Clinical trial NCT01898884: Safety and Pharmacology Study of VP 20629 in Adults With Friedreich's Ataxia
Official title: A Phase 1, Randomized, Double-blind, Placebo-controlled, Multicenter, Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Oral VP 20629 in Adult Subjects With Friedreich's Ataxia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Friedreich's Ataxia
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2013-07-15
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The objectives of the study are:

* To evaluate the safety and tolerability of single and multiple oral doses of VP 20629 in subjects with Friedreich's ataxia (FA). \[Primary\]
* To characterize the pharmacokinetics of VP 20629 by investigation of the plasma concentration-time profile following single and multiple oral doses in subjects with FA. \[Secondary\]
* To investigate the pharmacodynamic effects of VP 20629 on plasma 8-isoprostane and malondialdehyde and urinary 8-hydroxydeoxyguanosine concentrations following multiple oral doses in subjects with FA. \[Exploratory\]


Eligibility criteria: Inclusion Criteria:

1. Be 18 to 45 years of age (inclusive).
2. Have a body mass index between 18 and 27 kg/m\^2 (inclusive).
3. Have a clinical presentation consistent with FA.
4. Have a confirmed diagnosis of FA with a defined expanded guanosine, adenine, adenine (GAA) triplet repeat number.
5. Have an International Cooperative Ataxia Rating Scale (ICARS) mean total score of ≤75.
6. If female, be postmenopausal (cessation of menses ≥1 year), surgically sterile, or have a negative serum human chorionic gonadotropin pregnancy test within 5 days prior to the first dose of study drug. Women of child bearing potential must also be on an acceptable method of birth control, as determined by the Investigator, for 3 months prior to the first dose and must agree to continue use through 2 months after the last dose of study drug.

   If male, be surgically sterile or agree to follow an acceptable method of birth control as determined by the Investigator, from the screening visit through 2 months after the last dose of study drug.
7. Be able to swallow capsules whole.
8. Agree to adhere to the protocol-defined schedule of assessments and procedures.
9. Be informed of the nature of the study and provide written informed consent before any study-specific procedures are performed.

Exclusion Criteria:

1. Have taken coenzyme Q10, idebenone, other dietary or herbal supplements (with an anti-oxidative effect), or over-the-counter medications (including homeopathic medicines and vitamins) within 1 week prior to the first dose of study drug on Day 1.
2. If female, be pregnant or breastfeeding.
3. Have a positive test result for human immunodeficiency virus (HIV), hepatitis B surface antigen, or hepatitis C antibody.
4. Have ingested any alcohol within 48 hours before admission to the clinical study unit on Day -1. NOTE: Caffeine intake should be limited to 2 caffeine-containing beverages per day during this same time period.
5. Have participated in an investigational drug trial within 30 days prior to the first dose of study drug on Day 1. NOTE: Subjects who received study drug (VP 20629 or placebo) in a single-dose group in this study and completed the Post-treatment Safety Assessment are allowed to enroll in a multiple-dose group following a 21 day washout period, provided they continue to meet protocol eligibility criteria. Subjects cannot enroll in a multiple-dose group if they have an ongoing adverse event following participation in a single-dose group or had a serious adverse event during a single-dose group (regardless of causality).
6. Have a known hypersensitivity to any ingredient in the study formulation.
7. Have, as determined by the Investigator and/or medical monitor, any clinically relevant medical or surgical condition that could interfere with the administration of study drug, interpretation of study results, or compromise the safety or well-being of the subject.
8. Have a Columbia-Suicide Severity Rating Scale (C-SSRS) score of 4 or 5.

Primary outcomes:
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
timeFrame: From Start of Study Treatment up to Day 19
measure: Number of Participants With Clinically Significant Laboratory Abnormalities Recorded as Treatment-Emergent Adverse Events (TEAEs)
timeFrame: From Start of Study Treatment up to Day 19
measure: Number of Participants With Vital Signs Abnormalities Recorded as Treatment-Emergent Adverse Events (TEAEs)
timeFrame: From Start of Study Treatment up to Day 19
measure: Number of Participants With Clinically Relevant Electrocardiogram (ECG) Abnormalities Recorded as Adverse Events (AEs)
timeFrame: From Start of Study Treatment up to Day 19
Secondary outcomes:
measure: Maximum Observed Serum Concentration (Cmax) of VP 20629 and Its Metabolite (VP 20631) for Single Dose Groups
timeFrame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8,10, 12, 24 and 48 hours Postdose on Day 1
measure: Time of Maximum Observed Plasma Concentration (Tmax) of VP 20629 and Its Metabolite (VP 20631) for Single Dose Groups
timeFrame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8,10, 12, 24 and 48 hours Postdose on Day 1
measure: Area Under the Plasma Concentration Versus Time Curve (AUC) of VP 20629 and Its Metabolite (VP 20631) for Single Dose Groups
timeFrame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8,10, 12, 24 and 48 hours Postdose on Day 1
measure: Area Under the Plasma Concentration Versus Time Curve (AUC[0-8]) of VP 20629 and Its Metabolite (VP 20631) for Single Dose Groups
timeFrame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, and 8 hours Postdose on Day 1
measure: Area Under the Plasma Concentration Versus Time Curve to the Last Measurable Plasma Concentration (AUCt) of VP 20629 and Its Metabolite (VP 20631) for Single Dose Groups
timeFrame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8,10, 12, 24 and 48 hours Postdose on Day 1
measure: Terminal Plasma Half-Life (t1/2) of VP 20629 and Its Metabolite (VP 20631) for Single Dose Groups
timeFrame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8,10, 12, 24 and 48 hours Postdose on Day 1
measure: Volume of Distribution (Vz/F) of VP 20629 for Single Dose Groups
timeFrame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8,10, 12, 24 and 48 hours Postdose on Day 1
measure: Total Body Drug Clearance (CL/F) of VP 20629 for Single Dose Groups
timeFrame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8,10, 12, 24 and 48 hours Postdose on Day 1
measure: Elimination Rate Constant (Lambda[z]) of VP 20629 and Its Metabolite (VP 20631) for Single Dose Groups
timeFrame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8,10, 12, 24 and 48 hours Postdose on Day 1
measure: Cumulative Amount Excreted Into the Urine (Ae) for Unchanged VP 20629 and Its Metabolite (VP 20631) for Single Dose Groups
timeFrame: 0-4, 4-8, 8-16, 16-24, 24-36 and 36-48 hours postdose on Day 1
measure: Percentage of Drug Excreted in Urine (Ae%) of VP 20629 for Single Dose Groups
timeFrame: -4, 4-8, 8-16, 16-24, 24-36 and 36-48 hours postdose on Day 1
measure: Renal Clearance (CLR) of VP 20629 for Single Dose Groups
timeFrame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8,10, 12, 24 and 48 hours Postdose on Day 1
measure: Maximum Observed Serum Concentration (Cmax) of VP 20629 and Its Metabolite (VP 20631) for Multiple Dose Groups
timeFrame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 24 and 72 hours Postdose on Day 1
measure: Maximum Observed Serum Concentration at Steady State (Cmax,ss) of VP 20629 and Its Metabolite (VP 20631) for Multiple Dose Groups
timeFrame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 and 48 hours Postdose on Day 8
measure: Time of Maximum Observed Plasma Concentration (Tmax) of VP 20629 and Its Metabolite (VP 20631) for Multiple Dose Groups
timeFrame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 24 and 72 hours Postdose on Day 1
measure: Time of Maximum Observed Plasma Concentration at Steady State (Tmax,ss) of VP 20629 and Its Metabolite (VP 20631) for Multiple Dose Groups
timeFrame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 and 48 hours Postdose on Day 8
measure: Area Under the Plasma Concentration Versus Time Curve (AUC) of VP 20629 and Its Metabolite (VP 20631) for Multiple Dose Groups
timeFrame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 and 48 hours Postdose on Day 8
measure: Area Under the Plasma Concentration Versus Time Curve at Steady State (AUCss) of VP 20629 and Its Metabolite (VP 20631) for Multiple Dose Groups
timeFrame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, and 8 hours Postdose on Day 8
measure: Area Under the Plasma Concentration Versus Time Curve (AUC[0-8]) of VP 20629 and Its Metabolite (VP 20631) for Multiple Dose Groups
timeFrame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6 and 8 hours Postdose on Day 1
measure: Area Under the Plasma Concentration Versus Time Curve (AUCt) of VP 20629 and Its Metabolite (VP 20631) for Multiple Dose Groups
timeFrame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 and 48 hours Postdose on Day 8
measure: Terminal Plasma Half-Life (t1/2) of VP 20629 and Its Metabolite (VP 20631) for Multiple Dose Groups
timeFrame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 and 48 hours Postdose on Day 8
measure: Volume of Distribution (Vz/F) of VP 20629 for Multiple Dose Groups
timeFrame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 and 48 hours Postdose on Day 8
measure: Total Body Drug Clearance at Steady State (CLss/F) of VP 20629 for Multiple Dose Groups
timeFrame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 and 48 hours Postdose on Day 8
measure: Elimination Rate Constant (Lambda[z]) of VP 20629 and Its Metabolite (VP 20631) for Multiple Dose Groups
timeFrame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 and 48 hours Postdose on Day 8
measure: Cumulative Amount Excreted Into the Urine at Steady State (Ae,ss) of Unchanged VP 20629 and Its Metabolite (VP 20631) for Multiple Dose Groups
timeFrame: 0-4, 4-8, 8-16, 16-24, 24-36, and 36-48 hours postdose on Day 8
measure: Percentage of Drug Excreted in Urine at Steady-State (Ae%,ss) of VP 20629 for Multiple Dose Groups
timeFrame: 0-4, 4-8, 8-16, 16-24, 24-36, and 36-48 hours postdose on Day 8
measure: Renal Clearance at Steady State (CLR,ss) of VP 20629 for Multiple Dose Groups
timeFrame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 and 48 hours Postdose on Day 8
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA Medical Center
state: California
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Iowa City
country: United States
facility: University of Iowa Children's Hospital
state: Iowa
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References: