Drug-drug Interaction Study

• Sponsor: Amicus Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01380743
• Collaborator: (none)
• Enrollment: 25
• Locations: 15
• Arms: 4
• Actual Duration (Months): 14.2
• Patients Per Site: 1.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Pompe Disease	Drug: duvoglustat; Drug: rhGAA	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Multi-Center, International Study to Investigate Drug-Drug Interactions Between AT2220 and Alglucosidase Alfa in Patients With Pompe Disease
• Actual Study Start Date: Oct 31, 2011
• Actual Primary Completion Date: Jan 4, 2013
• Actual Study Completion Date: Jan 4, 2013

Arms and Interventions

Arm	Intervention/Treatment
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.	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
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.	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
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.	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
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.	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

Outcome Measures

Primary Outcome Measures

1. Number Of Participants Who Experienced Severe Treatment-Emergent Adverse Events (TEAEs) [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.

2. Pharmacokinetics (PK): Maximum Measured Plasma Concentration (Cmax) Of Total GAA And rhGAA Protein In Plasma In Participants With Pompe Disease [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.

3. PK: Time To The Maximum Plasma Concentration (Tmax) Of Total GAA And rhGAA Protein In Plasma In Participants With Pompe Disease [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.

4. PK: Elimination Half-life (T1/2) Of Total GAA And rhGAA Protein In Plasma In Participants With Pompe Disease [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.

5. 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 [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.

6. PK: AUC From Time 0 Extrapolated To Infinity (AUCinf) Of Total GAA And rhGAA Protein In Plasma In Participants With Pompe Disease [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.

Secondary Outcome Measures

1. Total GAA Activity In Skeletal Muscle [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.

2. Duvoglustat Concentration In Skeletal Muscle [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.

Eligibility Criteria

Criteria

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

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Phoenix	Arizona	United States	85018
2		Scottsdale	Arizona	United States	85258
3		Orange	California	United States	92868
4		Gainesville	Florida	United States	32610
5		Decatur	Georgia	United States	30033
6		Kansas City	Kansas	United States	66160
7		Great Falls	Montana	United States	59405
8		Durham	North Carolina	United States	27710
9		Cincinnati	Ohio	United States	45299
10		Portland	Oregon	United States	97239
11		Springfield	Virginia	United States	22152
12		Hamilton	Ontario	Canada	L8N 3Z5
13		Paris		France	75013
14		London	Queen Square	United Kingdom	WC1N 3BG
15		Salford		United Kingdom	M68 HD

Sponsors and Collaborators

• Amicus Therapeutics

Investigators

• Study Director: Medical Monitor, Study Sponsor (Amicus Therapeutics, Inc)

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Amicus Therapeutics
• ClinicalTrials.gov Identifier: NCT01380743
• Other Study ID Numbers: AT2220-010
• First Posted: Jun 27, 2011
• Last Update Posted: Oct 2, 2018
• Last Verified: Sep 1, 2018

• Keywords provided by Amicus Therapeutics: Amicus Therapeutics; duvoglustat; AT2220; alpha-glucosidase; alglucosidase alfa
• Additional relevant MeSH terms: Glycogen Storage Disease Type II; 1-Deoxynojirimycin

Study Results

Participant Flow

Pre-assignment Detail	A total of 27 participants were enrolled; 25 participants completed the study. Two participants were discontinued from the study prior to assignment to a cohort: 1 participant voluntarily withdrew before receiving study drug; 1 participant was screened twice and enrolled once, and was counted twice under the total number enrolled.

Arm/Group Title	Cohort 1, Duvoglustat 50 mg + rhGAA	Cohort 2, Duvoglustat 100 mg + rhGAA	Cohort 3, Duvoglustat 250 mg + rhGAA	Cohort 4, Duvoglustat 600 mg + rhGAA
Arm/Group Description	During Period 1, participants received a single intravenous infusion of rhGAA. During Period 2, each participant received a single 50 mg oral dose of duvoglustat 1 hour prior to 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 100 mg oral dose of duvoglustat 1 hour prior to 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 250 mg oral dose of duvoglustat 1 hour prior to 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 600 mg oral dose of duvoglustat 1 hour prior to initiation of a single rhGAA infusion.
Period Title: Overall Study
STARTED	6	6	6	7
Received at Least 1 Dose of Study Drug	6	6	6	7
COMPLETED	6	6	6	7
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Cohort 1, Duvoglustat 50 mg + rhGAA	Cohort 2, Duvoglustat 100 mg + rhGAA	Cohort 3, Duvoglustat 250 mg + rhGAA	Cohort 4, Duvoglustat 600 mg + rhGAA	Total
Arm/Group Description	During Period 1, participants received a single intravenous infusion of rhGAA. During Period 2, each participant received a single 50 mg oral dose of duvoglustat 1 hour prior to 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 100 mg oral dose of duvoglustat 1 hour prior to 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 250 mg oral dose of duvoglustat 1 hour prior to 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 600 mg oral dose of duvoglustat 1 hour prior to initiation of a single rhGAA infusion.	Total of all reporting groups
Overall Participants	6	6	6	7	25
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.7 (5.35)	52.8 (5.71)	50.0 (12.90)	40.0 (6.61)	47.3 (9.13)
Sex: Female, Male (Count of Participants)
Female	3 50%	3 50%	4 66.7%	2 28.6%	12 48%
Male	3 50%	3 50%	2 33.3%	5 71.4%	13 52%

Outcome Measures

1. Primary Outcome

Title	Number Of Participants Who Experienced Severe Treatment-Emergent Adverse Events (TEAEs)
Description	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.
Time Frame	Day 1 after dosing up to Day 60

Outcome Measure Data

Analysis Population Description

The Safety Population included all participants who were enrolled and received at least 1 dose of rhGAA or duvoglustat.

Arm/Group Title	Cohort 1, Duvoglustat 50 mg + rhGAA	Cohort 2, Duvoglustat 100 mg + rhGAA	Cohort 3, Duvoglustat 250 mg + rhGAA	Cohort 4, Duvoglustat 600 mg + rhGAA
Arm/Group Description	During Period 1, participants received a single intravenous infusion of rhGAA. During Period 2, each participant received a single 50 mg oral dose of duvoglustat 1 hour prior to 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 100 mg oral dose of duvoglustat 1 hour prior to 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 250 mg oral dose of duvoglustat 1 hour prior to 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 600 mg oral dose of duvoglustat 1 hour prior to initiation of a single rhGAA infusion.
Measure Participants	6	6	6	7
Count of Participants [Participants]	0 0%	0 0%	0 0%	1 14.3%

2. Primary Outcome

Title	Pharmacokinetics (PK): Maximum Measured Plasma Concentration (Cmax) Of Total GAA And rhGAA Protein In Plasma In Participants With Pompe Disease
Description	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.
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

Outcome Measure Data

Analysis Population Description

The Per Protocol population included all participants who successfully completed both periods.

Arm/Group Title	Cohort 1, Duvoglustat 50 mg + rhGAA	Cohort 2, Duvoglustat 100 mg + rhGAA	Cohort 3, Duvoglustat 250 mg + rhGAA	Cohort 4, Duvoglustat 600 mg + rhGAA
Arm/Group Description	During Period 1, participants received a single intravenous infusion of rhGAA. During Period 2, each participant received a single 50 mg oral dose of duvoglustat 1 hour prior to 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 100 mg oral dose of duvoglustat 1 hour prior to 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 250 mg oral dose of duvoglustat 1 hour prior to 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 600 mg oral dose of duvoglustat 1 hour prior to initiation of a single rhGAA infusion.
Measure Participants	6	6	6	7
Total GAA, Period 1	17269 (25.6)	22785 (18.1)	18986 (19.5)	18980 (34.6)
Total GAA, Period 2	20539 (21.2)	28607 (14.1)	22651 (9.0)	22989 (36.4)
rhGAA, Period 1	328660 (40.7)	399622 (33.2)	405543 (11.4)	507294 (47.9)
rhGAA, Period 2	385475 (35.7)	430738 (39.5)	438795 (7.0)	637571 (48.8)

3. Primary Outcome

Title	PK: Time To The Maximum Plasma Concentration (Tmax) Of Total GAA And rhGAA Protein In Plasma In Participants With Pompe Disease
Description	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.
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

Outcome Measure Data

Analysis Population Description

The Per Protocol population included all participants who successfully completed both periods.

Arm/Group Title	Cohort 1, Duvoglustat 50 mg + rhGAA	Cohort 2, Duvoglustat 100 mg + rhGAA	Cohort 3, Duvoglustat 250 mg + rhGAA	Cohort 4, Duvoglustat 600 mg + rhGAA
Arm/Group Description	During Period 1, participants received a single intravenous infusion of rhGAA. During Period 2, each participant received a single 50 mg oral dose of duvoglustat 1 hour prior to 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 100 mg oral dose of duvoglustat 1 hour prior to 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 250 mg oral dose of duvoglustat 1 hour prior to 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 600 mg oral dose of duvoglustat 1 hour prior to initiation of a single rhGAA infusion.
Measure Participants	6	6	6	7
Total GAA, Period 1	4.74	4.00	4.00	4.00
Total GAA, Period 2	4.51	4.00	4.00	4.00
rhGAA, Period 1	4.98	4.01	4.01	4.00
rhGAA, Period 2	4.98	4.00	4.50	4.00

4. Primary Outcome

Title	PK: Elimination Half-life (T1/2) Of Total GAA And rhGAA Protein In Plasma In Participants With Pompe Disease
Description	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.
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

Outcome Measure Data

Analysis Population Description

The Per Protocol population included all participants who successfully completed both periods.

Arm/Group Title	Cohort 1, Duvoglustat 50 mg + rhGAA	Cohort 2, Duvoglustat 100 mg + rhGAA	Cohort 3, Duvoglustat 250 mg + rhGAA	Cohort 4, Duvoglustat 600 mg + rhGAA
Arm/Group Description	During Period 1, participants received a single intravenous infusion of rhGAA. During Period 2, each participant received a single 50 mg oral dose of duvoglustat 1 hour prior to 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 100 mg oral dose of duvoglustat 1 hour prior to 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 250 mg oral dose of duvoglustat 1 hour prior to 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 600 mg oral dose of duvoglustat 1 hour prior to initiation of a single rhGAA infusion.
Measure Participants	6	6	6	7
Total GAA, Period 1	3.81 (12.7)	3.82 (17.7)	3.56 (13.7)	3.70 (19.9)
Total GAA, Period 2	4.42 (16.9)	4.77 (14.2)	5.36 (26.0)	6.33 (22.8)
rhGAA, Period 1	3.31 (39.6)	2.33 (59.5)	1.89 (46.9)	2.33 (54.3)
rhGAA, Period 2	4.43 (38.1)	5.76 (55.6)	4.23 (52.3)	5.71 (45.6)

5. Primary Outcome

Title	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
Description	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.
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

Outcome Measure Data

Analysis Population Description

The Per Protocol population included all participants who successfully completed both periods.

Arm/Group Title	Cohort 1, Duvoglustat 50 mg + rhGAA	Cohort 2, Duvoglustat 100 mg + rhGAA	Cohort 3, Duvoglustat 250 mg + rhGAA	Cohort 4, Duvoglustat 600 mg + rhGAA
Arm/Group Description	During Period 1, participants received a single intravenous infusion of rhGAA. During Period 2, each participant received a single 50 mg oral dose of duvoglustat 1 hour prior to 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 100 mg oral dose of duvoglustat 1 hour prior to 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 250 mg oral dose of duvoglustat 1 hour prior to 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 600 mg oral dose of duvoglustat 1 hour prior to initiation of a single rhGAA infusion.
Measure Participants	6	6	6	7
Total GAA, Period 1	108578 (24.1)	141515 (27.9)	107489 (21.7)	118483 (43.1)
Total GAA, Period 2	159994 (18.1)	226198 (25.4)	201044 (8.3)	228413 (38.4)
rhGAA, Period 1	1891079 (35.6)	2227356 (62.8)	2248866 (24.7)	2326168 (55.5)
rhGAA, Period 2	2914884 (49.2)	3466263 (59.5)	3618948 (26.4)	5293233 (68.2)

6. Primary Outcome

Title	PK: AUC From Time 0 Extrapolated To Infinity (AUCinf) Of Total GAA And rhGAA Protein In Plasma In Participants With Pompe Disease
Description	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.
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

Outcome Measure Data

Analysis Population Description

The Per Protocol population included all participants who successfully completed both periods.

Arm/Group Title	Cohort 1, Duvoglustat 50 mg + rhGAA	Cohort 2, Duvoglustat 100 mg + rhGAA	Cohort 3, Duvoglustat 250 mg + rhGAA	Cohort 4, Duvoglustat 600 mg + rhGAA
Arm/Group Description	During Period 1, participants received a single intravenous infusion of rhGAA. During Period 2, each participant received a single 50 mg oral dose of duvoglustat 1 hour prior to 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 100 mg oral dose of duvoglustat 1 hour prior to 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 250 mg oral dose of duvoglustat 1 hour prior to 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 600 mg oral dose of duvoglustat 1 hour prior to initiation of a single rhGAA infusion.
Measure Participants	6	6	6	7
Total GAA, Period 1	110388 (24.5)	144056 (28.6)	108862 (22.1)	120604 (44.3)
Total GAA, Period 2	165983 (19.1)	237613 (27.6)	215276 (9.5)	254074 (42.0)
rhGAA, Period 1	2274897 (35.5)	2232099 (54.0)	2468980 (26.4)	2452414 (70.5)
rhGAA, Period 2	3603068 (37.4)	3427088 (71.1)	4602726 (31.3)	6691323 (46.6)

7. Secondary Outcome

Title	Total GAA Activity In Skeletal Muscle
Description	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.
Time Frame	Day 3 or Day 7

Outcome Measure Data

Analysis Population Description

The Per Protocol population included all participants who successfully completed both periods.

Arm/Group Title	Cohort 1, Duvoglustat 50 mg + rhGAA	Cohort 2, Duvoglustat 100 mg + rhGAA	Cohort 3, Duvoglustat 250 mg + rhGAA	Cohort 4, Duvoglustat 600 mg + rhGAA
Arm/Group Description	During Period 1, participants received a single intravenous infusion of rhGAA. During Period 2, each participant received a single 50 mg oral dose of duvoglustat 1 hour prior to 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 100 mg oral dose of duvoglustat 1 hour prior to 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 250 mg oral dose of duvoglustat 1 hour prior to 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 600 mg oral dose of duvoglustat 1 hour prior to initiation of a single rhGAA infusion.
Measure Participants	6	6	6	6
Total GAA, Period 1, Day 3	1409 (130)	1926 (67)	2622 (14)	1887 (47)
Total GAA, Period 2, Day 3	1952 (8)	2320 (77)	2746 (35)	2710 (37)
Total GAA, Period 1, Day 7	1216 (24)	861 (16)	NA (91)	916 (25)
Total GAA, Period 2, Day 7	1197 (18)	1064 (39)	1690 (22)	1085 (14)

8. Secondary Outcome

Title	Duvoglustat Concentration In Skeletal Muscle
Description	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.
Time Frame	Day 3 or Day 7

Outcome Measure Data

Analysis Population Description

The Per Protocol population included all participants who successfully completed both periods.

Arm/Group Title	Cohort 1, Duvoglustat 50 mg + rhGAA	Cohort 2, Duvoglustat 100 mg + rhGAA	Cohort 3, Duvoglustat 250 mg + rhGAA	Cohort 4, Duvoglustat 600 mg + rhGAA
Arm/Group Description	During Period 1, participants received a single intravenous infusion of rhGAA. During Period 2, each participant received a single 50 mg oral dose of duvoglustat 1 hour prior to 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 100 mg oral dose of duvoglustat 1 hour prior to 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 250 mg oral dose of duvoglustat 1 hour prior to 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 600 mg oral dose of duvoglustat 1 hour prior to initiation of a single rhGAA infusion.
Measure Participants	6	6	6	7
Duvoglustat Concentration, Day 3	0 (NA)	5.9 (173)	38.8 (87)	83.6 (NA)
Duvoglustat Concentration, Day 7	8.7 (68)	0 (NA)	28.0 (0.5)	54.1 (25)

Adverse Events

Time Frame	Day 1 after dosing up to Day 60
Arm/Group Title	Cohort 1, Duvoglustat 50 mg + rhGAA		Cohort 2, Duvoglustat 100 mg + rhGAA		Cohort 3, Duvoglustat 250 mg + rhGAA		Cohort 4, Duvoglustat 600 mg + rhGAA
Arm/Group Description	During Period 1, participants received a single intravenous infusion of rhGAA. During Period 2, each participant received a single 50 mg oral dose of duvoglustat 1 hour prior to 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 100 mg oral dose of duvoglustat 1 hour prior to 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 250 mg oral dose of duvoglustat 1 hour prior to 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 600 mg oral dose of duvoglustat 1 hour prior to initiation of a single rhGAA infusion.
All Cause Mortality
	Cohort 1, Duvoglustat 50 mg + rhGAA		Cohort 2, Duvoglustat 100 mg + rhGAA		Cohort 3, Duvoglustat 250 mg + rhGAA		Cohort 4, Duvoglustat 600 mg + rhGAA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Cohort 1, Duvoglustat 50 mg + rhGAA		Cohort 2, Duvoglustat 100 mg + rhGAA		Cohort 3, Duvoglustat 250 mg + rhGAA		Cohort 4, Duvoglustat 600 mg + rhGAA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/7 (0%)
Investigations
Electrocardiogram QT prolonged	0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/7 (0%)
Other (Not Including Serious) Adverse Events
	Cohort 1, Duvoglustat 50 mg + rhGAA		Cohort 2, Duvoglustat 100 mg + rhGAA		Cohort 3, Duvoglustat 250 mg + rhGAA		Cohort 4, Duvoglustat 600 mg + rhGAA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/6 (83.3%)		3/6 (50%)		4/6 (66.7%)		4/7 (57.1%)
Cardiac disorders
Palpitations	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/7 (14.3%)
Ear and labyrinth disorders
Vertigo	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/7 (0%)
Gastrointestinal disorders
Dental caries	1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/7 (0%)
Constipation	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/7 (14.3%)
Oral pain	1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/7 (0%)
General disorders
Oedema peripheral	0/6 (0%)		0/6 (0%)		2/6 (33.3%)		0/7 (0%)
Fatigue	1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/7 (0%)
Nodule	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		1/7 (14.3%)
Infections and infestations
Oral candidiasis	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/7 (0%)
Otitis media	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/7 (0%)
Respiratory tract infection	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/7 (14.3%)
Sinusitis	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/7 (0%)
Tooth abscess	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/7 (0%)
Upper respiratory tract infection	1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/7 (0%)
Urinary tract infection	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/7 (0%)
Injury, poisoning and procedural complications
Post procedural haematoma	0/6 (0%)		1/6 (16.7%)		1/6 (16.7%)		0/7 (0%)
Procedural pain	0/6 (0%)		2/6 (33.3%)		4/6 (66.7%)		0/7 (0%)
Back injury	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/7 (0%)
Fall	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		1/7 (14.3%)
Muscle strain	0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/7 (0%)
Procedural complication	0/6 (0%)		0/6 (0%)		2/6 (33.3%)		0/7 (0%)
Tooth fracture	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/7 (0%)
Investigations
Weight increased	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/7 (14.3%)
Musculoskeletal and connective tissue disorders
Pain in extremity	2/6 (33.3%)		0/6 (0%)		0/6 (0%)		1/7 (14.3%)
Back pain	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		1/7 (14.3%)
Neck pain	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/7 (14.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Melanocytic naevus	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/7 (14.3%)
Ovarian neoplasm	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/7 (14.3%)
Nervous system disorders
Headache	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/7 (0%)
Hyperaesthesia	1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/7 (0%)
Somnolence	1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/7 (0%)
Renal and urinary disorders
Dysuria	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/7 (0%)
Nephrolithiasis	1/6 (16.7%)		1/6 (16.7%)		0/6 (0%)		0/7 (0%)
Pollakiuria	1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/7 (0%)
Urinary incontinence	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/7 (14.3%)
Reproductive system and breast disorders
Uterine enlargement	0/3 (0%)		0/3 (0%)		0/4 (0%)		1/2 (50%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/7 (14.3%)
Sinus congestion	1/6 (16.7%)		0/6 (0%)		0/6 (0%)		0/7 (0%)
Skin and subcutaneous tissue disorders
Dermatitis contact	0/6 (0%)		1/6 (16.7%)		0/6 (0%)		0/7 (0%)
Erythema	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/7 (0%)
Hyperhidrosis	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/7 (14.3%)
Scar pain	0/6 (0%)		0/6 (0%)		0/6 (0%)		1/7 (14.3%)
Vascular disorders
Haematoma	0/6 (0%)		0/6 (0%)		1/6 (16.7%)		0/7 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The investigator can only publish the results from this trial provided they supply the sponsor (or authorized entity) a copy of any proposed publication for review. If requested, the investigator will remove information deemed confidential or proprietary by the sponsor and will withhold publication for an additional period of time to allow the sponsor to take appropriate measures to establish and preserve its proprietary rights.