E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Fronto-Temporal Dementia with Progranulin Mutations (FTD-GRN) |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10068968 |
E.1.2 | Term | Frontotemporal dementia |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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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 |
- Evaluate the safety, tolerability and immunogenicity of 3 dose levels of LY3884963 administered via suboccipital injection into the cisterna magna. - Quantify PGRN levels in blood and CSF. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the effect of LY3884963 on:
• Clinical Dementia Rating staging instrument plus National Alzheimer's Coordinating Center frontotemporal lobar degeneration domains (CDR® plus NACC FTLD) • Neurofilament light chain (NfL) levels in blood and CSF |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Men or women aged 30 to 85 years (inclusive), at the time of informed consent. 2. Body weight range of ≥40 kg (88 lb) to ≤110 kg (242 lb) and a body mass index (BMI) of 18 to 34 kg/m2. 3. Has symptomatic FTD, including mild behavioral, cognitive, motor or language impairment per Investigator´s assessment (bvFTD, PPA-FTD, FTD with corticobasal syndrome, or a combination of syndromes are allowed for enrollment). 4. Score ≥.5 and ≤15 on CDR plus NACC FTLD sum of boxes. 5. Stable use of background medications at least 8 weeks prior to LY3884963 dosing. 6. Carrier of a pathogenic progranulin gene (GRN) mutation confirmed by the central laboratory. *All null mutations including nonsense, frameshift, splice site mutations, and complete or partial gene deletions: a.All previously published pathogenic mutations, with proven functional deleterious effect (selected missense mutations may be included provided they are known to be pathogenic), including any pathogenetic mutation published in 1 of the following GRN mutations databases: National Institutes of Health ClinVar database, Leiden Open Variation Database, and University of Antwerp Alzheimer Disease/Frontotemporal Dementia Mutation database. b.All new mutations with low plasma PGRN level (<70 ng/mL) based on central laboratory measurement. 7. Negative screening test for mycobacterium tuberculosis (MTB) or documented negative MTB test within 1 year prior to Screening. Text added. 8. Age- and gender-appropriate cancer screenings are up to date and completed per the Investigator's judgment and local standard of care prior to Screening. 9. Patient and/or patient's legally authorized representative (LAR) (where applicable by local regulation) has the ability to understand the purpose and risks of the study and provide written informed consent and authorization to use protected health information in accordance with national and local privacy regulations. The patient or LAR may also provide consent for future biomedical research in accordance with their national regulations; however, the patient may still participate in the study without providing consent for future biomedical research. 10. Patient has a reliable study partner/informant (e.g., family member or friend) willing and able to participate in the study as a source of information on the patient's health status and cognitive and functional abilities (including providing input into the rating scales). The study partner should have regular contact with the patient (in person or via phone/video communication). The study partner must sign a separate partner informed consent form (ICF) indicating that she/he understands the study requirements and is willing to participate and attend study visits requiring study partner input. 11. Women of nonchildbearing potential must be either surgically sterile (hysterectomy, bilateral tubal ligation, salpingectomy, and/or bilateral oophorectomy at least 26 weeks before Screening) or postmenopausal, defined as spontaneous amenorrhea for at least 2 years, with folliclestimulating hormone level in the postmenopausal range at Screening based on the central laboratory's range. 12. Men and women of childbearing potential (i.e., ovulating, premenopausal, and not surgically sterile) must use a highly effective method of contraception consistently and correctly for the duration of the study including the long-term follow-up. Highly effective methods of contraception are those that, alone or in combination, result in a failure rate of less than 1% per year when used consistently and correctly (i.e., perfect use) and include the following for female patients of childbearing potential: a. Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal hormonal contraception associated with inhibition of ovulation b. Oral, injectable, or implantable progestogen-only hormonal contraception associated with inhibition of ovulation c. Intrauterine device d. Intrauterine hormone-releasing system e. Bilateral tubal ligation or bilateral tubal occlusion (performed at least 3 months prior to Screening) f. Vasectomized partner (performed at least 3 months prior to Screening) g. Sexual abstinence (no sexual intercourse), if in line with the patient's usual and preferred lifestyle Acceptable forms of contraception for male patients include: a. Sexual abstinence (no sexual intercourse), if in line with the patient's usual and preferred lifestyle b. History of vasectomy (performed at least 3 months prior to Screening), with documented absence of sperm in the ejaculate) in combination with condom c. Condom with spermicide used together with highly effective female contraceptive methods if the female partner(s) is of childbearing potential (see above for list of acceptable female contraceptive methods). Text added. Please refer to protocol p.66 for rest of the inclusion criteria changes. |
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E.4 | Principal exclusion criteria |
1. Diagnosis of a significant CNS disease other than FTD that may be a cause for the patient’s FTD symptoms or may confound study objectives. 2. Brain or cervical spine MRI/magnetic resonance angiography (MRA) imaging indicating clinically significant abnormality, including evidence of prior hemorrhage, infarct >1 cm3 or >3 lacunar infarcts, or a structural or vascular abnormality deemed a contraindication to ICM injection. 3. Hypersensitivity or contraindications to corticosteroid, rituximab, and/or sirolimus use (including but not limited to osteoporosis with vertebral fractures within 1 year prior to Screening, poorly controlled diabetes [see Exclusion Criterion 5c], uncontrolled hypertension [see Exclusion Criterion 5f]), and uncontrolled hyperlipidemia or hypercholesterolemia per Investigator's assessment. 4. Clinical evidence of peripheral symmetric sensory polyneuropathy (stable sensory mononeuropathies and radiculopathies are not exclusionary). 5. Concomitant disease or condition within 6 months of Screening that could interfere with, or treatment of which might interfere with, the conduct of the study or that would, in the opinion of the Investigator, pose an unacceptable safety risk to the patient or interfere with the patient's ability to comply with study procedures; including, but not limited to, the following: a. Evidence of clinically significant liver disease b. Unstable autoimmune disease requiring chronic immunosuppression; severely immunocompromised patients c. Poorly controlled/not adequately managed diabetes (Screening hemoglobin A1c [HbA1c] ≥7%) d. History of unstable angina, myocardial infarction, chronic heart failure (New York Heart Association Class III or IV), or clinically significant conduction abnormalities (e.g., unstable atrial fibrillation) within 1 year prior to Screening e. Clinically significant 12-lead electrocardiogram (ECG) abnormalities at Screening, as determined by the Investigator f. Uncontrolled hypertension defined as: average of 3 systolic blood pressure [SBP]/diastolic blood pressure [DBP] readings >165/100 mm Hg at Screening, or persistent SBP/DBP readings >180/100 mm Hg within 3 months prior to Screening that, in the opinion of the Investigator, are indicative of chronic uncontrolled hypertension g. History of cancer, including B-cell cancers within 5 years of Screening or current presence of precancer lesions, with the exception of fully excised nonmelanoma skin cancers and fully excised prostate carcinoma in situ that have been stable for at least 6 months h. History or current alcohol or drug abuse within 2 years of Screening i. Any current psychiatric diagnosis according to the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition, International Statistical Classification of Diseases and Related Health Problems Tenth Revision, or equivalent, that may interfere with the patient’s ability to perform study procedures and all assessments. NOTE: Psychiatric manifestations of FTD are not exclusionary j. At imminent risk of self-harm, based on clinical interview and responses on the C-SSRS. Patient must be excluded if they report ideation with intent, with or without a plan or method (i.e., positive response to items 4 or 5 on the C-SSRS) in the past 2 months or suicidal behavior in the past 6 months k. Any medical disorders that, in the opinion of the Investigator, could interfere with study-related procedures (including safe performance of lumbar puncture (LP) or ICM injection), such as prohibitive spinal diseases, bleeding diathesis, clinically significant coagulopathy, thrombocytopenia, or increased intracranial pressure l. Documented stroke or transient ischemic attack within 1 year prior to Screening m. History of seizure or unexplained blackouts, with the exception of seizure due to known, transient cause (e.g., medication, electrolyte disturbance), within 10 years prior to Screening n. Currently active infection or severe infection (e.g., pneumonia, septicemia, CNS infections [e.g., meningitis, encephalitis]) within 12 weeks prior to Screening o. History of severe allergic or anaphylactic reactions. History of hypersensitivity to any inactive ingredient of LY3884963 (refer to the IB) or protocol required immunosuppressant medications p. Clinical evidence of vitamin B12 deficiency or vitamin B12 level less than the lower limit of normal if deemed clinically significant as per Investigator’s assessment at Screening q. History of neurosyphilis or history of syphilis infection without documentation of adequate treatment. Please refer to Protocol page 69 for full exclusion criteria changes. |
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E.5 End points |
E.5.1 | Primary end point(s) |
- Change from baseline in PGRN levels in blood on Days 7, 14, and 21 and at Months 1, 1.5, 2, 3, 6, 9, and 12. - Change from baseline in PGRN levels in CSF at Months 2, 6 and 12.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Days 7, 14, 21 and Months 1, 1.5, 2, 3, 6, 9, and 12
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E.5.2 | Secondary end point(s) |
- Change from baseline in CDR plus NACC FTLD SB at Months 6 and 12 - Change from baseline in NfL levels in blood on Days 7, 14, and 21 and at Months 1, 1.5, 2, 3, 6, 9, and 12. - Change from baseline in NFL levels in CSF at Months 2, 6 and 12 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Days 7, 14, 21 and Months 1, 1.5, 2, 3, 6, 9, and 12 |
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
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 |
United Kingdom |
United States |
Belgium |
France |
Spain |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
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 |