A Phase 1b, Multicenter, Randomized, Placebo-Controlled, Double-Blind Study, followed by an Open-Label Extension, to Determine the Safety, Pharmacokinetics, and Pharmacodynamics of DNL343 in Participants with Amyotrophic Lateral Sclerosis
- Conditions
- ALSAmyotrophic Lateral Sclerosis10029317
- Registration Number
- NL-OMON56265
- Lead Sponsor
- Denali Therapeutics Inc
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Recruiting
- Sex
- Not specified
- Target Recruitment
- 15
Participants must satisfy all of the following criteria for study entry:
1. Women of non-childbearing potential and men, aged 18 to 80 years, inclusive
2. BMI of 18 to 35 kg/m2
3. Willing and able to give informed consent (via legally authorized
representative is acceptable) for study participation
4. Able to communicate with the investigator and staff
5. Willing and able to comply with the requirements of the study, including
scheduled visits, study restrictions, laboratory tests, and all other study
procedures
6. Women must have been surgically sterilized (hysterectomy, bilateral
oophorectomy, or bilateral tubal ligation; proper documentation required) >= 3
months prior to dosing (Essure*fallopian tube coil placement is not accepted as
surgical sterilization because of the high failure rate), or be postmenopausal
(amenorrheic for >= 12 consecutive months before dosing, with a
follicle-stimulating hormone [FSH] level of > 40 IU/L at screening).
7. For men: When engaging in sex with a woman of childbearing potential
(WOCBP), both the male participant and his female partner must use highly
effective contraception consisting of two forms of birth control, one of which
must be a male barrier method such as a latex or polyurethane condom, from the
start of dosing, throughout the study period, and for 90 days after the final
administration of study intervention. See Section 10.6 of the protocol for
contraceptive guidance for female partners.
8. For men: The participant must not donate sperm at any time from the start of
dosing, throughout the study period, and for 90 days after the final
administration of study intervention.
9. Diagnosis of laboratory-supported probable, probable, or definite (sporadic
or familial) ALS according to the El Escorial World Federation of Neurology
revised research diagnostic criteria (Ludolph et al. 2015)
10. Years since symptom onset as follows:
a. <= 3 years (approximately 80% or more of the study population)
b. > 3 to <= 4 years (limited to approximately <= 20% of the study population)
11. SVC > 50% predicted, measured within 28 days of screening (forced vital
capacity at screening also acceptable)
12. If participant is taking locally approved ALS treatments, the following
guidelines must be met:
a. If the participant is taking riluzole, doses must be stable for >= 42 days
prior to the first dose of study intervention; participant is expected to stay
on a stable regimen throughout the double-blind period of the study.
Participants who initiated or changed medication doses within 42 days prior to
the planned first dose of study intervention may be rescreened after dose
stabilization.
b. If the participant is taking any other locally approved ALS treatment
besides riluzole (e.g., edaravone), doses must be stable for >= 21 days prior
to the first dose of study intervention; the participant is expected to stay on
a stable regimen throughout the double-blind period of the study. For
edaravone, stable treatment regimen means completion of at least the first 14
days of treatment during the first treatment cycle with intent to continue
treatment cycles during the double-blind period. Participants who initiated or
changed medication doses within 21 days prior to the planned first dose of
study intervention may be rescreened after dose sta
Participants who meet any of the following criteria will be excluded from study
entry:
1. Any history of unstable or poorly controlled psychiatric, endocrine,
pulmonary, cardiovascular, gastrointestinal, hepatic, pancreatic, renal,
metabolic, hematologic, immunologic, or allergic disease, or other major
disorders. Well-controlled conditions are permitted if investigator and Sponsor
agree.
2. Positive serum pregnancy test or currently lactating or breastfeeding
3. History of malignancy within 5 years, except fully resected basal cell
carcinoma or other malignancies at low risk of recurrence, depending on
investigator and Medical Monitor agreement
4. History of clinically significant neurologic disorders other than ALS,
including stroke, significant cognitive impairment, or seizure within 5 years
of the first dose of study intervention, or head trauma with loss of
consciousness, documented by a physician, within 1 year of the first dose of
study intervention
5. History of serious adverse reaction or serious hypersensitivity to two or
more drug classes or clinically significant history of previous allergy or
hypersensitivity to DNL343 or any of the excipients contained within theDNL343
drug product
6. History of clinically significant hypersensitivity to local anesthetics that
may be used for LP (e.g., lidocaine)
7. Have criteria that would preclude an LP, such as a local infection at the
site of the LP, < 100 GI/L(100,000/mm3) platelets or clinically significant
coagulation abnormality or significant active bleeding, or treatment with an
anticoagulant or more than two antiplatelet agents
8. History of clinically significant back pathology and/or back injury (e.g.,
degenerative disease, spinal deformity, or spinal surgery) or severe
respiratory compromise that may predispose to complications or technical
difficulty with LP. Participants with ALS who cannot tolerate lumbar punctures
in the prone or lateral recumbent position due to respiratory difficulties may
undergo the procedure in an upright sitting position if the position resolves
respiratory distress.
9. Current significant psychiatric disorder, suicidal ideation in the previous
6 months as assessed by the Baseline/Screening version of the C-SSRS (a *yes*
response to question 1 or 2 on the Suicidal Ideation section may be acceptable
pending investigator and Sponsor Medical Monitor agreement and Intensity of
Ideation scores are 2 or lower), or a lifetime suicide attempt (a *yes*
response to question 4 or 5 on the Suicidal Ideation section or an Intensity of
Ideation score of 4 or 5) at screening. A lifetime suicide attempt or score of
4 or 5 on the Intensity of Ideation > 5 years may be allowed pending
investigator and Sponsor review.
10. History of alcoholism, drug abuse, or drug addiction in the previous 12
months Note: Participants who test positive for drugs included in the urine
drug screen (see Section 10.2) may be enrolled at the investigator*s discretion.
11. Evidence of hepatic impairment, including alanine aminotransferase (ALT) or
aspartate aminotransferase(AST) > 3 x the upper limit of normal (ULN) or
bilirubin > 1.5×ULN at screening or baseline. Patients with Gilbert*s syndrome
without evidence of hepatic impairment may be enrolled.
12. History of clinically significant renal impairment o
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p> Incidence of treatment-emergent adverse events (TEAEs) throughout the<br /><br>double-blind period</p><br>
- Secondary Outcome Measures
Name Time Method <p>• DNL343 PK parameters, including, but not limited to, maximum concentration<br /><br>(Cmax), time to reach maximum concentration (tmax), trough concentration<br /><br>(Ctrough), and area under the concentration-time curve from time zero to 24<br /><br>hours (AUC0-24)<br /><br>• CSF-to-plasma concentration ratio</p><br>