Trial Review

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT04244175




Registration number
NCT04244175
Ethics application status
Date submitted
24/01/2020
Date registered
28/01/2020
Date last updated
30/05/2025

Titles & IDs
Public title
A Trial of the Efficacy and Safety of CVL-865 as Adjunctive Therapy in the Treatment of Focal Onset Seizures
Scientific title
A Randomized, Double-blind, Placebo-controlled, Parallel Group, Multicenter Trial of CVL-865 as Adjunctive Therapy in Adults With Drug-Resistant Focal Onset Seizures (REALIZE Trial)
Secondary ID [1] 0 0
2019-002576-14
Secondary ID [2] 0 0
CVL-865-SZ-001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Seizures 0 0
Condition category
Condition code
Neurological 0 0 0 0
Epilepsy
Neurological 0 0 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Placebo
Treatment: Drugs - CVL-865

Placebo comparator: Placebo - Participants received a placebo matched to CVL-865 tablets orally twice a day (BID) during the 2-week Titration Phase, the 8-week Maintenance Phase, and the 3-week Taper Phase.

Experimental: CVL-865 7.5 mg BID - CVL-865 tablets were administered orally as 2.5 mg twice a day (BID) for 1 week followed by 5 mg BID for another week during the Titration Phase, and then 7.5 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.

Experimental: CVL-865 25 mg BID - CVL-865 tablets were administered orally as 5 mg twice a day (BID) for 1 week followed by 12.5 mg for another week during the Titration Phase, and then 25 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.


Treatment: Drugs: Placebo
Participants received CVL-865 matched placebo tablets orally twice a day (BID) during the Treatment Period.

Treatment: Drugs: CVL-865
Participants received CVL-865 tablets orally twice a day (BID) up to the maximum dose of 7.5 mg BID or 25 mg BID during the Treatment Period.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Response Ratio (RRatio)
Assessment method [1] 0 0
Response Ratio (RRatio) is calculated as RRatio=(T-B)/(T+B) ×100, where T represents the focal onset seizure frequency rate per week in the Maintenance Phase and B represents the focal onset seizure frequency rate per week in the Baseline Period. The Response Ratio ranges between -100 and 100; negative values indicate reduction in seizure rate and positive values indicate increase in seizure rate during treatment.
Timepoint [1] 0 0
Baseline Period; Maintenance Phase Days 15 through 71
Secondary outcome [1] 0 0
Percentage Change From Baseline in Focal Onset Seizure Frequency Per Week Over the Maintenance Phase
Assessment method [1] 0 0
Seizure frequency is defined as the total number of focal onset seizures over the treatment period of interest divided by the total number of days with no missing seizure counts in the corresponding period multiplied by 7.
Timepoint [1] 0 0
Baseline Period; Maintenance Phase Days 15 through 71
Secondary outcome [2] 0 0
Percentage of Participants With 50 Percent (%) Responder Rate
Assessment method [2] 0 0
The 50% responder rate is defined as the percentage of participants with at least a 50% reduction in focal onset seizure frequency rate in the Maintenance Phase compared to the Baseline Period.
Timepoint [2] 0 0
Baseline Period; Maintenance Phase Days 15 through 71
Secondary outcome [3] 0 0
Percentage of Seizure-free Participants During the Maintenance Phase
Assessment method [3] 0 0
Seizure freedom is defined as no seizures during the Maintenance Phase.
Timepoint [3] 0 0
Maintenance Phase Days 15 through 71
Secondary outcome [4] 0 0
Weekly Seizure Rate During the Maintenance Phase
Assessment method [4] 0 0
Seizure frequency is defined as the total number of focal onset seizures over the treatment period of interest divided by the total number of days with no missing seizure counts in the corresponding period multiplied by 7.
Timepoint [4] 0 0
Maintenance Phase Weeks 1, 2, 3, 4, 5, 6, 7, 8
Secondary outcome [5] 0 0
Patient's Global Impression of Change (PGI-C) Score at Maintenance Phase Days 15, 43, and 71
Assessment method [5] 0 0
The self-report measure Patient's Global Impression of Change (PGI-C) reflects a participant's belief about the efficacy of treatment. It is a 7-point scale depicting a participant's rating of overall improvement where 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse and 7 = very much worse. Lower scores indicate improvement.
Timepoint [5] 0 0
Maintenance Phase Days 15, 43, and 71
Secondary outcome [6] 0 0
Change From Baseline in Clinical Global Impression-Severity of Symptoms Scale (CGI-S) Score at Maintenance Phase Days 15, 43, and 71
Assessment method [6] 0 0
The CGI-S is an observer-rated scale that was used to measure symptom severity. It is a 7-point scale depicting a participants rating of overall improvement. Participants rate their change as 0 = not assessed; 1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants. Negative changes from Baseline indicate improvement.
Timepoint [6] 0 0
Baseline, Maintenance Phase Days 15, 43, and 71
Secondary outcome [7] 0 0
Clinical Global Impression-Improvement Scale (CGI-I) Score at Maintenance Phase Days 15, 43, and 71
Assessment method [7] 0 0
The CGI-I is an observer-rated scale that was used to measure the participant's symptom severity compared with before initiation of treatment with the investigational medicinal product (IMP). It is a 7-point scale depicting a participant's change from Baseline in symptom severity using the following response choices: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. Lower scores indicate improvement.
Timepoint [7] 0 0
Baseline, Maintenance Phase Days 15, 43, and 71
Secondary outcome [8] 0 0
Change From Baseline in Quality of Life in Epilepsy-31 (QOLIE-31) Overall Score at Maintenance Phase Day 71
Assessment method [8] 0 0
The Quality of Life in Epilepsy-31 (QOLIE-31) contains 7 multi-item scales that cover the following health concepts: emotional well-being, social functioning, energy/fatigue, cognitive functioning, seizure worry, medication effects, and overall quality of life. A QOLIE-31 overall score is obtained using a weighted average of the multi-item scale scores. The QOLIE-31 also includes a single item that assessed overall health. The QOLIE-31 score range is from 0 to 100 with a higher score indicating a better outcome for quality of life. Positive changes from Baseline indicate improvement.
Timepoint [8] 0 0
Baseline, Maintenance Phase Day 71
Secondary outcome [9] 0 0
Change From Baseline in Health Utilities Index (HUI) Utility Score at Maintenance Phase Day 71
Assessment method [9] 0 0
The Health Utilities Index (HUI) is a rating scale used to measure general health status and health-related quality of life. In HUI, utility values range from -0.03 and -0.36 for the HUI-2 and HUI-3, respectively, to 1.00. A health utility value of 1.00 indicates perfect health while a score of 0.00 indicates death. Negative changes from Baseline indicate improvement.
Timepoint [9] 0 0
Baseline, Maintenance Phase Day 71
Secondary outcome [10] 0 0
Number of Participants With Treatment Emergent Adverse Event (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
Assessment method [10] 0 0
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. The investigator assesses the relationship of each event to the use of study drug. A serious adverse event (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent adverse events/treatment-emergent serious adverse events (TEAEs/TESAEs) are defined as any event that began or worsened in severity on or after the first dose of study drug.
Timepoint [10] 0 0
From first dose of study drug until 30 days following last dose of study drug (up to Day 120)
Secondary outcome [11] 0 0
Number of Participants With Clinically Significant Changes in Electrocardiogram (ECGs)
Assessment method [11] 0 0
12-lead electrocardiogram (ECG) recordings were obtained after the participant had been supine and at rest for at least 5 minutes.
Timepoint [11] 0 0
Baseline; From first dose of study drug until 30 days following last dose of study drug (up to Day 120)
Secondary outcome [12] 0 0
Number of Participants With Clinically Significant Changes in Vital Sign Measurements
Assessment method [12] 0 0
Vital signs were measured with the participant in a sitting/semi-recumbent position after 5 minutes rest and included temperature, systolic and diastolic blood pressure, respiratory rate, and heart rate.
Timepoint [12] 0 0
From first dose of study drug until 30 days following last dose of study drug (up to Day 120)
Secondary outcome [13] 0 0
Number of Participants With Clinically Significant Changes in Physical and Neurological Examination Results
Assessment method [13] 0 0
The number of participants with clinically significant changes in physical and neurological examination results was documented.
Timepoint [13] 0 0
Baseline; From first dose of study drug until 30 days following last dose of study drug (up to Day 120)
Secondary outcome [14] 0 0
Number of Participants With Positive Response to Columbia Suicide-Severity Rating Scale (C-SSRS)
Assessment method [14] 0 0
The C-SSRS rates an individual's degree of suicidal ideation (SI) on a scale, ranging from "wish to be dead" to "active suicidal ideation with specific plan and intent." The scale identifies SI severity and intensity, which may be indicative of an individual's intent to commit suicide. C-SSRS SI severity subscale ranges from 0 (no SI) to 5 (active SI with plan and intent).
Timepoint [14] 0 0
From first dose of study drug until 30 days following last dose of study drug (up to Day 120)
Secondary outcome [15] 0 0
Change in Modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B) From Last On-treatment Assessment
Assessment method [15] 0 0
The modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B) is a sensitive instrument to measure withdrawal under conditions where there is a taper of medication (rather than abrupt discontinuation). It consists of 17-items that monitor the type and severity of BZD withdrawal symptoms such as irritability, fatigue, appetite, and sleeplessness. The total score ranges from 1 to 68 with higher scores indicating more severe withdrawal. Baseline is defined as the last on-treatment assessment on Day 71. Negative changes from Baseline indicate a reduction in withdrawal symptoms.
Timepoint [15] 0 0
Maintenance Phase Day 71, Taper Phase Days 78, 85, and 92, and Safety Follow-up Days 99 and 120
Secondary outcome [16] 0 0
Number of Participants With Adverse Events That Are Abuse-related or Involve Medication Handling Irregularities (MHI)
Assessment method [16] 0 0
Adverse events potentially related to abuse or dependence of the investigational medicinal product (IMP) were documented.
Timepoint [16] 0 0
From first dose of study drug until 30 days following last dose of study drug (up to Day 120)
Secondary outcome [17] 0 0
Plasma Concentrations of CVL-865 on Maintenance Phase Days 15, 43, and 71, and Taper Phase Day 92
Assessment method [17] 0 0
Plasma concentration of CVL-865 was measured on Maintenance Phase Days 15, 43, and 71, and Taper Phase Day 92.
Timepoint [17] 0 0
Maintenance Phase Days 15, 43, and 71, and Taper Phase Day 92

Eligibility
Key inclusion criteria
* Participants with a diagnosis of epilepsy with focal onset, as defined in the International League Against Epilepsy (ILAE) Classification of Seizures, focal aware (except participants with only focal aware seizures without a motor component), focal impaired awareness, and focal to bilateral tonic-clonic seizures for at least 2 years prior to signing the Informed Consent Form (ICF)
* Participants must have history of an average of 4 or more spontaneous and observable focal onset, as defined in the ILAE Classification of Seizures, focal aware (except participants with only focal aware seizures without a motor component), focal impaired awareness, and focal to bilateral tonic-clonic seizures per 28-day period for at least 3 months (84 days) prior to signing the ICF
* Participants who have tried and failed at least 2 appropriate Anti- epileptic drugs (AEDs) in the past and also currently taking 1 to 3 permitted AEDs at a stable dose for 4 Weeks prior to the Screening Visit
* Participants with a minimum of 8 focal onset, focal aware, focal impaired awareness, or focal to bilateral tonic-clonic seizures during the 8 week baseline period with no 21-day period free of any of these seizure types
* Participants must have had magnetic resonance imaging or contrast enhance computed tomography scan of the brain that demonstrated no progressive structural central nervous system abnormality at the time of the diagnosis of epilepsy
* Participants must have a body mass index (BMI) of 17.5 to 40.0 kilogram per meter square (kg/m^2) and a total body weight greater than (>) 50 kilograms (kg) [110 pounds (lbs)]
* Women of childbearing potential must agree to use an effective method of contraception from signing of informed consent throughout the duration of the study and for 30 days post last dose
* Male must agree to use condom during treatment and until the end of relevant systemic exposure in the male participant for 94 days following the last dose with Investigational Manufacturing Product (IMP)
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Participants with (genetic) idiopathic generalized epilepsies or combined generalized and focal epilepsies, including a history of Lennox-Gastaut Syndrome
* Participants with a history of seizures over the past 12 months that occur at such a high frequency they cannot be counted (eg, repetitive seizures, cluster seizures)
* Participants with a history of psychogenic non-epileptic seizures within the year prior to signing the ICF
* Participants with a history of status epilepticus within 5 years prior to signing the ICF
* Participants with a history of neurosurgery for seizures less than 1 year prior to signing the ICF, or radiosurgery less than 2 years prior to signing the ICF
* Participants with a current history of significant cardiovascular, pulmonary, gastrointestinal, renal, hepatic, metabolic, hematological, immunological, or neurological (excluding focal onset epilepsy) disease
* Participants who test positive for human immunodeficiency virus (HIV), hepatitis B and/or or hepatitis C infection
* Participants with a 12-lead ECG demonstrating : QT interval corrected for heart rate using Fridericia's formula >450 milliseconds (msec) (average of 3 ECGs obtained at the Screening Visit); QRS interval >120 msec at the Screening Visit assessed by central reader
* Participants with abnormal laboratory test results which includes (Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) elevated to >2 × Upper limit of normal range (ULN); Total bilirubin greater than or equal to (>=)1.5 × ULN; Females: Hemoglobin <11 gram per deciliter (g/dL); Males: hemoglobin <12 g/dL; White blood cell (WBC) count <3.0 x 10 power 9 per liter (10^9/L); Neutrophil count <2.0 x 10^9/L; Platelet count <150 × 10^9/L
* Use of prohibited medications as listed in the protocol in the absence of appropriate washout phase or the likelihood of requiring treatment during the study period with drugs not permitted by the study protocol
* Participants taking any drug that is a sensitive P-glycoprotein (P-gp) and Breast cancer resistance protein (BCRP) substrate
* Female participants who are breastfeeding and/or who have a positive pregnancy test result prior to receiving IMP
* Participants who are known to be allergic or hypersensitive to the IMP or any of its components
* Participants who have participated in any clinical trial within 60 days prior to signing the ICF or who have participated in more than 2 clinical trials within the year prior to signing the ICF
* Participants with difficulty swallowing
* Participants who answer "Yes" on the C-SSRS Suicidal Ideation Item 4 (Active Suicidal Ideation with Some Intent to Act, Without Specific Plan) and whose most recent episode meeting criteria for this C-SSRS Item 4 occurred within the last 6 months, OR Subjects who answer "Yes" on the C-SSRS Suicidal Ideation Item 5 (Active Suicidal Ideation with Specific Plan and Intent) and whose most recent episode meeting criteria for this CSSRS Item 5 occurred within the last 6 months OR Subjects who answer "Yes" on any of the 5 C-SSRS Suicidal Behavior Items (actual attempt, interrupted attempt, aborted attempt, preparatory acts, or behavior) and whose most recent episode meeting criteria for any of these 5 C-SSRS Suicidal Behavior Items occurred in the last 2 years

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
27/01/2020
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
21/05/2024
Sample size
Target
Accrual to date
Final
154
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC
Recruitment hospital [1] 0 0
Camperdown, New South Wales - Camperdown
Recruitment hospital [2] 0 0
Randwick, New South Wales - Randwick
Recruitment hospital [3] 0 0
Westmead, New South Wales - Westmead
Recruitment hospital [4] 0 0
Herston, Queensland - Herston
Recruitment hospital [5] 0 0
South Brisbane, Queensland - South Brisbane
Recruitment hospital [6] 0 0
Fitzroy, Victoria - Fitzroy
Recruitment hospital [7] 0 0
Heidelberg, Victoria - Heidelberg
Recruitment hospital [8] 0 0
Melbourne, Victoria - Melbourne
Recruitment hospital [9] 0 0
Parkville, Victoria - Parkville
Recruitment postcode(s) [1] 0 0
2050 - Camperdown
Recruitment postcode(s) [2] 0 0
2031 - Randwick
Recruitment postcode(s) [3] 0 0
2145 - Westmead
Recruitment postcode(s) [4] 0 0
4029 - Herston
Recruitment postcode(s) [5] 0 0
4101 - South Brisbane
Recruitment postcode(s) [6] 0 0
3065 - Fitzroy
Recruitment postcode(s) [7] 0 0
3084 - Heidelberg
Recruitment postcode(s) [8] 0 0
3004 - Melbourne
Recruitment postcode(s) [9] 0 0
3050 - Parkville
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arkansas
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Connecticut
Country [4] 0 0
United States of America
State/province [4] 0 0
Florida
Country [5] 0 0
United States of America
State/province [5] 0 0
Georgia
Country [6] 0 0
United States of America
State/province [6] 0 0
Hawaii
Country [7] 0 0
United States of America
State/province [7] 0 0
Kentucky
Country [8] 0 0
United States of America
State/province [8] 0 0
Maine
Country [9] 0 0
United States of America
State/province [9] 0 0
Maryland
Country [10] 0 0
United States of America
State/province [10] 0 0
Massachusetts
Country [11] 0 0
United States of America
State/province [11] 0 0
Missouri
Country [12] 0 0
United States of America
State/province [12] 0 0
New Jersey
Country [13] 0 0
United States of America
State/province [13] 0 0
New York
Country [14] 0 0
United States of America
State/province [14] 0 0
Ohio
Country [15] 0 0
United States of America
State/province [15] 0 0
Oklahoma
Country [16] 0 0
United States of America
State/province [16] 0 0
Pennsylvania
Country [17] 0 0
United States of America
State/province [17] 0 0
South Carolina
Country [18] 0 0
United States of America
State/province [18] 0 0
Tennessee
Country [19] 0 0
United States of America
State/province [19] 0 0
Utah
Country [20] 0 0
Korea, Republic of
State/province [20] 0 0
Seoul
Country [21] 0 0
Poland
State/province [21] 0 0
Kujawsko-Pomorskie
Country [22] 0 0
Poland
State/province [22] 0 0
Lodz
Country [23] 0 0
Poland
State/province [23] 0 0
Malopolskie
Country [24] 0 0
Poland
State/province [24] 0 0
Mazowieckie
Country [25] 0 0
Poland
State/province [25] 0 0
Pomorskie
Country [26] 0 0
Poland
State/province [26] 0 0
Wojnicz Lskie
Country [27] 0 0
Poland
State/province [27] 0 0
Bialystok
Country [28] 0 0
Poland
State/province [28] 0 0
Lublin
Country [29] 0 0
Poland
State/province [29] 0 0
Warszawa
Country [30] 0 0
Serbia
State/province [30] 0 0
Sumadija
Country [31] 0 0
Serbia
State/province [31] 0 0
Belgrade
Country [32] 0 0
Serbia
State/province [32] 0 0
Niš
Country [33] 0 0
Spain
State/province [33] 0 0
Andalusia
Country [34] 0 0
Spain
State/province [34] 0 0
Catalonia
Country [35] 0 0
Spain
State/province [35] 0 0
Navarra
Country [36] 0 0
Spain
State/province [36] 0 0
Barcelona
Country [37] 0 0
Spain
State/province [37] 0 0
Madrid
Country [38] 0 0
Spain
State/province [38] 0 0
Sevilla
Country [39] 0 0
Spain
State/province [39] 0 0
Valencia
Country [40] 0 0
Ukraine
State/province [40] 0 0
Uzhgorod
Country [41] 0 0
Ukraine
State/province [41] 0 0
Kyiv
Country [42] 0 0
Ukraine
State/province [42] 0 0
Lviv

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
AbbVie
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
ABBVIE INC.
Address 0 0
AbbVie
Country 0 0
Phone 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement


What supporting documents are/will be available?



Results publications and other study-related documents

No documents have been uploaded by study researchers.

Results are available at https://clinicaltrials.gov/study/NCT04244175