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

• ClinicalTrials.gov Identifier: NCT03166215
• Recruitment Status: Completed
• First Posted: May 25, 2017
• Last Update Posted: November 5, 2018
• Sponsor: Takeda
• Collaborator: Ovid Therapeutics Inc.
• Information provided by (Responsible Party): Takeda

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Developmental and/or Epileptic Encephalopathies	Drug: TAK-935; Drug: Placebo	Phase 1; Phase 2

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 low/ medium/ high dose
• 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, twice daily, in Part 1 (Day 1) and dose will be increased to 200 mg (Day 11) and to 300 mg (Day 21). 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 200 mg TAK-935 tablets, orally or through G-tube/PEG tube, twice daily and dose will be increased to 300 mg tablets, orally, twice daily (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 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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 18 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: June 13, 2017
• Actual Primary Completion Date: September 19, 2018
• Actual Study Completion Date: September 19, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: TAK-935: Part 1 (double-blind dose escalation); TAK-935 low dose, tablets, orally or through gastronomy tube (G-tube)/percutaneous endoscopic gastronomy (PEG) tube, twice daily from Days 1 to 10 followed by TAK-935 medium dose, tablets, orally or through G-tube/PEG tube, twice daily from Days 11 to 20 followed by TAK-935 high dose, tablets, orally or through G-tube/PEG tube, twice daily from Days 21 to 30. The dose of TAK-935 will be gradually escalated or de-escalated during Part 1.	Drug: TAK-935; TAK-935 tablets.
Placebo Comparator: Placebo: Part 1 (double-blind dose escalation); TAK-935 placebo-matching tablets, orally or through G-tube/PEG tube, twice daily from Days 1 for up to 30 days.	Drug: Placebo; TAK-935 placebo-matching tablets.
Experimental: TAK-935: Part 2 (open-label dose escalation); TAK-935 medium dose, tablets, orally or through G-tube/PEG tube, twice daily from Days 31 to 40 followed by TAK-935 low dose/ medium dose/ high dose, tablets, orally or through G-tube/PEG tube, twice daily from Days 31 to Day 85. At the end of Part 2, the dose of TAK-935 will be de-escalated before dosing is discontinued.	Drug: TAK-935; TAK-935 tablets.

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants with at least One Treatment-Emergent Adverse Event (TEAE), as Reported by the Participants or Participants' Caregivers or Observed by the Investigator, After TAK-935 Treatment [ Time Frame: Baseline up to Day 121 ]
   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 (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 is defined as an adverse event with an onset that occurs after receiving study drug.

Secondary Outcome Measures :

1. Oral Clearance (CL/F) and Intercompartmental Clearance (Q) 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 ]
2. Apparent Volume of Distribution (Vz/F) of Central Compartment (Vc) and Peripheral Compartment (Vp) 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 ]
3. 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 ]
4. Cmax: Maximum Observed Plasma Concentration 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 ]
5. AUCtau: Area Under the Plasma Concentration-time Curve Over the Dosing Interval 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 ]
6. Cav,ss: Average Plasma Concentration at Steady State 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 ]
7. Ctrough: Plasma Concentration Immediately Prior to Dosing 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 ]
8. Percentage of Participants with at least 1 Markedly Abnormal Value for Clinical Laboratory Evaluations, Vital Signs and Electrocardiogram (ECG) Parameters After TAK-935 Treatment Reported as Adverse Events [ Time Frame: Baseline up to Day 121 ]
   The percentage of participants with any markedly abnormal standard safety laboratory values will be collected throughout study. Vital signs will include oral body temperature, sitting blood pressure (after the participant has rested for at least 5 minutes), and heart rate (beats per minute [bpm]). Change relative to baseline in electrocardiograms will be measured throughout study.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, Arizona

Xenoscience

Phoenix, Arizona, United States, 85004

United States, Florida

Medsol Clinical Research Center

Port Charlotte, Florida, United States, 33952

University of South Florida

Tampa, Florida, United States, 33606

United States, Georgia

Center for Integrative Rare Disease Research

Atlanta, Georgia, United States, 30318

United States, Kentucky

Bluegrass Epilepsy Research

Lexington, Kentucky, United States, 40504

United States, Maryland

Mid-Atlantic Epilepsy and Sleep Center

Bethesda, Maryland, United States, 20817

United States, Missouri

The Comprehensive Epilepsy Care Center for Children and Adults

Saint Louis, Missouri, United States, 63131

United States, New Jersey

Northeast Regional Epilepsy Group

Hackensack, New Jersey, United States, 07601

United States, Pennsylvania

Thomas Jefferson University

Philadelphia, Pennsylvania, United States, 19107

United States, South Carolina

Medical University of South Carolina

Charleston, South Carolina, United States, 29425

United States, Virginia

University of Virginia Health Sciences Center

Charlottesville, Virginia, United States, 22903

Sponsors and Collaborators

Takeda

Ovid Therapeutics Inc.

Investigators

• Study Director: Medical Monitor Clinical Science; Takeda

More Information

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT03166215 History of Changes
• Other Study ID Numbers: TAK-935-2001; U1111-1192-7890 ( Other Identifier: WHO )
• First Posted: May 25, 2017
• Last Update Posted: November 5, 2018
• Last Verified: November 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Takeda:

Drug therapy

Additional relevant MeSH terms:

Brain Diseases; Epilepsy; Central Nervous System Diseases; Nervous System Diseases