Safety of Engensis in Participants With Amyotrophic Later... | NCT04632225

NCT04632225

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

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Document Section

Large Document Module

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Miscellaneous Info Module

Status Module

Description Module

Detailed Description

VMALS-002-2 was a controlled study to evaluate the safety of intramuscular administration of Engensis to subjects with Amyotrophic Lateral Sclerosis, as compared to Placebo. Subjects randomly assigned to Engensis were to receive a total dose of 192 mg Engensis divided into 3 treatment cycles of 64 mg Engensis each. A dosing schedule developed from those used in the Phase 1/2 Amyotrophic Lateral Sclerosis study and in three diabetic peripheral neuropathy studies were used in this study. The intramuscular injections to each target muscle group were divided into three Injection Visits (equal halves), two weeks apart on Days 0, and 14, with retreatment at Days 60 and 74, and Days 120 and 134. Engensis was delivered in a solution of 0.5 mg VM202/mL.

Results from this Phase 1/2 study suggest that targeted delivery of hepatic growth factor to motor neurons via intramuscular injections of Engensis was safe and well tolerated, based on data from 18 enrolled subjects who were followed through 90 days after the first injection [Sufit et al., 2017]. Following injections until Day 90, a plateau or a relative slowing in decline of the Amyotrophic Lateral Sclerosis Functional Rating Scale scores and muscle strength was noted, suggesting a slowing of disease progression. After 90 days, the plateau was no longer observed in the Amyotrophic Lateral Sclerosis Functional Rating Scale, with the notable exception of a trend toward better preservation of bulbar and breathing functions as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale subscore, which appeared to persist out to 180 days. The change in Amyotrophic Lateral Sclerosis Functional Rating Scale total score over time or "slope" (>0, indicating clinical stability or improvement) following Engensis treatment was greatest at 2 months in 50% of subjects. At 3 months following Engensis, this improvement was observed in 25% of subjects. Muscle strength was stable for the first 3 months following Engensis administration and then steadily declined in both upper and lower limbs at subsequent months.

Label	Type	Description	Intervention Names
Engensis	Active Comparator	64 mg Engensis per Treatment Cycle, with each of 3 cycles composed of 2 days of 128 injections each to the right and left target muscles, spaced 2 weeks apart	Biological: Engensis
Placebo	Placebo Comparator	32 mL of Placebo per Treatment Cycle, with each of 3 cycles composed of 2 days of 128 injections each to the right and left target muscles, spaced 2 weeks apart	Other: Placebo

Name	Type	Description	Arm Group Labels	Other Names
Engensis	Biological	Lyophilized biologic to be reconstituted containing Engensis	Engensis

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Safety of Intramuscular Injections of Engensis in Participants With Amyotrophic Lateral Sclerosis Compared to Placebo	Incidence of treatment-emergent adverse events in more than or equal to 10% of subjects, and treatment-emergent serious adverse events after injections, injection site reactions, and clinically significant laboratory values for Engensis compared to Placebo.	From the Day 0 Visit to the Day 180 Visit

Other Outcomes

Measure	Description	Time Frame
Changes in Muscle Function Following Engensis Injections Compared to Placebo	Change from Baseline (Day 0) in total mean Revised Amyotrophic Lateral Sclerosis Function Rating scores, subscores for Fine and Gross Motor Functions and Bulbar Function, and slope of the total score. The Revised Amyotrophic Lateral Sclerosis Function Rating scores includes twelve questions that ask the physician to rate his/her impression of the patient's level of functional impairment in performing one of twelve common tasks e.g., climbing stairs). Each task is rated on a five-point scale from 0 = can't do, to 4 = normal ability. Individual item scores are summed to produce a reported score of between 0 = worst and 48 = best. The Revised Amyotrophic Lateral Sclerosis Function Rating scores was conducted at Screening, pre-dose on Days 0, 60, and 120, and on Days 30, 84, 144, and 180.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Clinically definite or probable Amyotrophic Lateral Sclerosis or laboratory-supported probable Amyotrophic Lateral Sclerosis as defined in the revised El Escorial/Airlie House diagnostic criteria
The site of onset of Amyotrophic Lateral Sclerosis symptoms is a limb and experiencing symptoms of lower motor dysfunction (e.g., weakness, atrophy, cramps, poor circulation, etc.) with upper motor neuron symptoms (e.g., weakness, brisk reflexes, spasticity)
Onset of Amyotrophic Lateral Sclerosis symptoms ≤ 4 years
Slow Vital Capacity ≥ 50% of predicted value at Screening
Not taking riluzole, or on a stable dose (defined as no noted toxicities) for at least 30 days prior to Screening and throughout the study
Not taking edaravone or on a maintenance cycle for at least 30 days prior to Screening and throughout the study
For females of childbearing potential, a negative urine pregnancy test at Screening and on Day 0
Male Participants and their female partners must agree to use double-barrier contraception during the study or provide proof of postmenopausal state (minimum 1 year) or surgical sterility
Male Participants must not donate sperm during the study
Female Participants must be nonpregnant, nonlactating, and either postmenopausal for at least 1 year, or surgically sterile for at least 3 months, or agree to use double-barrier contraception from 28 days prior to randomization (Day 0) and/or their last confirmed menstrual period prior to study randomization (whichever is longer) until the end of the study
Capable of complying and willing to comply with the requirements and restrictions in the informed consent form and this protocol
Willing to forgo new experimental Amyotrophic Lateral Sclerosis treatments for at least 6 months following randomization

Exclusion Criteria:

Progressive or degenerative neurological disorder such as Alzheimer's disease, Parkinson's disease, vascular dementia, multiple sclerosis, and other neurological or vascular disorders felt by the Investigator to preclude participation
Requires tracheotomy ventilation or noninvasive ventilation related to bulbar function
Evidence by physical examination, history, or laboratory evaluation of significant concomitant disease with a life expectancy of < 6 months at Screening
International Normalized Ratio values >2.0
Platelet count <100,000/µL
Inflammatory disorder of the blood vessels (inflammatory angiopathy or vasculitis, such as Buerger's disease)
Active infection (chronic infection or severe active infection that may compromise the Participant's wellbeing or participation in the study in the Investigator's judgment)
Chronic inflammatory disease (e.g., Crohn's disease, rheumatoid arthritis)
Positive human immunodeficiency virus or human T-cell lymphotrophic virus I/II test at Screening
Active acute or chronic hepatitis B
Active hepatitis C
Immunosuppression due to underlying disease (e.g., rheumatoid arthritis, systemic lupus erythematosus) or to currently receiving immunosuppressive drugs, (e.g., chemotherapy, corticosteroids) or to radiation therapy
Stroke or myocardial infarction within 3 months prior to Screening
Active deep vein thrombosis
Recent history (< 3 years) or presence of cancer except basal cell carcinoma or squamous cell carcinoma of the skin that was excised and has shown no evidence of recurrence for at least 1 year
Major psychiatric disorder diagnosed in the past 6 months that has not been stabilized or in the Investigator's opinion would not allow the patient to participate in the scheduled procedures
Use of an investigational drug for the treatment of Amyotrophic Lateral Sclerosis in the past 30 days or 5 half-lives (if available), whichever is longer, or previous participation in a clinical study with Engensis
Stem cell administration for investigational treatment of Amyotrophic Lateral Sclerosis or other conditions in the 6 months prior to Screening

Facility	Status	City	State	ZIP	Country	Contacts
St. Joseph's Hospital and Medical Center, Barrows Neurological Institute		Phoenix	Arizona	85013	United States

ID	Title	Description
FG000	Engensis	64 mg Engensis per Treatment Cycle, with each of 3 cycles composed of 2 days of 128 injections each to the right and left target muscles, spaced 2 weeks apart Engensis: Lyophilized biologic to be reconstituted containing Engensis
FG001	Placebo	32 mL of Placebo per Treatment Cycle, with each of 3 cycles composed of 2 days of 128 injections each to the right and left target muscles, spaced 2 weeks apart Placebo: Injectable liquid

ID	Title	Description
BG000	Engensis	64 mg Engensis per Treatment Cycle, with each of 3 cycles composed of 2 days of 128 injections each to the right and left target muscles, spaced 2 weeks apart Engensis: Lyophilized biologic to be reconstituted containing Engensis
BG001	Placebo

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Categorical			Count of Participants

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Safety of Intramuscular Injections of Engensis in Participants With Amyotrophic Lateral Sclerosis Compared to Placebo

Incidence of treatment-emergent adverse events in more than or equal to 10% of subjects, and treatment-emergent serious adverse events after injections, injection site reactions, and clinically significant laboratory values for Engensis compared to Placebo.

Treatment-Emergent Adverse Events in ≥10% of Subjects Overall by System Organ Class and Preferred Term (Safety Analysis Population)

Posted

Count of Participants

Participants

From the Day 0 Visit to the Day 180 Visit

ID	Title	Description
OG000	Engensis	64 mg Engensis per Treatment Cycle, with each of 3 cycles composed of 2 days of 128 injections each to the right and left target muscles, spaced 2 weeks apart Engensis: Lyophilized biologic to be reconstituted containing Engensis

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Engensis	64 mg Engensis per Treatment Cycle, with each of 3 cycles composed of 2 days of 128 injections each to the right and left target muscles, spaced 2 weeks apart Engensis: Lyophilized biologic to be reconstituted containing Engensis

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Jan 20, 2021	Oct 31, 2024	Prot_000.pdf
SAP	No	Yes	No	Statistical Analysis Plan	Aug 5, 2022	Oct 31, 2024	SAP_001.pdf

ID	Term
D013118	Spinal Cord Diseases
D002493	Central Nervous System Diseases
D009422	Nervous System Diseases
D016472	Motor Neuron Disease