Study to Evaluate the Safety of AT2220 (Duvoglustat) in Pompe Disease

• Sponsor: Amicus Therapeutics (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00688597
• Collaborator: (none)
• Enrollment: 3
• Location: 1
• Arms: 3
• Actual Duration (Months): 12.2
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The main purpose of this study was to determine the safety and tolerability of 3 different doses of duvoglustat (AT2220) in participants affected by Pompe disease. The study also evaluated the effects of duvoglustat on functional parameters in Pompe disease.

Condition or Disease	Intervention/Treatment	Phase
Pompe Disease	Drug: Duvoglustat	Phase 2

Detailed Description

This was a Phase 2, open-label study in participants with Pompe disease, a lysosomal storage disorder. Duvoglustat is designed to act as a pharmacological chaperone of alpha-glucosidase, in order to restore enzyme activity. This study consisted of a 28-day screening period, an 11-week treatment period, and a 1-week follow-up period. Three dosing regimens of oral duvoglustat were to be evaluated (Cohort 1: 2.5 g daily for 3 days, followed by no study drug for 4 days; Cohort 2: 5 g daily for 3 days, followed by no study drug for 4 days; Cohort 3: 5 g daily for 7 days, followed by no study drug for 7 days).

Participants meeting all eligibility criteria underwent physical examination, electrocardiogram, spirometry, muscular strength test, functional muscle test, 6-minute walk test (when appropriate), laboratory tests, magnetic resonance imaging, and muscle (needle) biopsy. Quality of life was assessed via the 36-Item Short Form Health Survey questionnaire. Functional ability and level of handicap was assessed by Rotterdam handicap scale.

Study Design

• Study Type: Interventional
• Actual Enrollment: 3 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Multicenter Study to Evaluate the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of Three Dosing Regimens of Oral AT2220 in Patients With Pompe Disease
• Actual Study Start Date: Dec 8, 2008
• Actual Primary Completion Date: Dec 14, 2009
• Actual Study Completion Date: Dec 14, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1 Regimen 1: Low-dose duvoglustat (2.5 grams [g]) once a day (QD) for 3 days, followed by no drug for 4 days, for 11 weeks.	Drug: Duvoglustat; Powder in a bottle for dissolution in water for oral administration; Other Names: Duvoglustat hydrochloride 1-Deoxynojirimycin hydrochloride AT2220
Experimental: Cohort 2 Regimen 1: High-dose duvoglustat (5.0 g) QD for 3 days, followed by no drug for 4 days, for 11 weeks.	Drug: Duvoglustat; Powder in a bottle for dissolution in water for oral administration; Other Names: Duvoglustat hydrochloride 1-Deoxynojirimycin hydrochloride AT2220
Experimental: Cohort 3 Regimen 2: High-dose duvoglustat (5.0 g) QD for 7 days, followed by no drug for 7 days, for 11 weeks.	Drug: Duvoglustat; Powder in a bottle for dissolution in water for oral administration; Other Names: Duvoglustat hydrochloride 1-Deoxynojirimycin hydrochloride AT2220

Outcome Measures

Primary Outcome Measures

1. Proportion Of Participants Experiencing Severe Treatment-emergent Adverse Events (TEAEs) [Baseline, Week 11]

   The number of participants experiencing severe TEAEs is presented for participants who received duvoglustat treatment in this open-label study. The duration of duvoglustat exposure for Cohort 1 ranged from 2 to 24 days, and their exposure ranged from a total of 7,500 to 32,500 milligrams of duvoglustat. An adverse event (AE) refers to any unfavorable and unintended sign, symptom, syndrome, or illness that develops or worsens during the period of observation in the clinical study. The following guideline was used to grade the intensity of an AE: mild, the AE is easily tolerated and does not interfere with daily activity; moderate, the AE interferes with the daily activity but the participant is still able to function; severe, the AE is incapacitating and requires medical intervention. A summary of serious and all other non-serious AEs regardless of causality is located in the Reported Adverse Events module.

Secondary Outcome Measures

1. Change In 6-minute Walk Test (6MWT) From Baseline To End Of Study [Baseline, Week 11]

   The 6MWT (American Thoracic Society standards) was evaluated in ambulatory participants at screening, baseline, and to the end of the study. It was a standardized test that measured the distance in meters (m) covered over a 6-minute walk. Reference equations used (for 6MWT distance in healthy adults) included: (height in centimeters [cm], weight in kilograms [kg]) 6MWT distance for men = [7.57 × height (cm)] - [5.02 × age] - [1.76 × weight (kg)] - 309 m; 6MWT distance for women = [2.11 × height (cm)] - [5.78 × age] - [2.29 × weight (kg)] + 667 m

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 74 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female, 18 to 74 years of age inclusive

• Diagnosis of Pompe disease based on clinical assessment, enzyme assay, and/or genotyping. Confirmatory genotyping will be performed on all participants who are screened for the study

• Naïve to enzyme replacement therapy (ERT) or has not received ERT in the 3 months prior to screening

• Willing not to initiate ERT or other prohibited treatment during study participation

• Functional grade for arms and/or legs ≥2 OR sitting forced vital capacity ≥30% and <80% of predicted value, reproducible between screening and baseline (±15%)

• Participants of reproductive potential agree to use reliable methods of contraception during the study

• Participant or legal representative is willing and able to provide written informed consent

Exclusion Criteria:

• Any intercurrent condition that may preclude accurate interpretation of study data

• Obstructive pulmonary disease

• Invasive ventilatory support

• Use of noninvasive ventilatory support >8 hours/day while awake

• History of QTc prolongation >450 milliseconds (msec) for males and >470 msec for females

• History of allergy or sensitivity to the study drug, including any prior serious adverse reaction to iminosugars (such as miglustat or miglitol)

• Pregnancy or breast-feeding

• Current or recent drug or alcohol abuse

• Treatment with another investigational drug within 30 days of study start

• Use of prohibited medications ≤3 months prior to screening

• Otherwise unsuitable for the study in the opinion of the Investigator

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Decatur	Georgia	United States	30033

Sponsors and Collaborators

• Amicus Therapeutics

Investigators

• Study Director: Medical Monitor Clinical Research, Amicus Therapeutics

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Amicus Therapeutics
• ClinicalTrials.gov Identifier: NCT00688597
• Other Study ID Numbers: POM-CL-201
• First Posted: Jun 3, 2008
• Last Update Posted: Aug 17, 2018
• Last Verified: Jul 1, 2018

• Keywords provided by Amicus Therapeutics: Amicus Therapeutics; Duvoglustat; AT2220
• Additional relevant MeSH terms: Glycogen Storage Disease Type II; 1-Deoxynojirimycin

Study Results

Participant Flow

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3
Arm/Group Description	Regimen 1: Low-dose duvoglustat (2.5 grams [g]) once a day (QD) for 3 days, followed by no drug for 4 days, for 11 weeks.	Regimen 1: High-dose duvoglustat (5.0 g) QD for 3 days, followed by no drug for 4 days, for 11 weeks.	Regimen 2: High-dose duvoglustat (5.0 g) QD for 7 days, followed by no drug for 7 days, for 11 weeks.
Period Title: Overall Study
STARTED	3	0	0
Received at Least 1 Dose of Study Drug	3	0	0
COMPLETED	0	0	0
NOT COMPLETED	3	0	0

Baseline Characteristics

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Total
Arm/Group Description	Regimen 1: Low-dose duvoglustat (2.5 g) QD for 3 days, followed by no drug for 4 days, for 11 weeks.	Regimen 1: High-dose duvoglustat (5.0 g) QD for 3 days, followed by no drug for 4 days, for 11 weeks.	Regimen 2: High-dose duvoglustat (5.0 g) QD for 7 days, followed by no drug for 7 days, for 11 weeks.	Total of all reporting groups
Overall Participants	3	0	0	3
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49.07 (11.02)	49.07 (11.02)
Sex: Female, Male (Count of Participants)
Female	2 66.7%	2 Infinity
Male	1 33.3%	1 Infinity

Outcome Measures

1. Primary Outcome

Title	Proportion Of Participants Experiencing Severe Treatment-emergent Adverse Events (TEAEs)
Description	The number of participants experiencing severe TEAEs is presented for participants who received duvoglustat treatment in this open-label study. The duration of duvoglustat exposure for Cohort 1 ranged from 2 to 24 days, and their exposure ranged from a total of 7,500 to 32,500 milligrams of duvoglustat. An adverse event (AE) refers to any unfavorable and unintended sign, symptom, syndrome, or illness that develops or worsens during the period of observation in the clinical study. The following guideline was used to grade the intensity of an AE: mild, the AE is easily tolerated and does not interfere with daily activity; moderate, the AE interferes with the daily activity but the participant is still able to function; severe, the AE is incapacitating and requires medical intervention. A summary of serious and all other non-serious AEs regardless of causality is located in the Reported Adverse Events module.
Time Frame	Baseline, Week 11

Outcome Measure Data

Analysis Population Description

Safety Population: All participants who received at least 1 dose of duvoglustat.

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3
Arm/Group Description	Regimen 1: Low-dose duvoglustat (2.5 g) QD for 3 days, followed by no drug for 4 days, for 11 weeks.	Regimen 1: High-dose duvoglustat (5.0 g) QD for 3 days, followed by no drug for 4 days, for 11 weeks.	Regimen 2: High-dose duvoglustat (5.0 g) QD for 7 days, followed by no drug for 7 days, for 11 weeks.
Measure Participants	3	0	0
Count of Participants [Participants]	1 33.3%

2. Secondary Outcome

Title	Change In 6-minute Walk Test (6MWT) From Baseline To End Of Study
Description	The 6MWT (American Thoracic Society standards) was evaluated in ambulatory participants at screening, baseline, and to the end of the study. It was a standardized test that measured the distance in meters (m) covered over a 6-minute walk. Reference equations used (for 6MWT distance in healthy adults) included: (height in centimeters [cm], weight in kilograms [kg]) 6MWT distance for men = [7.57 × height (cm)] - [5.02 × age] - [1.76 × weight (kg)] - 309 m; 6MWT distance for women = [2.11 × height (cm)] - [5.78 × age] - [2.29 × weight (kg)] + 667 m
Time Frame	Baseline, Week 11

Outcome Measure Data

Analysis Population Description

Safety Population: All participants who received at least 1 dose of duvoglustat.

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3
Arm/Group Description	Regimen 1: Low-dose duvoglustat (2.5 g) QD for 3 days, followed by no drug for 4 days, for 11 weeks.	Regimen 1: High-dose duvoglustat (5.0 g) QD for 3 days, followed by no drug for 4 days, for 11 weeks.	Regimen 2: High-dose duvoglustat (5.0 g) QD for 7 days, followed by no drug for 7 days, for 11 weeks.
Measure Participants	3	0	0
Mean (Standard Deviation) [m]	-19.660 (41.1845)

Adverse Events

Time Frame	Day 1 (after dosing) through end of follow up.
Adverse Event Reporting Description	Due to the discontinuation of the study, AEs were not encoded.
Arm/Group Title	Cohort 1		Cohort 2		Cohort 3
Arm/Group Description	Regimen 1: Low-dose duvoglustat (2.5 g) QD for 3 days, followed by no drug for 4 days, for 11 weeks.		Regimen 1: High-dose duvoglustat (5.0 g) QD for 3 days, followed by no drug for 4 days, for 11 weeks.		Regimen 2: High-dose duvoglustat (5.0 g) QD for 7 days, followed by no drug for 7 days, for 11 weeks.
All Cause Mortality
	Cohort 1		Cohort 2		Cohort 3
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Cohort 1		Cohort 2		Cohort 3
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)		0/0 (NaN)		0/0 (NaN)
General disorders
Muscular weakness	2/3 (66.7%)		0/0 (NaN)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Cohort 1		Cohort 2		Cohort 3
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		0/0 (NaN)		0/0 (NaN)
General disorders
Muscular weakness	2/3 (66.7%)		0/0 (NaN)		0/0 (NaN)
Flatulence	1/3 (33.3%)		0/0 (NaN)		0/0 (NaN)
Abdominal pain upper	1/3 (33.3%)		0/0 (NaN)		0/0 (NaN)
Alanine aminotransferase increased	3/3 (100%)		0/0 (NaN)		0/0 (NaN)
Aspartate aminotransferase increased	3/3 (100%)		0/0 (NaN)		0/0 (NaN)
Blood creatine phosphokinase increased	3/3 (100%)		0/0 (NaN)		0/0 (NaN)
Fall	2/3 (66.7%)		0/0 (NaN)		0/0 (NaN)
Dysphagia	1/3 (33.3%)		0/0 (NaN)		0/0 (NaN)
Joint injury	1/3 (33.3%)		0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

The serious adverse event of muscle weakness was the main contributor to the study not reaching the target number of participants needed to achieve target power and statistically reliable results.

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.