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Drug-drug Interaction Study

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ClinicalTrials.gov Identifier: NCT01380743
Recruitment Status : Completed
First Posted : June 27, 2011
Results First Posted : August 17, 2018
Last Update Posted : October 2, 2018
Sponsor:
Information provided by (Responsible Party):
Amicus Therapeutics

Tracking Information
First Submitted Date  ICMJE June 23, 2011
First Posted Date  ICMJE June 27, 2011
Results First Submitted Date  ICMJE July 23, 2018
Results First Posted Date  ICMJE August 17, 2018
Last Update Posted Date October 2, 2018
Actual Study Start Date  ICMJE October 31, 2011
Actual Primary Completion Date January 4, 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 23, 2018)
  • Number Of Participants Who Experienced Severe Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: Day 1 after dosing up to Day 60 ]
    A TEAE was defined as an adverse event (AE) with an onset date on or after the first dose of investigational medicinal product (IMP), or an AE with an onset date before the first dose date that worsened in severity after the first dose date. A severe AE was defined as an AE that was incapacitating and required medical intervention. The number of participants who experienced 1 or more severe TEAEs after dosing on Day 1 up to Day 60 (includes end of study follow-up period) is reported. A summary of serious and all other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module.
  • Pharmacokinetics (PK): Maximum Measured Plasma Concentration (Cmax) Of Total GAA And rhGAA Protein In Plasma In Participants With Pompe Disease [ Time Frame: Predose, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, and 24 hours, and 3 or 7 days postdose during Periods 1 and 2, and 24 to 30 days postdose during Period 2 ]
    The Cmax of total GAA and rhGAA protein in plasma was measured after a single rhGAA intravenous infusion and after pre-administration of single ascending oral doses of duvoglustat. During Treatment Period 1, participants received a single intravenous infusion of rhGAA. During Treatment Period 2, participants received a single oral dose of duvoglustat 1 hour before initiation of a single rhGAA intravenous infusion. PK samples were taken at time points Predose, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, and 24 hours, and 3 or 7 days postdose during Periods 1 and 2, and 24 to 30 days postdose during Period 2.
  • PK: Time To The Maximum Plasma Concentration (Tmax) Of Total GAA And rhGAA Protein In Plasma In Participants With Pompe Disease [ Time Frame: Predose, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, and 24 hours, and 3 or 7 days postdose during Periods 1 and 2, and 24 to 30 days postdose during Period 2 ]
    The Tmax of total GAA and rhGAA protein in plasma was measured after a single rhGAA intravenous infusion and after pre-administration of single ascending oral doses of duvoglustat. During Treatment Period 1, participants received a single intravenous infusion of rhGAA. During Treatment Period 2, participants received a single oral dose of duvoglustat 1 hour before initiation of a single rhGAA intravenous infusion. PK samples were taken at time points Predose, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, and 24 hours, and 3 or 7 days postdose during Periods 1 and 2, and 24 to 30 days postdose during Period 2.
  • PK: Elimination Half-life (T1/2) Of Total GAA And rhGAA Protein In Plasma In Participants With Pompe Disease [ Time Frame: Predose, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, and 24 hours, and 3 or 7 days postdose during Periods 1 and 2, and 24 to 30 days postdose during Period 2 ]
    The T1/2 of total GAA and rhGAA protein in plasma was measured after a single rhGAA intravenous infusion and after pre-administration of single ascending oral doses of duvoglustat. During Treatment Period 1, participants received a single intravenous infusion of rhGAA. During Treatment Period 2, participants received a single oral dose of duvoglustat 1 hour before initiation of a single rhGAA intravenous infusion. PK samples were taken at time points Predose, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, and 24 hours, and 3 or 7 days postdose during Periods 1 and 2, and 24 to 30 days postdose during Period 2. Values presented are arithmetic mean (percent coefficient of variation, [CV%]). The number of participants analyzed for some cohorts are reduced because the terminal phase of the concentration profile for these participants was not estimable.
  • PK: Area Under The Plasma Concentration Versus Time Curve From Time 0 To The Time Of The Last Measurable Concentration (AUC0-t) Of Total GAA And rhGAA Protein In Plasma In Participants With Pompe Disease [ Time Frame: Predose, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, and 24 hours, and 3 or 7 days postdose during Periods 1 and 2, and 24 to 30 days postdose during Period 2 ]
    The AUC0-t of total GAA and rhGAA protein in plasma was measured after a single rhGAA intravenous infusion and after pre-administration of single ascending oral doses of duvoglustat. During Treatment Period 1, participants received a single intravenous infusion of rhGAA. During Treatment Period 2, participants received a single oral dose of duvoglustat 1 hour before initiation of a single rhGAA intravenous infusion. PK samples were taken at time points Predose, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, and 24 hours, and 3 or 7 days postdose during Periods 1 and 2, and 24 to 30 days postdose during Period 2.
  • PK: AUC From Time 0 Extrapolated To Infinity (AUCinf) Of Total GAA And rhGAA Protein In Plasma In Participants With Pompe Disease [ Time Frame: Predose, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, and 24 hours, and 3 or 7 days postdose during Periods 1 and 2, and 24 to 30 days postdose during Period 2 ]
    The AUCinf of total GAA and rhGAA protein in plasma was measured after a single rhGAA intravenous infusion and after pre-administration of single ascending oral doses of duvoglustat. During Treatment Period 1, participants received a single intravenous infusion of rhGAA. During Treatment Period 2, participants received a single oral dose of duvoglustat 1 hour before initiation of a single rhGAA intravenous infusion. PK samples were taken at time points Predose, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, and 24 hours, and 3 or 7 days postdose during Periods 1 and 2, and 24 to 30 days postdose during Period 2. The number of participants analyzed for some cohorts are reduced because the terminal phase of the concentration profile for these participants was not estimable.
Original Primary Outcome Measures  ICMJE
 (submitted: June 23, 2011)
  • Safety [ Time Frame: 3 months ]
    adverse events (AE) (including infusion reactions), clinical laboratory tests (hematology, urinalysis, serum chemistry including creatine kinase, LDH, alkaline phosphatase, ALT and AST), urinary tetrasaccharides (Hex4), 12-lead ECGs, physical examinations, vital signs, and muscle strength tests
  • Pharmacokinetics [ Time Frame: 1 month ]
    GAA plasma pharmacokinetic parameter values by measurement of enzyme activity and protein levels after an alglucosidase alfa infusion alone and after pre-administration of AT2220
Change History Complete list of historical versions of study NCT01380743 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 23, 2018)
  • Total GAA Activity In Skeletal Muscle [ Time Frame: Day 3 or Day 7 ]
    The total GAA activity in skeletal muscle was measured after a single intravenous administration of rhGAA alone and after pre-administration of single ascending oral doses of duvoglustat. Participants were assessed using skeletal muscle biopsies at either Day 3 or Day 7 during Treatment Periods 1 and 2.
  • Duvoglustat Concentration In Skeletal Muscle [ Time Frame: Day 3 or Day 7 ]
    The concentration of duvoglustat in skeletal muscle tissue homogenate was measured after pre-administration of single ascending oral doses of duvoglustat during Treatment Period 2. Participants had skeletal muscle biopsies at either Day 3 or Day 7 during Treatment Period 2. Three participants were excluded from this analysis due to the following reasons: treatment sequence was inadvertently switched due to study site error, follow-up biopsy sample could not be conclusively identified, or muscle biopsies were mislabeled at the clinical site. Values presented are arithmetic mean (percent coefficient of variation, [CV%]) because of the prevalence of participants with values below the limit of quantification. Concentrations below the limit of quantification were treated as zero.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 23, 2011)
GAA activity [ Time Frame: 1 month ]
The change in GAA activity in muscle after alglucosidase alfa alone compared to alglucosidase alfa in combination with AT2220 7 days after dosing by measuring GAA activity and protein levels
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Drug-drug Interaction Study
Official Title  ICMJE An Open-Label, Multi-Center, International Study to Investigate Drug-Drug Interactions Between AT2220 and Alglucosidase Alfa in Patients With Pompe Disease
Brief Summary This study evaluates drug-drug interactions between AT2220 (duvoglustat) and recombinant human alpha-glucosidase (rhGAA, also known as alglucosidase alfa) in participants with Pompe Disease.
Detailed Description This was a multi-center, international, open-label, two-period, fixed-sequence crossover study to evaluate the safety and pharmacokinetic effect of single ascending doses of duvoglustat on rhGAA administered 1 hour before initiation of a single rhGAA infusion. During Period 1, participants received a single intravenous infusion of rhGAA. During Period 2, each participant received a single oral dose of duvoglustat 1 hour prior to initiation of a single rhGAA infusion.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Pompe Disease
Intervention  ICMJE
  • Drug: duvoglustat
    Single oral dose
    Other Names:
    • AT2220
    • duvoglustat hydrochloride
  • Drug: rhGAA
    Single intravenous infusion
    Other Names:
    • alglucosidase alfa
    • recombinant human alpha-glucosidase
    • Myozyme
    • Lumizyme
Study Arms  ICMJE
  • Experimental: Cohort 1, Duvoglustat 50 mg + rhGAA

    During Period 1, participants received a single intravenous infusion of rhGAA. During Period 2, each participant received a single 50 milligram (mg) oral dose of duvoglustat 1 hour prior to initiation of a single rhGAA infusion.

    Participants were on a stable regimen and dose of rhGAA for at least 3 months before screening.

    Interventions:
    • Drug: duvoglustat
    • Drug: rhGAA
  • Experimental: Cohort 2, Duvoglustat 100 mg + rhGAA

    During Period 1, participants received a single intravenous infusion of rhGAA. During Period 2, each participant received a single 100 mg oral dose of duvoglustat 1 hour prior to initiation of a single rhGAA infusion.

    Participants were on a stable regimen and dose of rhGAA for at least 3 months before screening.

    Interventions:
    • Drug: duvoglustat
    • Drug: rhGAA
  • Experimental: Cohort 3, Duvoglustat 250 mg + rhGAA

    During Period 1, participants received a single intravenous infusion of rhGAA. During Period 2, each participant received a single 250 mg oral dose of duvoglustat 1 hour prior to initiation of a single rhGAA infusion.

    Participants were on a stable regimen and dose of rhGAA for at least 3 months before screening.

    Interventions:
    • Drug: duvoglustat
    • Drug: rhGAA
  • Experimental: Cohort 4, Duvoglustat 600 mg + rhGAA

    During Period 1, participants received a single intravenous infusion of rhGAA. During Period 2, each participant received a single 600 mg oral dose of duvoglustat 1 hour prior to initiation of a single rhGAA infusion.

    Participants were on a stable regimen and dose of rhGAA for at least 3 months before screening.

    Interventions:
    • Drug: duvoglustat
    • Drug: rhGAA
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 4, 2013)
25
Original Estimated Enrollment  ICMJE
 (submitted: June 23, 2011)
16
Actual Study Completion Date  ICMJE January 4, 2013
Actual Primary Completion Date January 4, 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Male or female, diagnosed with Pompe disease and between 18 and 65 years of age, inclusive
  • Participant has been on a stable regimen and dose of rhGAA for at least 3 months before screening (stable regimen defined as currently receiving rhGAA every 2 weeks and stable dose defined as not varying by more than ± 10%)
  • Participant has an estimated glomerular filtration rate (eGFR) ≥ 50 mL/min at Screening; eGFR to be estimated using the 4-parameter Modification of Diet in Renal Disease (MDRD) equation:

eGFR (mL/min/1.73 m^2) = 175 x (Scr)^(-1.154) x (Age)^(-0.203) x (0.742 if female) x (1.212 if African-American)

  • Male and female participants of childbearing potential agree to use medically accepted methods of contraception during the study and for 30 days after study completion
  • Participant is willing and able to provide written informed consent and is able to comply with all study procedures

Exclusion Criteria:

  • Participant has had a documented transient ischemic attack, ischemic stroke, unstable angina, or myocardial infarction within the 3 months before Screening
  • Participant has clinically significant unstable cardiac disease (for example, cardiac disease requiring active management, such as symptomatic arrhythmia, unstable angina, or New York Heart Association class III or IV congestive heart failure)
  • Participant requiring mechanical ventilation or is confined to a wheelchair
  • Participant has a history of allergy or sensitivity to study drug (including excipients) or other iminosugars (for example, miglustat, miglitol)
  • Participant is pregnant or breastfeeding
  • Participant tests positive for hepatitis B surface antigen or hepatitis C antibody
  • Participant has received any investigational/experimental drug or device within 30 days of Screening
  • Participant has any intercurrent illness or condition that may preclude the participant from fulfilling the protocol requirements or suggests to the investigator that the potential participant may have an unacceptable risk by participating in this study
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   France,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01380743
Other Study ID Numbers  ICMJE AT2220-010
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Amicus Therapeutics
Study Sponsor  ICMJE Amicus Therapeutics
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Monitor Study Sponsor (Amicus Therapeutics, Inc)
PRS Account Amicus Therapeutics
Verification Date September 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP