Study of TAK-935 as an Adjunctive Therapy in Participants With Developmental and/or Epileptic Encephalopathies

A Phase 1b/2a Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Dose-Escalation Study With an Open-Label Part to Examine the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of TAK-935 as an Adjunctive Therapy in Subjects With Developmental and/or Epileptic Encephalopathies

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03166215

Enrollment

Registered

2017-05-25

Start date

2017-08-17

Completion date

2018-09-19

Last updated

2026-09-14

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Developmental and/or Epileptic Encephalopathies

Keywords

Drug therapy

Brief summary

The purpose of this study is to characterize the multiple-dose safety and tolerability profile of TAK-935 in adult participants with developmental and/or epileptic encephalopathies.

Detailed description

The drug being tested in this study is called TAK-935. TAK-935 is being tested to treat people who have developmental and/or epileptic encephalopathies. This study will look at safety, tolerability and pharmacokinetics of people who take TAK-935. Study drug will be administered in a double-blind manner in Part 1 and in an open-label manner in Part 2. The study will enroll approximately 20 participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups in Part 1-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need): * TAK-935 * Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient Participants will receive placebo or 100 milligram (mg) TAK-935 tablets, orally or through stable G-tube/PEG tube, BID, in Part 1 (Day 1) and dose will be increased to 200 mg (Day 11) BID and to 300 mg (Day 21) BID in dose titration period. All participants who complete the Double-Blind Treatment Period in Part 1 will have the option to continue directly into the Open-Label Treatment Period in Part 2 where they will receive TAK-935 as two 100 mg tablets (total dose is 200 mg TAK-935) orally or through G-tube/PEG tube, BID and dose will be increased to three 100 mg tablets (total dose is 300 mg TAK-935), orally, BID (Day 41). This dose level will be maintained until the final visit (Day 85) for the dose de-escalation phase. This multi-center trial will be conducted in North America. The overall time to participate in this study is 121 days excluding screening period of 30-41 days. Participants will make multiple visits to the clinic, and a follow-up phone call will be conducted on Day 91 and at the end of the 30-day follow-up period (Day 121), participants will return to the clinic for a follow-up assessment.

Interventions

DRUGTAK-935

TAK-935 tablets.

DRUGPlacebo

TAK-935 placebo-matching tablets.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 65 Years

Healthy volunteers

Inclusion criteria

1. Has a documented clinical diagnosis of developmental and/or epileptic encephalopathies with countable bilateral motor seizures, defined as an average of greater than or equal to (\>=) 2 per month during the past 3 months, based on the investigator's assessment, and a monthly average of \>=1 per month during the Baseline Period, based on the seizure diary record. 2. Has been taking 1 to 4 antiepileptic drug (AEDs) at a stable dose for \>=4 weeks before Screening and the participant or participant's legally acceptable representative is willing to keep the regimen(s) stable throughout the study. 3. Has an average of \>=1 bilateral motor seizure per month during the 4-week Baseline Period (that is., drop seizures, tonic-clonic, tonic, bilateral clonic, atonic, myoclonic-atonic, myoclonic-tonic-clonic, focal seizures with bilateral hyperkinetic motor features). 4. Must agree to not post any participant's personal medical data related to the study or information related to the study on any web site or social media site (example, Facebook, Twitter) until the study has been completed. 5. For participants with G-tube/PEG tube, G-tubes/PEG tubes should have been placed and been functioning for at least 3 months prior to screening. Naso-gastric tubes are not allowed.

Exclusion criteria

1. Has received TAK-935 in a previous clinical study or as a therapeutic agent. 2. Was admitted to a medical facility for treatment of status epilepticus requiring mechanical respiration within 3 months before Screening. 3. Had a vagal nerve stimulator implanted within 6 months before Screening and settings have been changed within 1 month of the Screening Visit and/or anticipated to change during the study. 4. Is on ketogenic diet that has been started within 6 months of the Screening Visit, has been changed within 1 month of the Screening Visit, or is anticipated to change during the study. 5. Has degenerative eye disease. 6. Has a history of suicidal behavior or any suicidal ideation of type 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) at Screening. If the participant is unable to comply with the C-SSRS due to developmental status, a parent proxy may be used for the completion of the C-SSRS. The Investigator may also use clinical judgment, which must then be documented in the source document. 7. Positive for human immunodeficiency virus, hepatitis B, or hepatitis C infections. (Note that participants who have been vaccinated against hepatitis B \[hepatitis B surface antibody (Ab)-positive\] who are negative for other markers of prior hepatitis B infection \[example, negative for hepatitis B core Ab\] are eligible. Also note that participants who are positive for hepatitis C Ab are eligible as long as they have a negative hepatitis C viral load by quantitative polymerase chain reaction \[qPCR\]). 8. Has an abnormal and clinically significant ECG at Screening in the opinion of the investigator, for example, second or third degree heart block or a corrected QT interval (QTc) greater than (\>) 450 millisecond (msec). Entry of any participant with an abnormal but not clinically significant ECG must be approved and documented by signature by the principal investigator or appropriately qualified delegate. 9. Has abnormal clinical laboratory test results at Screening that suggest a clinically significant underlying disease. If the participant has alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) \>2.5\*the upper limit of normal (ULN), the Medical Monitor should be consulted. 10. Has received any excluded medications, procedures, or treatments during the time periods. 11. Has any a history of alcohol, opioid, or other drug use disorder, as per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, within the previous 2 years before Screening. Medical marijuana use is allowed. 12. Has unstable, clinically significant neurologic (other than the disease being studied), psychiatric, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, immunologic, hematopoietic, or endocrine disease or other abnormality, which may impact the ability of the participant to participate or potentially confound the study results.

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Participants With at Least One Treatment-Emergent Adverse Event (TEAE), as Reported by the Participants or Participant's Caregivers or Observed by the Investigator, After TAK-935 Treatment	From first dose up to 30 days post last dose (approximately up to 120 days)	An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, 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 treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug

Secondary

Measure	Time frame	Description
Drug Clearance (CL) and Intercompartmental Clearance (Q) for TAK-935 Calculated Using the Observed Value of the Last Quantifiable Concentration	Day 1 pre-dose and at multiple timepoints (up to 5 hours) post-dose; Days 11 and 21 pre-dose and 1-hour post-dose; Days 31, 41, and 85 pre-dose	—
Apparent Volume of Distribution (Vz/F) of Central Compartment (Vc) and Peripheral Compartment (Vp) for TAK-935 Calculated Using the Observed Value of the Last Quantifiable Concentration	Day 1 pre-dose and at multiple timepoints (up to 5 hours) post-dose; Days 11 and 21 pre-dose and 1-hour post-dose; Days 31, 41, and 85 pre-dose	—
Absorption Rate Constant (Ka) for TAK-935	Day 1 pre-dose and at multiple timepoints (up to 5 hours) post-dose; Days 11 and 21 pre-dose and 1-hour post-dose; Days 31, 41, and 85 pre-dose	—
Cmax,ss: Maximum Observed Plasma Concentration for TAK-935 at Steady State	Day 1 pre-dose and at multiple timepoints (up to 5 hours) post-dose; Days 11 and 21 pre-dose and 1-hour post-dose; Days 31, 41, and 85 pre-dose	—
AUC0-tau,ss: Area Under the Plasma Concentration-time Curve Over the Dosing Interval for TAK-935 at Steady State	Day 1 pre-dose and at multiple timepoints (up to 5 hours) post-dose; Days 11 and 21 pre-dose and 1-hour post-dose; Days 31, 41, and 85 pre-dose	—
Cav,ss: Average Plasma Concentration During a Dosing Interval at Steady State for TAK-935	Day 1 pre-dose and at multiple timepoints (up to 5 hours) post-dose; Days 11 and 21 pre-dose and 1-hour post-dose; Days 31, 41, and 85 pre-dose	—
Ctrough,ss: Plasma Concentration Immediately Prior to Dosing for TAK-935 at Steady State	Days 1, 11, 21; Days 31, 41 and 85 pre-dose	—
Percentage of Participants With at Least 1 Markedly Abnormal Value for Clinical Laboratory Evaluations After TAK-935	From first dose up to last dose (up to Day 85)	Clinical Laboratory parameters: hematology, serum chemistry and urinalysis. Participants with at least 1 markedly abnormal values during treatment period were reported: Erythrocytes: \<0.8xLLN-\>1.5xULN, Hematocrit: \<0.8x LLN \>1.2xULN,Hemoglobin: \<0.8xLLN-\>1.2xULN Leukocytes: \<0.5xLLN, Platelets (10\^9/L): \<75x10\^9/L-\>600x10\^9/L, Prothrombin Ratio: \>1.5xULN, Alanine Aminotransferase: \>3xULN, Albumin:\<25 g/L, Alkaline Phosphatase: \>3xULN,Alpha-1 Acid Glycoprotein: \<47 mg/DL-\>125 mg/DL, Aspartate Aminotransferase:\>3xULN, Bicarbonate:\<8.0 mmol/L, Calcium:\<1.75 mmol/L-\>2.88 mmol/L, Chloride:\<75 mmol/L-\>126 mmol/L, Cholesterol: \>7.72,Creatine Kinase:\>5xULN, Creatinine:\>177 umol/L, Gamma Glutamyl Transferase: \>3xULN, Glucose:\<2.8 mmol/L- \>19.4 mmol/L,HDL Cholesterol: \<1.04 mmol/L-\>1.55 mmol/L, LDL Cholesterol: \<1.30 mmol/L-\>4.14 mmol/L, Potassium:\<3.0 mmol/L-\>6.0 mEq/L, Protein:\<0.8xLLN-\>1.2 x ULN, Sodium: \<130 mmol/L-\>150 mmol/L, Triglycerides: \>2.5xULN, Urea Nitrogen: \>10.7 mmol/L.
Percentage of Participants With at Least 1 Markedly Abnormal Value for Vital Signs After TAK-935	From first dose up to 30 days post last dose (approximately up 120 days)	Vital signs included heart rate, blood pressure and body temperature. markedly abnormal values during treatment period were categorized as: heart rate 1,3 and 5 min standing (beats/min) \<50-\>120, systolic blood pressure 1,3 and 5 min standing (mmHg) \<85-\>180, diastolic blood pressure 1,3 and 5 min standing (mmHg) \<50-\>110 and body temperature (degree centigrade) \<35.6- \>37.7. Only categories with values have been reported.
Percentage of Participants With at Least 1 Markedly Abnormal Value for Electrocardiogram (ECG) Parameters After TAK-935	From first dose up to last dose (up to Day 85)	A 12-lead ECG was performed. Markedly abnormal values during treatment period were categorized as: ECG ventricular rate \<50-\>120, PR Interval, (msec) \<=80-\>=200, QRS Duration, (msec) \<=80-\>=180, QT Interval, (msec) \<=50-\>=460, QTcF Interval, (msec) \<=50-\>=500 OR \>=30 change from baseline and \>=450 milliseconds, RR interval \<600-\>=1440.

Countries

United States

Contacts

STUDY_DIRECTORMedical Monitor Clinical Science

Takeda (Note: This product was divested to Mistrau Bio, Inc. in 2026)

Participant flow

Recruitment details

Participants took part in the study at 10 investigative sites in the United States from 17 August 2017 to 19 September 2018.

Pre-assignment details

Participants with a diagnosis of developmental and/or epileptic encephalopathies were enrolled to receive TAK-935 or placebo in Part 1 \[Double Blind Treatment Period (TP)\] and Part 2 (Open Label TP).

Participants by arm

Arm	Count
Part 1: Placebo TAK-935 matching-placebo tablets, orally or through G-tube/PEG tube, BID from Days 1 to 30 in dose titration period.	4
Part 1: TAK-935 TAK-935 100 mg, tablet, orally or through G-tube/PEG tube, BID from Days 1 to 10 followed by TAK-935 100 mg tablets x2, orally or through G-tube/PEG tube, BID from Days 11 to 20 followed by TAK-935 100 mg tablets x3, orally or through G-tube/PEG tube, BID from Days 21 to 30 in dose titration period. The dose of TAK-935 was escalated or de-escalated during Part 1 as per investigator's discretion.	14
Total	18

Baseline characteristics

Characteristic	Part 1: Placebo	Part 1: TAK-935	Total
Age, Continuous	27.8 years STANDARD_DEVIATION 8.38	29.4 years STANDARD_DEVIATION 7.83	29.1 years STANDARD_DEVIATION 7.73
Body Mass Index (BMI)	29.08 kg/m^2 STANDARD_DEVIATION 5.688	24.61 kg/m^2 STANDARD_DEVIATION 6.639	25.61 kg/m^2 STANDARD_DEVIATION 6.562
Epilepsy Diagnosis Cerebral Dysgenesis	0 Participants	1 Participants	1 Participants
Epilepsy Diagnosis Complex Partial Seizure Disorder	0 Participants	1 Participants	1 Participants
Epilepsy Diagnosis Dravet Syndrome	0 Participants	1 Participants	1 Participants
Epilepsy Diagnosis Epilepsy	1 Participants	2 Participants	3 Participants
Epilepsy Diagnosis Epilepsy With Significant Learning Problem and GDD	1 Participants	0 Participants	1 Participants
Epilepsy Diagnosis Epileptic Encephalopathy	1 Participants	3 Participants	4 Participants
Epilepsy Diagnosis Frontal Lobe Epilepsy	0 Participants	1 Participants	1 Participants
Epilepsy Diagnosis Hypothalamic Hamartoma	0 Participants	1 Participants	1 Participants
Epilepsy Diagnosis Infantile Spasms	0 Participants	1 Participants	1 Participants
Epilepsy Diagnosis Infantile Spasms That Went On To Lennox-Gastaut	0 Participants	1 Participants	1 Participants
Epilepsy Diagnosis Lennox-Gastaut Syndrome	1 Participants	4 Participants	5 Participants
Epilepsy Diagnosis Medically Intractable Focal Epilepsy	0 Participants	1 Participants	1 Participants
Epilepsy Diagnosis Mental Retardation	0 Participants	2 Participants	2 Participants
Epilepsy Diagnosis Partial Seizures With Secondary Generalization	0 Participants	1 Participants	1 Participants
Epilepsy Diagnosis Tuberous Sclerosis	0 Participants	1 Participants	1 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	2 Participants	2 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	4 Participants	12 Participants	16 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Height	170.78 cm STANDARD_DEVIATION 14.115	163.80 cm STANDARD_DEVIATION 9.746	165.35 cm STANDARD_DEVIATION 10.802
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) White	3 Participants	13 Participants	16 Participants
Region of Enrollment United States	4 Participants	14 Participants	18 Participants
Sex: Female, Male Female	0 Participants	4 Participants	4 Participants
Sex: Female, Male Male	4 Participants	10 Participants	14 Participants
Weight	86.35 kg STANDARD_DEVIATION 26.651	68.57 kg STANDARD_DEVIATION 21.702	72.52 kg STANDARD_DEVIATION 23.31

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 4	0 / 14	0 / 16
other Total, other adverse events	4 / 4	10 / 14	11 / 16
serious Total, serious adverse events	0 / 4	1 / 14	3 / 16

Outcome results

Primary

Percentage of Participants With at Least One Treatment-Emergent Adverse Event (TEAE), as Reported by the Participants or Participant's Caregivers or Observed by the Investigator, After TAK-935 Treatment

An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, 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 treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug

Time frame: From first dose up to 30 days post last dose (approximately up to 120 days)

Population: Safety Analysis Set for Parts 1 and 2 included all participants who received at least 1 dose of study drug.

Arm	Measure	Value (NUMBER)
Part 1: Placebo	Percentage of Participants With at Least One Treatment-Emergent Adverse Event (TEAE), as Reported by the Participants or Participant's Caregivers or Observed by the Investigator, After TAK-935 Treatment	100 percentage of participants
Part 1: TAK-935	Percentage of Participants With at Least One Treatment-Emergent Adverse Event (TEAE), as Reported by the Participants or Participant's Caregivers or Observed by the Investigator, After TAK-935 Treatment	71.4 percentage of participants
Part 2: TAK-935	Percentage of Participants With at Least One Treatment-Emergent Adverse Event (TEAE), as Reported by the Participants or Participant's Caregivers or Observed by the Investigator, After TAK-935 Treatment	68.8 percentage of participants

Secondary

Absorption Rate Constant (Ka) for TAK-935

Time frame: Day 1 pre-dose and at multiple timepoints (up to 5 hours) post-dose; Days 11 and 21 pre-dose and 1-hour post-dose; Days 31, 41, and 85 pre-dose