A Phase 1 Study to Evaluate Effects of Sapropterin Dihydrochloride on QTc Intervals in Healthy Adult Subjects

NCT00789568 | Completed Phase 1

• 1 other identifier: QTC-001
• Study Type: interventional
• Target: 56
• Locations: 1 country
• Sites: 1

Brief Summary

Sapropterin dihydrochloride (subsequently referred to as sapropterin) (Kuvan®) was approved by the FDA for the treatment of hyperphenylalaninemia in 2007. Preclinical and clinical studies and post-marketing surveillance have not demonstrated any specific cardiovascular concerns with sapropterin (Kuvan®). Nonetheless, nonantiarrhythmic drugs may have the potential to prolong QT interval, leading to potentially fatal ventricular tachycardias, including torsades de pointes. As part of the post-marketing commitment, a thorough QT/QTc study will be conducted according to ICH guidelines.

Conditions

Phenylketonuria

Keywords

Hyperphenylalanemia due to Phenylketonuria

Outcome Measures

Primary Outcomes (1)

• To determine if a single supratherapeutic dose of sapropterin or a single therapeutic dose of sapropterin has an effect on cardiac repolarization compared with placebo as a change from baseline measured by the subject specific QT correction formula(QTci)

  Complete study

Secondary Outcomes (3)

• Determine if there is a pharmacodynamic relationship between the duration of the QT/QTc intervals and the plasma concentration of sapropterin

  Complete Study

• To obtain additional pharmacokinetic information for oral sapropterin at the proposed therapeutic and supra-therapeutic doses.

  Complete Study

• To generate additional safety information

  Complete Study

Study Arms (4)

Sapropterin Dihydrochloride 100mg/kg and placebo Moxifloxacin

EXPERIMENTAL

A single dose of 100mg/kg of Sapropterin Dihydrochloride taken along with placebo Moxifloxacin.

Drug: sapropterin dihydrochloride; Drug: Moxifloxacin placebo

Sapropterin Dihydrochloride 20mg/kg and placebo Moxifloxacin

EXPERIMENTAL

A single dose of 20mg/kg of Sapropterin Dihydrochloride taken along with a placebo Moxifloxacin.

Drug: sapropterin dihydrochloride; Drug: Moxifloxacin placebo

Sapropterin Dihydrochloride placebo and Moxifloxacin

ACTIVE COMPARATOR

No placebo tablets for Sapropterin Dihydrochloride will be administered, but instead will be apple juice only, taken along with 400mg of Moxifloxacin.

Drug: Moxifloxacin

Sapropterin Dihydrocholide placebo and Moxifloxacin placebo

PLACEBO COMPARATOR

No placebo tablets for Sapropterin Dihydrochloride will be administered, but instead will be apple juice only, taken along with placebo of Moxifloxacin.

Drug: Moxifloxacin placebo

Interventions

sapropterin dihydrochloride DRUG

20 mg/kg and 100 mg/kg

Also known as: Kuvan

Sapropterin Dihydrochloride 100mg/kg and placebo Moxifloxacin; Sapropterin Dihydrochloride 20mg/kg and placebo Moxifloxacin

Moxifloxacin DRUG

Moxifloxacin is included as a positive control to demonstrate the assay sensitivity based on the expected increased QTc response.

Sapropterin Dihydrochloride placebo and Moxifloxacin

Moxifloxacin placebo DRUG

Moxifloxacin placebo tablet

Sapropterin Dihydrochloride 100mg/kg and placebo Moxifloxacin; Sapropterin Dihydrochloride 20mg/kg and placebo Moxifloxacin; Sapropterin Dihydrocholide placebo and Moxifloxacin placebo

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Willing and able to provide written, signed informed consent, after the nature of the study has been explained, and prior to any research-related procedures.
• Sexually active subjects must be willing to use an acceptable method of contraception (double barrier) while participating in the study from screening onwards and for at least 4 weeks after the last dose of study drug.
• Females of childbearing potential must have a negative pregnancy test at Screening and be willing to have additional pregnancy tests during the study. Females considered not of childbearing potential include those who have been in menopause at least 2 years, or had tubal ligation at least 1 year prior to Screening, or who have had total hysterectomy.
• Willing and able to comply with all study procedures.
• Healthy male and female subjects between 18 and 50 years of age, inclusive.
• Body mass index (BMI) of ≥ 18 to \< 30 kg/m2 inclusive.
• Blood pressure in the range of 90 140 mmHg systolic and 50 90 mmHg diastolic at Screening and Check-in. Blood pressures can be repeated up to three times within 10 minutes of initial assessment while remaining in the supine position.
• No clinically significant 12-lead ECG abnormalities; and a QTc interval \< 450 ms for males and \< 470 ms for females and a resting heart rate between 45 90 beats/minute at Screening and Check-in.

You may not qualify if:

• Has known hypersensitivity to sapropterin or its excipients, or moxifloxacin.
• Pregnant or breastfeeding at Screening or planning to become pregnant (self or partner) at any time during the study.
• Use of any investigational product or investigational medical device within 30 days prior to Screening, or requirement for any investigational agent prior to completion of all scheduled study assessments.
• Concurrent disease or condition that would interfere with study participation or safety or any condition that, in the view of the PI, places the subject at high risk of poor treatment compliance or of not completing the study.
• History of clinically significant cardiac condition, eg, myocardial ischemia (including angina) or infarction, congestive heart failure, left ventricular hypertrophy, or cardiomyopathy.
• Screening, Check-in, or Baseline ECG shows any of the following:
• Sinus arrhythmia with unacceptable rate variation as judged by the Investigator.
• Excessive heart rate variation at rest, in the Investigator's opinion.
• PR interval \> 210 ms.
• QRS interval \> 110 ms.
• QRS and/or T wave that the Investigator judges to be unfavorable for consistently accurate QT measurements (eg, indistinct QRS onset, low amplitude T wave, inverted or terminally inverted T wave, merged T and U waves, or indistinct T offset, prominent U-wave that affects QT measurement).
• Neuromuscular artifact that cannot be readily eliminated.
• Documented history of arrhythmias (eg, ventricular arrhythmias and atrial fibrillation).
• Clinically significant electrolyte disturbances at Screening or Check-in (eg, hypo or hyperkalemia or hypocalcemia) or any condition that could lead to electrolyte disturbances (eg, eating disorder), in the Investigator's opinion.
• History of palpitations, seizures, unexplained syncopal episodes, or symptomatic arrhythmias.

Sponsors & Collaborators

• BioMarin Pharmaceutical: lead

Study Sites (1)

PRACS Institute, Ltd.

Fargo, North Dakota, 58104, United States

Location

MeSH Terms

Conditions

Phenylketonurias

Interventions

sapropterin; Moxifloxacin

Condition Hierarchy (Ancestors)

Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Amino Acid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Don Nwose, MD

  BioMarin Pharmaceutical

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 10, 2008
• First Posted: November 13, 2008
• Study Start: October 1, 2008
• Primary Completion: January 1, 2009
• Study Completion: October 1, 2009
• Last Updated: July 23, 2021

Record last verified: 2014-08

Locations

US (1)