Narcolepsy Type 1
Conditions
Keywords
Drug Therapy
Brief summary
The main aim of this study is to see how TAK-861 works on symptoms of narcolepsy, including excessive daytime sleepiness and cataplexy. Approximately 100 participants will take part in the study across North America, Europe and Asia Pacific. The treatment (TAK-861 or placebo) will be administered for 8 or 12 weeks. After this treatment period the participant will have the option to participate in a separate, long- term extension study during which all participants will be treated with TAK-861.
Detailed description
The drug being tested in this study is called TAK-861. This study will look at the effect of TAK-861 on improvement in narcolepsy symptoms, including excessive daytime sleepiness (EDS) and number of cataplexy episodes. The study will enroll approximately 100 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the five treatment groups which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need): * TAK-861 Dose 1 * TAK-861 Dose 2 * TAK-861 Dose 3 * TAK-861 Dose 4 * Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient This multi-center trial will be conducted worldwide. The overall time to participate in this study is up to 23 weeks. Participants will make multiple visits to the clinic during the treatment period and then will either enroll in a long-term extension study in which all participants will receive TAK-861 or have 2 final visits 7 and 28 days after last dose of study drug for follow-up assessments.
Interventions
DRUGTAK-861
TAK-861 oral tablets
DRUGPlacebo
Placebo oral tablets matching TAK-861
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
16 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. The participant is aged 18 to 70 years, inclusive, at the time of signing the informed consent form (ICF). Note: In Japan, participants aged 16 to 70 years, inclusive, may be included. 2. The participant has body mass index (BMI) within the range 18 to 40 kilogram per square meter \[kg/m\^2\] (inclusive). 3. The participant has an International Classification of Sleep Disorders, 3rd Edition (ICSD-3) diagnosis of narcolepsy type 1 (NT1) by polysomnography (PSG)/Multiple Sleep Latency Test (MSLT), performed within the past 10 years. 4. The participant is positive for the human leukocyte antigen (HLA) genotype HLA-DQB1\*06:02 or results from cerebrospinal fluid (CSF) testing indicate the participant's CSF orexin (OX)/hypocretin-1 concentration is \<110 picograms per milliliter (\[pg/mL\] (or less than one-third of the mean values obtained in normal participants within the same standardized assay).
Exclusion criteria
1. The participant has a current medical disorder, other than narcolepsy with cataplexy, associated with EDS. 2. The participant has medically significant hepatic or thyroid disease. 3. The participant has a history of cancer in the past 5 years (does not apply to participants with carcinoma in situ that has been resolved without further treatment or basal cell cancer). 4. The participant has clinically significant coronary artery disease, a history of myocardial infarction, clinically significant angina, clinically significant cardiac rhythm abnormality, or heart failure. 5. The participant has a clinically significant history of head injury or head trauma. 6. The participant has history of epilepsy, seizure, or convulsion, or has a family history of inherited disorders associated with seizure (except for a single febrile seizure in childhood). 7. The participant has one or more of the following psychiatric disorders: 1. Any current unstable psychiatric disorder. 2. Current or history of manic or hypomanic episode, schizophrenia or any other psychotic disorder, including schizoaffective disorder, major depression with psychotic features, bipolar depression with psychotic features, obsessive compulsive disorder, intellectual disability, organic mental disorders, or mental disorders due to a general medical condition as defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). 3. Current diagnosis or history of substance use disorder as defined in the DSM-5. 4. Current active major depressive episode (MDE) or who have had an active MDE in the past 6 months. 8. The participant has a history of cerebral ischemia, transient ischemic attack (\<5 years ago), intracranial aneurysm, or arteriovenous malformation. 9. The participant has a positive test result for hepatitis B surface antigen, hepatitis C virus antibody, or human immunodeficiency virus (HIV) antibody/antigen. 10. The participant's renal creatinine clearance (Cockcroft-Gault Equation) is ≤50 mL/minute. 11. The participant has alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values \>1.5 times the upper limit of normal (ULN). 12. The participant is considered by the investigator to be at imminent risk of suicide or injury to self, others, or property, or the participant has attempted suicide within the past year.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Average Sleep Latency as Determined From the MWT at Week 8 | Baseline, Week 8 | The MWT is a validated, objective measure that evaluates a participant's ability to remain awake under soporific conditions for a defined period. During each MWT session (1 session = 40 minutes), participants were instructed to sit quietly and remain awake for as long as possible. Sleep latency in each session was recorded on EEG. If no sleep was observed according to these rules, then the latency was defined as 40 minutes. The linear mixed effects model for repeated measures (MMRM) was used for analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Epworth Sleepiness Scale (ESS) Total Score at Week 8 | Baseline, Week 8 | The ESS is a subjective, self-administered, validated scale (scored 0 to 3) to respond to each of the 8 questions of daily life that asks participants how likely they are to fall asleep in those situations. The scores are summed to give an overall score of 0 to 24. Higher scores indicate stronger subjective daytime sleepiness, and scores below 10 are considered to be within the normal range. The MMRM was used for analysis. |
| Weekly Cataplexy Rate (WCR) at Week 8 | Week 8 | Participants completed a daily patient-reported sleep diary to record self-reported narcolepsy symptoms. Participants recorded episodes of cataplexy attacks in the diary. The total number of events averaged for a week were reported. WCR = (total number of cataplexy attacks over a number of non-missing diary days for a given duration/number of non-missing diary days in that duration)\*7. The generalized estimating equations (GEE) model was used for analysis. |
| Number of Participants With at Least One Treatment-emergent Adverse Event (TEAE) | From first dose of the study drug up to end of the study (up to 3 months) | An adverse event (AE) was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of the study intervention, whether or not the occurrence was considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE was defined as an AE with an onset that occurred after receiving study drug. |
Countries
Australia, Finland, France, Germany, Italy, Japan, Netherlands, Norway, Spain, Sweden, Switzerland, United States
Participant flow
Recruitment details
Participants took part in the study at 33 investigative sites globally from 09 January 2023 to 14 December 2023.
Pre-assignment details
Participants with a diagnosis of narcolepsy type 1 (NT1) were enrolled in the study to receive either TAK-861 or placebo.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo tablets matching TAK-861, orally, BID, from Days 1 to 56. | 22 |
| TAK-861 0.5 mg BID Participants received TAK-861 0.5 mg, orally, BID, from Days 1 to 56. | 23 |
| TAK-861 2 mg BID Participants received TAK-861 2 mg, orally, BID, from Days 1 to 56. | 21 |
| TAK-861 2 mg and 5 mg Participants received TAK-861 2 mg followed by the 5 mg dose, orally, from Days 1 to 56. | 23 |
| TAK-861 7 mg QD Participants received TAK-861 7 mg, orally, QD, from Days 1 to 56. Placebo was given as the second dose. | 23 |
| Total | 112 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Protocol Deviation | 1 | 1 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | TAK-861 2 mg BID | TAK-861 2 mg and 5 mg | TAK-861 7 mg QD | Total | Placebo | TAK-861 0.5 mg BID |
|---|---|---|---|---|---|---|
| Age, Continuous | 31.7 years STANDARD_DEVIATION 11.31 | 34.7 years STANDARD_DEVIATION 11.48 | 33.3 years STANDARD_DEVIATION 11.94 | 34 years STANDARD_DEVIATION 11.5 | 37.5 years STANDARD_DEVIATION 11.86 | 32.7 years STANDARD_DEVIATION 11.06 |
| Average Sleep Latency From the Maintenance of Wakefulness Test (MWT) | 3.9 minutes STANDARD_DEVIATION 5.98 | 4.2 minutes STANDARD_DEVIATION 3.63 | 3.6 minutes STANDARD_DEVIATION 4.87 | 4.7 minutes STANDARD_DEVIATION 6.48 | 6.1 minutes STANDARD_DEVIATION 8.82 | 5.6 minutes STANDARD_DEVIATION 7.89 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 2 Participants | 8 Participants | 3 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 23 Participants | 20 Participants | 103 Participants | 19 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 3 Participants | 2 Participants | 8 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 1 Participants | 6 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 19 Participants | 19 Participants | 20 Participants | 96 Participants | 19 Participants | 19 Participants |
| Sex: Female, Male Female | 9 Participants | 14 Participants | 10 Participants | 58 Participants | 14 Participants | 11 Participants |
| Sex: Female, Male Male | 12 Participants | 9 Participants | 13 Participants | 54 Participants | 8 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 23 | 0 / 21 | 0 / 23 | 0 / 23 |
| other Total, other adverse events | 5 / 22 | 11 / 23 | 15 / 21 | 20 / 23 | 20 / 23 |
| serious Total, serious adverse events | 0 / 22 | 0 / 23 | 0 / 21 | 1 / 23 | 0 / 23 |
Outcome results
Primary
Change From Baseline in the Average Sleep Latency as Determined From the MWT at Week 8
The MWT is a validated, objective measure that evaluates a participant's ability to remain awake under soporific conditions for a defined period. During each MWT session (1 session = 40 minutes), participants were instructed to sit quietly and remain awake for as long as possible. Sleep latency in each session was recorded on EEG. If no sleep was observed according to these rules, then the latency was defined as 40 minutes. The linear mixed effects model for repeated measures (MMRM) was used for analysis.
Time frame: Baseline, Week 8
Population: Full Analysis Set included all participants who were randomized and received at least one dose of study drug and had at least one post-dose efficacy measurement. Overall number of participants analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Average Sleep Latency as Determined From the MWT at Week 8 | -1.16 minutes | Standard Error 2.061 |
| TAK-861 0.5 mg BID | Change From Baseline in the Average Sleep Latency as Determined From the MWT at Week 8 | 12.49 minutes | Standard Error 2.128 |
| TAK-861 2 mg BID | Change From Baseline in the Average Sleep Latency as Determined From the MWT at Week 8 | 23.50 minutes | Standard Error 2.042 |
| TAK-861 2 mg and 5 mg | Change From Baseline in the Average Sleep Latency as Determined From the MWT at Week 8 | 25.42 minutes | Standard Error 2.071 |
| TAK-861 7 mg QD | Change From Baseline in the Average Sleep Latency as Determined From the MWT at Week 8 | 14.96 minutes | Standard Error 1.953 |
p-value: =0.00195% CI: [7.74, 19.57]MMRM
p-value: <0.00195% CI: [18.87, 30.46]MMRM
p-value: <0.00195% CI: [20.81, 32.35]MMRM
p-value: <0.00195% CI: [10.49, 21.76]MMRM
Secondary
Change From Baseline in Epworth Sleepiness Scale (ESS) Total Score at Week 8
The ESS is a subjective, self-administered, validated scale (scored 0 to 3) to respond to each of the 8 questions of daily life that asks participants how likely they are to fall asleep in those situations. The scores are summed to give an overall score of 0 to 24. Higher scores indicate stronger subjective daytime sleepiness, and scores below 10 are considered to be within the normal range. The MMRM was used for analysis.
Time frame: Baseline, Week 8
Population: Full Analysis Set included all participants who were randomized and received at least one dose of study drug and had at least one post-dose efficacy measurement. Overall number of participants analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Epworth Sleepiness Scale (ESS) Total Score at Week 8 | -2.50 score on a scale | Standard Error 1.109 |
| TAK-861 0.5 mg BID | Change From Baseline in Epworth Sleepiness Scale (ESS) Total Score at Week 8 | -8.92 score on a scale | Standard Error 1.085 |
| TAK-861 2 mg BID | Change From Baseline in Epworth Sleepiness Scale (ESS) Total Score at Week 8 | -13.79 score on a scale | Standard Error 1.115 |
| TAK-861 2 mg and 5 mg | Change From Baseline in Epworth Sleepiness Scale (ESS) Total Score at Week 8 | -12.81 score on a scale | Standard Error 1.073 |
| TAK-861 7 mg QD | Change From Baseline in Epworth Sleepiness Scale (ESS) Total Score at Week 8 | -11.29 score on a scale | Standard Error 1.064 |
p-value: =0.00495% CI: [-9.53, -3.32]MMRM
p-value: <0.00195% CI: [-14.44, -8.16]MMRM
p-value: <0.00195% CI: [-13.35, -7.27]MMRM
p-value: <0.00195% CI: [-11.84, -5.75]MMRM
Secondary
Number of Participants With at Least One Treatment-emergent Adverse Event (TEAE)
An adverse event (AE) was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of the study intervention, whether or not the occurrence was considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE was defined as an AE with an onset that occurred after receiving study drug.
Time frame: From first dose of the study drug up to end of the study (up to 3 months)
Population: Safety Analysis Set included all participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With at Least One Treatment-emergent Adverse Event (TEAE) | 7 Participants |
| TAK-861 0.5 mg BID | Number of Participants With at Least One Treatment-emergent Adverse Event (TEAE) | 13 Participants |
| TAK-861 2 mg BID | Number of Participants With at Least One Treatment-emergent Adverse Event (TEAE) | 15 Participants |
| TAK-861 2 mg and 5 mg | Number of Participants With at Least One Treatment-emergent Adverse Event (TEAE) | 21 Participants |
| TAK-861 7 mg QD | Number of Participants With at Least One Treatment-emergent Adverse Event (TEAE) | 21 Participants |
Secondary
Weekly Cataplexy Rate (WCR) at Week 8
Participants completed a daily patient-reported sleep diary to record self-reported narcolepsy symptoms. Participants recorded episodes of cataplexy attacks in the diary. The total number of events averaged for a week were reported. WCR = (total number of cataplexy attacks over a number of non-missing diary days for a given duration/number of non-missing diary days in that duration)\*7. The generalized estimating equations (GEE) model was used for analysis.
Time frame: Week 8
Population: Full Analysis Set included all participants who were randomized and received at least one dose of study drug and had at least one post-dose efficacy measurement. Overall number of participants analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Weekly Cataplexy Rate (WCR) at Week 8 | 8.76 cataplexy attacks per week |
| TAK-861 0.5 mg BID | Weekly Cataplexy Rate (WCR) at Week 8 | 4.24 cataplexy attacks per week |
| TAK-861 2 mg BID | Weekly Cataplexy Rate (WCR) at Week 8 | 3.14 cataplexy attacks per week |
| TAK-861 2 mg and 5 mg | Weekly Cataplexy Rate (WCR) at Week 8 | 2.48 cataplexy attacks per week |
| TAK-861 7 mg QD | Weekly Cataplexy Rate (WCR) at Week 8 | 5.89 cataplexy attacks per week |
Comparison: The GEE model was used for analysis with fixed effects for visit, treatment, treatment-by-visit interaction, Baseline WCR, age, and prior use of narcolepsy medications.p-value: =0.2595% CI: [0.25, 0.93]GEE
Comparison: The GEE model was used for analysis with fixed effects for visit, treatment, treatment-by-visit interaction, Baseline WCR, age, and prior use of narcolepsy medications.p-value: =0.03495% CI: [0.16, 0.79]GEE
Comparison: The GEE model was used for analysis with fixed effects for visit, treatment, treatment-by-visit interaction, Baseline WCR, age, and prior use of narcolepsy medications.p-value: =0.00395% CI: [0.13, 0.6]GEE
Comparison: The GEE model was used for analysis with fixed effects for visit, treatment, treatment-by-visit interaction, Baseline WCR, age, and prior use of narcolepsy medications.p-value: =0.2595% CI: [0.35, 1.29]GEE