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

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03166215
• Collaborator: Ovid Therapeutics Inc. (Industry)
• Enrollment: 18
• Locations: 11
• Arms: 3
• Actual Duration (Months): 13.1
• Patients Per Site: 1.6
• Patients Per Site Per Month: 0.1

Study Details

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

• 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 Design

• Study Type: Interventional
• 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: Aug 17, 2017
• Actual Primary Completion Date: Sep 19, 2018
• Actual Study Completion Date: Sep 19, 2018

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Part 1: Placebo 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.	Drug: TAK-935; TAK-935 tablets.
Experimental: 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.	Drug: Placebo; TAK-935 placebo-matching tablets.
Experimental: Part 2: 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.	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 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

1. 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]

2. 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]

3. 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]

4. 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]

5. 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]

6. 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]

7. 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]

8. 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.

9. 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.

10. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

	Site	City	State	Country	Postal Code
1	Xenoscience	Phoenix	Arizona	United States	85004
2	Medsol Clinical Research Center	Port Charlotte	Florida	United States	33952
3	University of South Florida	Tampa	Florida	United States	33606
4	Center for Integrative Rare Disease Research	Atlanta	Georgia	United States	30318
5	Bluegrass Epilepsy Research	Lexington	Kentucky	United States	40504
6	Mid-Atlantic Epilepsy and Sleep Center	Bethesda	Maryland	United States	20817
7	The Comprehensive Epilepsy Care Center for Children and Adults	Saint Louis	Missouri	United States	63131
8	Northeast Regional Epilepsy Group	Hackensack	New Jersey	United States	07601
9	Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19107
10	Medical University of South Carolina	Charleston	South Carolina	United States	29425
11	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

Study Documents (Full-Text)

• Study Protocol - Mar 21, 2018
• Statistical Analysis Plan - Oct 26, 2018

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT03166215
• Other Study ID Numbers: TAK-935-2001; U1111-1192-7890
• First Posted: May 25, 2017
• Last Update Posted: Jan 7, 2021
• Last Verified: Dec 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• 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

Study Results

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 Detail	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).

Arm/Group Title	Part 1: Placebo	Part 1: TAK-935	Part 2: TAK-935
Arm/Group Description	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.	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.	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.
Period Title: Part 1 (Double-blind TP: Days 1 - 30)
STARTED	4	14	0
COMPLETED	4	12	0
NOT COMPLETED	0	2	0
Period Title: Part 1 (Double-blind TP: Days 1 - 30)
STARTED	0	0	16
COMPLETED	0	0	14
NOT COMPLETED	0	0	2

Baseline Characteristics

Arm/Group Title	Part 1: Placebo	Part 1: TAK-935	Total
Arm/Group Description	TAK-935 matching-placebo tablets, orally or through G-tube/PEG tube, BID from Days 1 to 30 in dose titration period.	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.	Total of all reporting groups
Overall Participants	4	14	18
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	27.8 (8.38)	29.4 (7.83)	29.1 (7.73)
Sex: Female, Male (Count of Participants)
Female	0 0%	4 28.6%	4 22.2%
Male	4 100%	10 71.4%	14 77.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	2 14.3%	2 11.1%
Not Hispanic or Latino	4 100%	12 85.7%	16 88.9%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 25%	0 0%	1 5.6%
White	3 75%	13 92.9%	16 88.9%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 7.1%	1 5.6%
Region of Enrollment (Count of Participants)
United States	4 100%	14 100%	18 100%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	170.78 (14.115)	163.80 (9.746)	165.35 (10.802)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	86.35 (26.651)	68.57 (21.702)	72.52 (23.310)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	29.08 (5.688)	24.61 (6.639)	25.61 (6.562)
Epilepsy Diagnosis (Count of Participants)
Cerebral Dysgenesis	0 0%	1 7.1%	1 5.6%
Complex Partial Seizure Disorder	0 0%	1 7.1%	1 5.6%
Dravet Syndrome	0 0%	1 7.1%	1 5.6%
Epilepsy	1 25%	2 14.3%	3 16.7%
Epileptic Encephalopathy	1 25%	3 21.4%	4 22.2%
Frontal Lobe Epilepsy	0 0%	1 7.1%	1 5.6%
Hypothalamic Hamartoma	0 0%	1 7.1%	1 5.6%
Infantile Spasms	0 0%	1 7.1%	1 5.6%
Infantile Spasms That Went On To Lennox-Gastaut	0 0%	1 7.1%	1 5.6%
Lennox-Gastaut Syndrome	1 25%	4 28.6%	5 27.8%
Medically Intractable Focal Epilepsy	0 0%	1 7.1%	1 5.6%
Mental Retardation	0 0%	2 14.3%	2 11.1%
Partial Seizures With Secondary Generalization	0 0%	1 7.1%	1 5.6%
Epilepsy With Significant Learning Problem and GDD	1 25%	0 0%	1 5.6%
Tuberous Sclerosis	0 0%	1 7.1%	1 5.6%

Outcome Measures

1. Primary Outcome

Title	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
Description	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)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Part 1: Placebo	Part 1: TAK-935	Part 2: TAK-935
Arm/Group Description	TAK-935 matching-placebo tablets, orally or through G-tube/PEG tube, BID from Days 1 to 30 in dose titration period.	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.	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.
Measure Participants	4	14	16
Number [percentage of participants]	100 2500%	71.4 510%	68.8 382.2%

2. Secondary Outcome

Title	Drug Clearance (CL) and Intercompartmental Clearance (Q) for TAK-935 Calculated Using the Observed Value of the Last Quantifiable Concentration
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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Analysis Set for Parts 1 and 2 included all participants who received at least 1 dose of study drug and have at least 1 post-dose measurable TAK-935 or metabolite of TAK-935 (M-I) plasma concentration.

Arm/Group Title	TAK-935 100 mg BID	TAK-935 200 mg BID	TAK-935 300 mg BID
Arm/Group Description	TAK-935 100 mg, tablet, orally or through G-tube/PEG tube, BID for 10 days in Part 1 and for 44 days in Part 2.	TAK-935 100 mg tablets x2, orally or through G-tube/PEG tube, BID for 10 days in Part 1 and Part 2.	TAK-935 100 mg tablets x3, orally or through G-tube/PEG tube, BID for 10 days in Part 1 and for 44 days in Part 2.
Measure Participants	13	16	13
CL	259.4 (148.1)	195.8 (116.3)	190 (108.5)
Q	100.6 (22.24)	70.99 (14.6)	57.77 (11.36)

3. Secondary Outcome

Title	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
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

Outcome Measure Data

Analysis Population Description

PK Analysis Set for Parts 1 and 2 included all participants who received at least 1 dose of study drug and have at least 1 post-dose measurable TAK-935 or M-I plasma concentration.

Arm/Group Title	TAK-935 100 mg BID	TAK-935 200 mg BID	TAK-935 300 mg BID
Arm/Group Description	TAK-935 100 mg, tablet, orally or through G-tube/PEG tube, BID for 10 days in Part 1 and for 44 days in Part 2.	TAK-935 100 mg tablets x2, orally or through G-tube/PEG tube, BID for 10 days in Part 1 and Part 2.	TAK-935 100 mg tablets x3, orally or through G-tube/PEG tube, BID for 10 days in Part 1 and for 44 days in Part 2.
Measure Participants	13	16	13
Vc	56.59 (22.72)	60.51 (23.79)	62 (26.54)
Vp	677.1 (296.2)	474.3 (201.9)	352.9 (138.7)

4. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

PK Analysis Set for Parts 1 and 2 included all participants who received at least 1 dose of study drug and have at least 1 post-dose measurable TAK-935 or M-I plasma concentration.

Arm/Group Title	TAK-935 100 mg BID	TAK-935 200 mg BID	TAK-935 300 mg BID
Arm/Group Description	TAK-935 100 mg, tablet, orally or through G-tube/PEG tube, BID for 10 days in Part 1 and for 44 days in Part 2.	TAK-935 100 mg tablets x2, orally or through G-tube/PEG tube, BID for 10 days in Part 1 and Part 2.	TAK-935 100 mg tablets x3, orally or through G-tube/PEG tube, BID for 10 days in Part 1 and for 44 days in Part 2.
Measure Participants	13	16	13
Mean (Standard Deviation) [1/hr]	2.13 (0)	2.13 (0)	2.13 (0)

5. Secondary Outcome

Title	Cmax,ss: Maximum Observed Plasma Concentration for TAK-935 at Steady State
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

Outcome Measure Data

Analysis Population Description

PK Analysis Set for Parts 1 and 2 included all participants who received at least 1 dose of study drug and have at least 1 post-dose measurable TAK-935 or M-I plasma concentration.

Arm/Group Title	TAK-935 100 mg BID	TAK-935 200 mg BID	TAK-935 300 mg BID
Arm/Group Description	TAK-935 100 mg, tablet, orally or through G-tube/PEG tube, BID for 10 days in Part 1 and for 44 days in Part 2.	TAK-935 100 mg tablets x2, orally or through G-tube/PEG tube, BID for 10 days in Part 1 and Part 2.	TAK-935 100 mg tablets x3, orally or through G-tube/PEG tube, BID for 10 days in Part 1 and for 44 days in Part 2.
Measure Participants	13	16	13
Mean (Standard Deviation) [ng/mL]	269.6 (159.6)	639.8 (354.8)	975.3 (411.5)

6. Secondary Outcome

Title	AUC0-tau,ss: Area Under the Plasma Concentration-time Curve Over the Dosing Interval for TAK-935 at Steady State
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

Outcome Measure Data

Analysis Population Description

PK Analysis Set for Parts 1 and 2 included all participants who received at least 1 dose of study drug and have at least 1 post-dose measurable TAK-935 or M-I plasma concentration.

Arm/Group Title	TAK-935 100 mg BID	TAK-935 200 mg BID	TAK-935 300 mg BID
Arm/Group Description	TAK-935 100 mg, tablet, orally or through G-tube/PEG tube, BID for 10 days in Part 1 and for 44 days in Part 2.	TAK-935 100 mg tablets x2, orally or through G-tube/PEG tube, BID for 10 days in Part 1 and Part 2.	TAK-935 100 mg tablets x3, orally or through G-tube/PEG tube, BID for 10 days in Part 1 and for 44 days in Part 2.
Measure Participants	13	16	13
Mean (Standard Deviation) [ng*hr/mL]	562.5 (406.8)	1437 (909)	2188 (1357)

7. Secondary Outcome

Title	Cav,ss: Average Plasma Concentration During a Dosing Interval 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

Outcome Measure Data

Analysis Population Description

PK Analysis Set for Parts 1 and 2 included all participants who received at least 1 dose of study drug and have at least 1 post-dose measurable TAK-935 or M-I plasma concentration.

Arm/Group Title	TAK-935 100 mg BID	TAK-935 200 mg BID	TAK-935 300 mg BID
Arm/Group Description	TAK-935 100 mg, tablet, orally or through G-tube/PEG tube, BID for 10 days in Part 1 and for 44 days in Part 2.	TAK-935 100 mg tablets x2, orally or through G-tube/PEG tube, BID for 10 days in Part 1 and Part 2.	TAK-935 100 mg tablets x3, orally or through G-tube/PEG tube, BID for 10 days in Part 1 and for 44 days in Part 2.
Measure Participants	13	16	13
Mean (Standard Deviation) [ng/mL]	46.9 (33.9)	119.8 (75.75)	182.3 (113.1)

8. Secondary Outcome

Title	Ctrough,ss: Plasma Concentration Immediately Prior to Dosing for TAK-935 at Steady State
Time Frame	Days 1, 11, 21; Days 31, 41 and 85 pre-dose

Outcome Measure Data

Analysis Population Description

PK Analysis Set for Parts 1 and 2 included all participants who received at least 1 dose of study drug and have at least 1 post-dose measurable TAK-935 or M-I plasma concentration.

Arm/Group Title	TAK-935 100 mg BID	TAK-935 200 mg BID	TAK-935 300 mg BID
Arm/Group Description	TAK-935 100 mg, tablet, orally or through G-tube/PEG tube, BID for 10 days in Part 1 and for 44 days in Part 2.	TAK-935 100 mg tablets x2, orally or through G-tube/PEG tube, BID for 10 days in Part 1 and Part 2.	TAK-935 100 mg tablets x3, orally or through G-tube/PEG tube, BID for 10 days in Part 1 and for 44 days in Part 2.
Measure Participants	13	16	13
Mean (Standard Deviation) [ng/mL]	10.5 (13.83)	26 (29.2)	30.2 (29.12)

9. Secondary Outcome

Title	Percentage of Participants With at Least 1 Markedly Abnormal Value for Clinical Laboratory Evaluations After TAK-935
Description	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.
Time Frame	From first dose up to last dose (up to Day 85)

Outcome Measure Data

Analysis Population Description

Safety Analysis Set for Parts 1 and 2 included all participants who received at least 1 dose of study drug. Data reported is the data available for the specific parameter.

Arm/Group Title	Part 1: Placebo	Part 1: TAK-935	Part 2: TAK-935
Arm/Group Description	TAK-935 matching-placebo tablets, orally or through G-tube/PEG tube, BID from Days 1 to 30 in dose titration period.	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.	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.
Measure Participants	4	14	16
Alpha-1 Acid Glycoprotein (>125 mg/DL)	0 0%	11.1 79.3%	14.3 79.4%
Gamma Glutamyl Transferase ( >3 x ULN)	0 0%	9.1 65%	6.7 37.2%
HDL Cholesterol (<1.04 mmol/L)	75.0 1875%	18.2 130%	40.0 222.2%
HDL Cholesterol (>1.55 mmol/L)	0 0%	27.3 195%	13.3 73.9%
LDL Cholesterol (>4.14 mmol/L)	0 0%	9.1 65%	0 0%
Potassium (>6.0 mmol/L)	0 0%	9.1 65%	0 0%

10. Secondary Outcome

Title	Percentage of Participants With at Least 1 Markedly Abnormal Value for Vital Signs After TAK-935
Description	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.
Time Frame	From first dose up to 30 days post last dose (approximately up 120 days)

Outcome Measure Data

Analysis Population Description

Safety Analysis Set for Parts 1 and 2 included all participants who received at least 1 dose of study drug. Data reported is the data available for the specific parameter.

Arm/Group Title	Part 1: Placebo	Part 1: TAK-935	Part 2: TAK-935
Arm/Group Description	TAK-935 matching-placebo tablets, orally or through G-tube/PEG tube, BID from Days 1 to 30 in dose titration period.	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.	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.
Measure Participants	4	14	16
Diastolic Blood Pressure 3 min Standing (<50 mmHg)	33.3 832.5%	0 0%	0 0%
Diastolic Blood Pressure 5 min Sitting (<50 mmHg)	0 0%	7.1 50.7%	0 0%
Diastolic Blood Pressure 5 min Supine (<50 mmHg)	25.0 625%	0 0%	0 0%
Heart Rate 1 min Standing (>120 beats/min)	0 0%	16.7 119.3%	0 0%
Heart Rate 5 min Sitting (<50 beats/min)	50.0 1250%	0 0%	6.3 35%
Heart Rate 5 min Supine (<50 beats/min)	25.0 625%	0 0%	0 0%
Systolic Blood Pressure 5 min Sitting (<85 mmHg)	0 0%	7.1 50.7%	0 0%
Temperature (<35.6 C)	25.0 625%	7.7 55%	18.8 104.4%

11. Secondary Outcome

Title	Percentage of Participants With at Least 1 Markedly Abnormal Value for Electrocardiogram (ECG) Parameters After TAK-935
Description	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.
Time Frame	From first dose up to last dose (up to Day 85)

Outcome Measure Data

Analysis Population Description

Safety Analysis Set for Parts 1 and 2 included all participants who received at least 1 dose of study drug. Data reported is the data available for the specific parameter.

Arm/Group Title	Part 1: Placebo	Part 1: TAK-935	Part 2: TAK-935
Arm/Group Description	TAK-935 matching-placebo tablets, orally or through G-tube/PEG tube, BID from Days 1 to 30 in dose titration period.	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.	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.
Measure Participants	4	14	16
ECG Ventricular Rate (<50 beats/min)	33.3 832.5%	0 0%	0 0%
QRS Duration (<=80 msec)	0 0%	12.5 89.3%	6.7 37.2%
RR Interval (<=600 msec)	0 0%	0 0%	13.3 73.9%

Adverse Events

Time Frame	From first dose up to 30 days post last dose (approximately up to 120 days)
Arm/Group Title	Part 1: Placebo		Part 1: TAK-935		Part 2: TAK-935
Arm/Group Description	TAK-935 matching-placebo tablets, orally or through G-tube/PEG tube, BID from Days 1 to 30 in dose titration period.		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.		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.
All Cause Mortality
	Part 1: Placebo		Part 1: TAK-935		Part 2: TAK-935
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		0/14 (0%)		0/16 (0%)
Serious Adverse Events
	Part 1: Placebo		Part 1: TAK-935		Part 2: TAK-935
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		1/14 (7.1%)		3/16 (18.8%)
Nervous system disorders
Seizure Cluster	0/4 (0%)		1/14 (7.1%)		2/16 (12.5%)
Seizure	0/4 (0%)		0/14 (0%)		1/16 (6.3%)
Other (Not Including Serious) Adverse Events
	Part 1: Placebo		Part 1: TAK-935		Part 2: TAK-935
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/4 (100%)		10/14 (71.4%)		11/16 (68.8%)
Gastrointestinal disorders
Vomiting	1/4 (25%)		1/14 (7.1%)		1/16 (6.3%)
Constipation	1/4 (25%)		0/14 (0%)		0/16 (0%)
Diarrhoea	0/4 (0%)		1/14 (7.1%)		0/16 (0%)
Nausea	0/4 (0%)		1/14 (7.1%)		0/16 (0%)
General disorders
Fatigue	1/4 (25%)		2/14 (14.3%)		0/16 (0%)
Pyrexia	0/4 (0%)		1/14 (7.1%)		1/16 (6.3%)
Asthenia	0/4 (0%)		1/14 (7.1%)		0/16 (0%)
Gait disturbance	0/4 (0%)		1/14 (7.1%)		0/16 (0%)
Peripheral swelling	0/4 (0%)		1/14 (7.1%)		0/16 (0%)
Infections and infestations
Upper respiratory tract infection	0/4 (0%)		2/14 (14.3%)		1/16 (6.3%)
Bronchitis	0/4 (0%)		0/14 (0%)		1/16 (6.3%)
Ear infection	0/4 (0%)		0/14 (0%)		1/16 (6.3%)
Influenza	0/4 (0%)		0/14 (0%)		1/16 (6.3%)
Rhinitis	0/4 (0%)		1/14 (7.1%)		0/16 (0%)
Sinusitis	0/4 (0%)		1/14 (7.1%)		0/16 (0%)
Injury, poisoning and procedural complications
Fall	0/4 (0%)		1/14 (7.1%)		2/16 (12.5%)
Eye contusion	0/4 (0%)		1/14 (7.1%)		0/16 (0%)
Facial bones fracture	0/4 (0%)		0/14 (0%)		1/16 (6.3%)
Foot fracture	0/4 (0%)		0/14 (0%)		1/16 (6.3%)
Human bite	0/4 (0%)		1/14 (7.1%)		0/16 (0%)
Skin abrasion	0/4 (0%)		1/14 (7.1%)		0/16 (0%)
Investigations
Weight increased	0/4 (0%)		0/14 (0%)		1/16 (6.3%)
Metabolism and nutrition disorders
Decreased appetite	0/4 (0%)		0/14 (0%)		1/16 (6.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/4 (0%)		1/14 (7.1%)		0/16 (0%)
Nervous system disorders
Dysarthria	0/4 (0%)		3/14 (21.4%)		0/16 (0%)
Headache	1/4 (25%)		2/14 (14.3%)		0/16 (0%)
Lethargy	0/4 (0%)		2/14 (14.3%)		2/16 (12.5%)
Seizure	0/4 (0%)		0/14 (0%)		3/16 (18.8%)
Balance disorder	0/4 (0%)		1/14 (7.1%)		1/16 (6.3%)
Somnolence	0/4 (0%)		1/14 (7.1%)		1/16 (6.3%)
Burning sensation	0/4 (0%)		1/14 (7.1%)		0/16 (0%)
Repetitive speech	0/4 (0%)		1/14 (7.1%)		0/16 (0%)
Sedation	1/4 (25%)		0/14 (0%)		0/16 (0%)
Tonic convulsion	1/4 (25%)		0/14 (0%)		0/16 (0%)
Psychiatric disorders
Insomnia	0/4 (0%)		0/14 (0%)		3/16 (18.8%)
Agitation	0/4 (0%)		1/14 (7.1%)		1/16 (6.3%)
Communication disorder	0/4 (0%)		0/14 (0%)		1/16 (6.3%)
Irritability	0/4 (0%)		1/14 (7.1%)		0/16 (0%)
Listless	0/4 (0%)		0/14 (0%)		1/16 (6.3%)
Sleep talking	1/4 (25%)		0/14 (0%)		0/16 (0%)
Tic	0/4 (0%)		1/14 (7.1%)		1/16 (6.3%)
Renal and urinary disorders
Urinary incontinence	1/4 (25%)		1/14 (7.1%)		0/16 (0%)
Proteinuria	0/4 (0%)		0/14 (0%)		1/16 (6.3%)
Respiratory, thoracic and mediastinal disorders
Cough	0/4 (0%)		0/14 (0%)		1/16 (6.3%)
Wheezing	0/4 (0%)		0/14 (0%)		1/16 (6.3%)
Skin and subcutaneous tissue disorders
Rash	1/4 (25%)		0/14 (0%)		1/16 (6.3%)
Hyperhidrosis	1/4 (25%)		0/14 (0%)		0/16 (0%)
Vascular disorders
Haematoma	0/4 (0%)		0/14 (0%)		1/16 (6.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Research Organization shall not publish any articles or papers nor make any presentations, nor assist any other person in publishing any articles or papers or in making any presentations relating or referring to the Study or any results, data or insights from or any data, information or materials obtained or generated in the performance of its obligations without the prior written consent of Takeda, which consent may be granted or withheld in Takeda's sole discretion.