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

Phase 1

Completed

• Conditions: Developmental and/or Epileptic Encephalopathies
• Interventions: Drug: TAK-935; Drug: Placebo

• Registration Number: NCT03166215
• Lead Sponsor: Takeda

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.

Study Timeline

• Study First Submitted: 2017-05-23
• Study First Submitted QC: 2017-05-23
• Study First Posted: 2017-05-25
• Study Start: 2017-08-17
• Primary Completion: 2018-09-19
• Study Completion: 2018-09-19
• Results First Submitted: 2019-09-17
• Results First Submitted QC: 2019-12-23
• Results First Posted: 2020-01-10
• Status Verified: 2020-12
• Last Update Submitted: 2020-12-16
• Last Update Posted: 2021-01-07

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 18

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Part 1: Placebo	TAK-935	TAK-935 matching-placebo tablets, orally or through gastrostomy tube (G-tube)/ percutaneous endoscopic gastrostomy (PEG) tube, twice daily (BID) from Days 1 to 30 in dose titration period.
Part 1: TAK-935	Placebo	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.
Part 2: TAK-935	TAK-935	TAK-935 100 mg tablets x2, orally or through G-tube/PEG tube, BID from Days 31 to 40 followed by TAK-935 100 mg tablets x1, x2 or x3, orally or through G-tube/PEG tube, BID from Days 31 to Day 85 as per investigator's discretion in the maintenance period. At the end of Part 2, the dose of TAK-935 was de-escalated until discontinuation.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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
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
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
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
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
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.
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
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.

Trial Locations

Locations (11)

Xenoscience; 🇺🇸 Phoenix, Arizona, United States

Medsol Clinical Research Center; 🇺🇸 Port Charlotte, Florida, United States

University of South Florida; 🇺🇸 Tampa, Florida, United States

Center for Integrative Rare Disease Research; 🇺🇸 Atlanta, Georgia, United States

Mid-Atlantic Epilepsy and Sleep Center; 🇺🇸 Bethesda, Maryland, United States

Bluegrass Epilepsy Research; 🇺🇸 Lexington, Kentucky, United States

The Comprehensive Epilepsy Care Center for Children and Adults; 🇺🇸 Saint Louis, Missouri, United States

University of Virginia Health Sciences Center; 🇺🇸 Charlottesville, Virginia, United States

Northeast Regional Epilepsy Group; 🇺🇸 Hackensack, New Jersey, United States

Medical University of South Carolina; 🇺🇸 Charleston, South Carolina, United States

Thomas Jefferson University; 🇺🇸 Philadelphia, Pennsylvania, United States