Safety and Pharmacology Study of VP 20629 in Adults With Friedreich's Ataxia

• ClinicalTrials.gov Identifier: NCT01898884
• Recruitment Status: Completed
• First Posted: July 15, 2013
• Results First Posted: October 6, 2016
• Last Update Posted: June 2, 2021
• Sponsor: Shire
• Information provided by (Responsible Party): Takeda ( Shire )

Tracking Information

• First Submitted Date: July 3, 2013
• First Posted Date: July 15, 2013
• Results First Submitted Date: June 16, 2016
• Results First Posted Date: October 6, 2016
• Last Update Posted Date: June 2, 2021
• Actual Study Start Date: August 13, 2013
• Actual Primary Completion Date: June 18, 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 12, 2016)

• Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) [ Time Frame: From Start of Study Treatment up to Day 19 ]
  An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs (TEAEs), defined as all AEs that start during study drug treatment (and up to 7 days after the last dose of the study drug) and were not seen at baseline, or were seen at baseline but increased in frequency and/or severity during study drug treatment (and up to 7 days after the last dose of study drug).
• Number of Participants With Clinically Significant Laboratory Abnormalities Recorded as Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: From Start of Study Treatment up to Day 19 ]
  An abnormal laboratory finding which required an action or intervention by the investigator, or a finding judged by the investigator to represent a change beyond the range of normal physiologic fluctuation were reported as an adverse event. Treatment-emergent were events between first dose of study drug and 7 days after the last dose that were absent before treatment or that worsened relative to pretreatment state. Number of participants with Grade 3 or higher treatment-emergent adverse events for laboratory abnormalities were reported as clinically relevant laboratory changes.
• Number of Participants With Vital Signs Abnormalities Recorded as Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: From Start of Study Treatment up to Day 19 ]
  Vital sign assessments included systolic blood pressure, diastolic blood pressure, heart rate, and temperature. Vital signs abnormalities reported as TEAEs were reported.
• Number of Participants With Clinically Relevant Electrocardiogram (ECG) Abnormalities Recorded as Adverse Events (AEs) [ Time Frame: From Start of Study Treatment up to Day 19 ]
  ECG included PR interval, QRS interval, QTcB interval, QTcF interval were considered as clinically significant ECG abnormalities.

• Original Primary Outcome Measures (submitted: July 11, 2013): Incidence of adverse events and clinically relevant changes in safety laboratory testing, vital signs, and 12-lead electrocardiograms [ Time Frame: 10 days (single-dose groups) or 17 days (multiple-dose groups) ]

Current Secondary Outcome Measures (submitted: August 12, 2016)

• Maximum Observed Serum Concentration (Cmax) of VP 20629 and Its Metabolite (VP 20631) for Single Dose Groups [ Time Frame: 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 ]
  The Cmax is the maximum observed plasma concentration of single dose of VP 20629 and VP 20631.
• Time of Maximum Observed Plasma Concentration (Tmax) of VP 20629 and Its Metabolite (VP 20631) for Single Dose Groups [ Time Frame: 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 ]
  The Tmax is the time to reach maximum observed plasma concentration of single dose of VP 20629 and VP 20631.
• Area Under the Plasma Concentration Versus Time Curve (AUC) of VP 20629 and Its Metabolite (VP 20631) for Single Dose Groups [ Time Frame: 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 ]
  The AUC is the area under the plasma concentration-time curve observed.
• Area Under the Plasma Concentration Versus Time Curve (AUC[0-8]) of VP 20629 and Its Metabolite (VP 20631) for Single Dose Groups [ Time Frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, and 8 hours Postdose on Day 1 ]
  The AUC(0-8) is the area under the plasma concentration-time curve from time zero to 8 hours postdose.
• 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 [ Time Frame: 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 ]
  The AUCt is the measure of the plasma drug concentration from time zero to time t.
• Terminal Plasma Half-Life (t1/2) of VP 20629 and Its Metabolite (VP 20631) for Single Dose Groups [ Time Frame: 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 ]
  The elimination half-life (t1/2) is the time measured for the plasma concentration to decrease by 1 half to its original concentration. It is associated with the terminal slope of the semi logarithmic drug concentration-time curve, and is calculated as 0.693/lambda(z).
• Volume of Distribution (Vz/F) of VP 20629 for Single Dose Groups [ Time Frame: 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 ]
  The Vz is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug.
• Total Body Drug Clearance (CL/F) of VP 20629 for Single Dose Groups [ Time Frame: 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 ]
  Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
• Elimination Rate Constant (Lambda[z]) of VP 20629 and Its Metabolite (VP 20631) for Single Dose Groups [ Time Frame: 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 ]
  Lambda(z) is first-order elimination rate constant associated with the terminal portion of the curve, determined as the negative slope of the terminal log-linear phase of the drug concentration-time curve.
• Cumulative Amount Excreted Into the Urine (Ae) for Unchanged VP 20629 and Its Metabolite (VP 20631) for Single Dose Groups [ Time Frame: 0-4, 4-8, 8-16, 16-24, 24-36 and 36-48 hours postdose on Day 1 ]
  The Ae is the amount of drug excreted in urine. It is calculated by multiplying the urinary volume with the urinary drug concentration.
• Percentage of Drug Excreted in Urine (Ae%) of VP 20629 for Single Dose Groups [ Time Frame: -4, 4-8, 8-16, 16-24, 24-36 and 36-48 hours postdose on Day 1 ]
  The Ae% is the percentage of drug dose excreted into the urine calculated as (Ae divided by dose)∗100.
• Renal Clearance (CLR) of VP 20629 for Single Dose Groups [ Time Frame: 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 ]
  The CLR is the renal clearance of the drug, calculated as Ae/AUC(0-infinity) on Day 1 or Ae(0-24)/AUC(0-24) on Day 1.
• Maximum Observed Serum Concentration (Cmax) of VP 20629 and Its Metabolite (VP 20631) for Multiple Dose Groups [ Time Frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 24 and 72 hours Postdose on Day 1 ]
  The Cmax is the maximum observed plasma concentration of Multiple Dose of VP 20629 and VP 20631.
• Maximum Observed Serum Concentration at Steady State (Cmax,ss) of VP 20629 and Its Metabolite (VP 20631) for Multiple Dose Groups [ Time Frame: 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 ]
  The Cmax,ss is the maximum observed plasma concentration at steady state.
• Time of Maximum Observed Plasma Concentration (Tmax) of VP 20629 and Its Metabolite (VP 20631) for Multiple Dose Groups [ Time Frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 24 and 72 hours Postdose on Day 1 ]
  The Tmax is the time to reach maximum observed plasma concentration of multiple dose of VP 20629 and VP 20631.
• Time of Maximum Observed Plasma Concentration at Steady State (Tmax,ss) of VP 20629 and Its Metabolite (VP 20631) for Multiple Dose Groups [ Time Frame: 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 ]
  The Tmax,ss is the time to reach maximum observed plasma concentration at steady state of multiple dose of VP 20629 and VP 20631.
• Area Under the Plasma Concentration Versus Time Curve (AUC) of VP 20629 and Its Metabolite (VP 20631) for Multiple Dose Groups [ Time Frame: 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 ]
  The AUC is the area under the plasma concentration-time curve observed.
• Area Under the Plasma Concentration Versus Time Curve at Steady State (AUCss) of VP 20629 and Its Metabolite (VP 20631) for Multiple Dose Groups [ Time Frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, and 8 hours Postdose on Day 8 ]
  The AUCss is the area under the plasma concentration time curve observed during a dosing at steady state.
• Area Under the Plasma Concentration Versus Time Curve (AUC[0-8]) of VP 20629 and Its Metabolite (VP 20631) for Multiple Dose Groups [ Time Frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6 and 8 hours Postdose on Day 1 ]
  The AUC(0-8) is the area under the plasma concentration-time curve from time zero to 8 hours postdose.
• Area Under the Plasma Concentration Versus Time Curve (AUCt) of VP 20629 and Its Metabolite (VP 20631) for Multiple Dose Groups [ Time Frame: 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 ]
  The AUCtau is the measure of the plasma drug concentration from time zero to time t.
• Terminal Plasma Half-Life (t1/2) of VP 20629 and Its Metabolite (VP 20631) for Multiple Dose Groups [ Time Frame: 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 ]
  The elimination half-life (t1/2) is the time measured for the plasma concentration to decrease by 1 half to its original concentration. It is associated with the terminal slope of the semi logarithmic drug concentration-time curve, and is calculated as 0.693/lambda(z).
• Volume of Distribution (Vz/F) of VP 20629 for Multiple Dose Groups [ Time Frame: 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 ]
  The Vz is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug.
• Total Body Drug Clearance at Steady State (CLss/F) of VP 20629 for Multiple Dose Groups [ Time Frame: 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 ]
  Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
• Elimination Rate Constant (Lambda[z]) of VP 20629 and Its Metabolite (VP 20631) for Multiple Dose Groups [ Time Frame: 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 ]
  Lambda(z) is first-order elimination rate constant associated with the terminal portion of the curve, determined as the negative slope of the terminal log-linear phase of the drug concentration-time curve.
• Cumulative Amount Excreted Into the Urine at Steady State (Ae,ss) of Unchanged VP 20629 and Its Metabolite (VP 20631) for Multiple Dose Groups [ Time Frame: 0-4, 4-8, 8-16, 16-24, 24-36, and 36-48 hours postdose on Day 8 ]
  The Ae,ss is the amount of drug excreted in urine. It is calculated by multiplying the urinary volume with the urinary drug concentration.
• Percentage of Drug Excreted in Urine at Steady-State (Ae%,ss) of VP 20629 for Multiple Dose Groups [ Time Frame: 0-4, 4-8, 8-16, 16-24, 24-36, and 36-48 hours postdose on Day 8 ]
  The Ae%,ss is the percentage of drug dose excreted into the urine calculated as (Ae divided by dose)∗100.
• Renal Clearance at Steady State (CLR,ss) of VP 20629 for Multiple Dose Groups [ Time Frame: 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 ]
  The CLR,ss is the renal clearance of the drug, calculated as Ae/AUC(0-infinity) on Day 8.

Original Secondary Outcome Measures (submitted: July 11, 2013)

Pharmacokinetic parameters (e.g., Cmax, Tmax, AUC, t1/2) [ Time Frame: 3 days (single-dose groups) or 10 days (multiple-dose groups) ]

Blood and urine samples will be collected to assess the pharmacokinetics of VP 20629 and a potential metabolite in plasma and urine after single and multiple doses of VP 20629.

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: July 11, 2013)

Pharmacodynamic parameters [ Time Frame: 10 days (multiple-dose groups only) ]

Blood and urine samples will be collected to measure biomarkers of oxidative stress and damage in the multiple-dose groups. These markers are plasma 8-isoprostane and malondialdehyde and urinary 8-hydroxydeoxyguanosine.

Descriptive Information

• Brief Title: 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

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]

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Friedreich's Ataxia

Intervention

• Drug: VP 20629
  Other Name: Indole-3-propionic acid
• Drug: Placebo

Study Arms

• Experimental: Single dose of VP 20629 or placebo
  Four groups of 8 subjects each will receive a single dose of VP 20629 (150 mg, 450 mg, 900 mg, or 1200 mg) or placebo.
  Interventions:

  • Drug: VP 20629
  • Drug: Placebo
• Experimental: Multiple doses of VP 20629 or placebo
  Three groups of 8 subjects each will receive multiple doses of VP 20629 (300 mg, 600 mg, or 900 mg total daily dose) or placebo. VP 20629 or placebo will be administered every 8 hours for 7 days with a single morning dose on Day 8.
  Interventions:

  • Drug: VP 20629
  • Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 12, 2016): 46
• Original Estimated Enrollment (submitted: July 11, 2013): 56
• Actual Study Completion Date: June 18, 2015
• Actual Primary Completion Date: June 18, 2015 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 45 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01898884
• Other Study ID Numbers: 20629-100
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Takeda ( Shire )
• Original Responsible Party: ViroPharma
• Current Study Sponsor: Shire
• Original Study Sponsor: ViroPharma
• Collaborators: Not Provided

Investigators

• Study Director: Study Director; Takeda

• PRS Account: Takeda
• Verification Date: May 2021