric brain MRI at 52 weeks. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Title: Saccadic eye movements Date and version: Same as protocol amendment 3; no separate document, only sub-section in the protocol. At pre-selected sites, and for patients consenting in only, an exploratory substudy measuring visually guided horizontal saccades will be conducted. The objectives of this substudy are to assess whether davunetide treatment leads to changes in: - the dynamic properties of the saccades in individuals with PSP, and - the rate of progression of horizontal and vertical saccade abnormalties in PSP. It will be performed on subset of subjects enrolled by sites able to measure vertical saccades using infrared or search coil technology, vertical saccade measurements will be also be derived (no additional informed consent will be collected as it is sites speicific). (protocol section 9.1.8). Two other optional studies : genetic optional study (protocol section 9.2.3) and lumbar puncture optional study for PK measures (protocol section 9.2.1) will be performed to patients giving their consent. |
|
| E.3 | Principal inclusion criteria |
Subjects may be included in the study only if they meet all of the following criteria:
1. Probable or possible PSP defined as:
a) at least a 12-month history of postural instability or falls during the first 3 years that symptoms are present and
b) at screening (Visit 1), a 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; and
c) age at symptom onset of 40 to 85 years by history; and
d) 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 exception 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). |
|
| E.4 | Principal 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 inclusion criteria 1 (IC1) associated with ictal events
b. Head trauma related to onset of symptoms defined in IC1
c. Severe amnesia within 6 months of the symptoms defined in IC1
d. Cerebellar ataxia
e. Choreoathetosis
f. Early symptomatic autonomic dysfunction or
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 space-occupying 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 wks 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 administration
b. Subjects who take short acting benzodiazepines for sleep may continue to do so if they have been on a stable dose for 30 days 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 days 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 y of the screening visit 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, vitamin 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 investigational drugs 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 FTL) causative genes not associated with underlying tau pathology (e.g., Chromosome 9 associated FTD)
15. History of DB) surgery other than sham surgery for DBS clinical trial
16. History of early, prominent RE) sleep behavior disorder
17. Women who are pregnant or lactating and women of childbearing potential who are not using at least two different forms of medically recognized and highly effective methods of birth control, resulting in a low failure rate when used consistently and correctly such as implants, injectables, combined oral contraceptives, some IUDs, sexual abstinence or vasectomised partner
18. An employee or relative of an employee of the Sponsor, a clinical site, or CRO participating in the study
19. Significant anatomical nasal abnormality or history of nasal turbinate surgery
20. History of a clinically significant medical condition 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
22. Structural abnormality on MRI that precludes diagnosis of PSP, 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 with normal functioning following overnight withdrawal of the anti-Parkinson medication
24. Known hypersensitivity to davunetide or any ingredient of the formulation |
|
| E.5 End points |
| E.5.1 | 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) and 52 weeks (Visit 7).
Blood pressure and heart rate will be obtained at screening (Visit 1) and 0, 6, 13, 26, 39, and 52 weeks (Visits 2 through 7), and clinical laboratory tests will be obtained at screening (Visit 1) and weeks 6, 13, 26, 39, and 52 (Visits 3-7) |
|
| E.5.1.1 | 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 |
|
| E.5.2 | 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) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| France |
| Germany |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Visit 8, Day 372 (+/- 3 days) (Week 53), Telephone Contact |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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