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Safety and Efficacy of Clenbuterol in Individuals With Late-onset Pompe Disease and Receiving Enzyme Replacement Therapy

Primary Purpose

Pompe Disease

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Clenbuterol
Placebo
Sponsored by
Dwight Koeberl, M.D., Ph.D.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pompe Disease focused on measuring Pompe disease

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Diagnosis of Pompe disease by blood acid alpha-glucosidase assay and acid alpha-glucosidase gene sequencing,
  2. Age: 18+ years at enrollment,
  3. Receiving ERT at standard dose (20 mg/kg every 2 weeks) for at least 52 weeks,
  4. Subjects are capable of giving written consent.

Exclusion Criteria:

  1. Continuous invasive ventilation (via tracheostomy or endotracheal tube)
  2. Clinically relevant illness within two weeks of enrollment including fever > 38.2 C, vomiting more than once in 24 hours, seizure, or other symptom deemed contraindicative to new therapy.
  3. Chronic heart disease (Myocardial infarction, arrythmia, cardiomyopathy)
  4. Tachycardia
  5. History of seizure disorder
  6. Hyperthyroidism
  7. Pheochromocytoma
  8. Pregnancy
  9. History of diabetes
  10. History of hypersensitivity to beta 2-agonist drugs such as albuterol, levalbuterol (Xopenex), bitolterol (Tornalate), pirbuterol (Maxair), terbutaline, salmeterol (Serevent),
  11. Patients on a non-standard schedule for ERT; for example, weekly infusions as opposed to infusions every two weeks.
  12. Treatment for asthma in the previous 12 months.
  13. The use of the following concommitant meds is prohibited during the study:

    • diuretics (water pill);
    • digoxin (digitalis, Lanoxin);
    • beta-blockers such as atenolol (Tenormin), metoprolol (Lopressor), and propranolol (Inderal);
    • tricyclic antidepressants such as amitriptyline (Elavil, Etrafon), doxepin (Sinequan), imipramine (Janimine, Tofranil), and nortriptyline (Pamelor);
    • Monoamine oxidase inhibitors such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate); or
    • other bronchodilators such as albuterol, levalbuterol (Xopenex), bitolterol (Tornalate), pirbuterol (Maxair), terbutaline (Brethine, Bricanyl), salmeterol (Serevent), isoetherine (Bronkometer), metaproterenol (Alupent, Metaprel), or isoproterenol (Isuprel Mistometer).

Sites / Locations

  • Duke University Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Clenbuterol

Placebo Comparator

Arm Description

Initially, 40 mcg each morning for one week. Then, increase to 40 mcg BID for the next 5 weeks. If tolerated, will increase to 80 mcg in the morning and 40 mcg in the evening for one week. Then, last dose increase will be 80 mcg BID until week 52.

Initially, one capsule each morning for one week. Then, increase to one capsule BID for the next 5 weeks. If tolerated, will increase to two capsules in the morning and one capsule in the evening for one week. Then, last dose increase will be two capsules BID until week 52.

Outcomes

Primary Outcome Measures

Number of Participants With a Change in Creatine Kinase (CK) Reflecting Worsening of Muscle Involvement
Worsening muscle involvement, as defined by >3x increase in CK from baseline that is >2x the upper limit of normal
Number of Participants With a Change in Aspartate Aminotransferase (AST), Alanine Transaminase (ALT), and Bilirubin Representing Liver Toxicity
Liver toxicity, as defined by a >3x increase in AST or ALT from the respective baseline values and/or an increase in direct, indirect or total bilirubin of >3x the upper limit of normal

Secondary Outcome Measures

Change in 6 Minute Walk Test
Assess exercise tolerance in study patients; test administered by physical therapist. Subjects were asked to walk for 6 minutes, unassisted. The distance walked was recorded in meters.
Change in 6 Minute Walk Test
Assess exercise tolerance in study patients; test administered by physical therapist. Subjects were asked to walk for 6 minutes, unassisted. The distance walked was recorded in meters.
Change in Forced Vital Capacity (FVC) in Pulmonary Function Testing
Forced vital capacity (FVC) is the total amount of air exhaled during the lung function test.
Change in Forced Vital Capacity (FVC) in Pulmonary Function Testing
Forced vital capacity (FVC) is the total amount of air exhaled during the lung function test.
Change in Urinary Glc4 Biomarker
The Glc4 biomarker is measured in urine and correlates with muscle glycogen content. It is a noninvasive measurement that serves as a biomarker for Pompe disease.
Change in Urinary Glc4 Biomarker
GSGC (Gait, Stairs, Gowers, Arising From a Chair.)
The GSGC is a criterion referenced assessment designed to measure functional status and change in gross motor function over time and, in particular, to measure clinically relevant change. Consists of 4 components: Gait, Climbing Stairs, Gower's Manuever, Arising From a Chair. Lowest score 4 = normal muscle function, highest score 27 = unable to perform motor function tests.
Quick Motor Function Test (QMFT)
The QMFT is a criterion referenced assessment designed to measure functional status and change in gross motor function over time and, in particular, to measure clinically relevant change. Consists of 16 motor function tests. Lowest score 0 = unable to perform motor function tests, highest score 64 = normal muscle function.
Late-Life Function and Disability Instrument (LLFDI)
The Late-Life Function & Disability Instrument (Late-Life FDI) is an evaluative outcome instrument for community-dwelling older adults. Highest score 240 = normal function and no disability, lowest score 0 = low levels of frequency of participating in life tasks.
Predicted Maximum Inspiration Pressure (MIP)
MIP is a measurement of inspiratory muscle weakness, including weakness of the diaphragm. MIP is decreased in Pompe disease and reflects weakness of respiratory muscles.
Maximum Expiratory Pressure (MEP)
MEP reflects the strength of the abdominal muscles and other expiratory muscles.

Full Information

First Posted
September 11, 2013
Last Updated
June 28, 2019
Sponsor
Dwight Koeberl, M.D., Ph.D.
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1. Study Identification

Unique Protocol Identification Number
NCT01942590
Brief Title
Safety and Efficacy of Clenbuterol in Individuals With Late-onset Pompe Disease and Receiving Enzyme Replacement Therapy
Official Title
A Clinical Investigation of the Safety and Efficacy of Clenbuterol on Motor Function in Individuals With Late-onset Pompe Disease and Receiving Enzyme Replacement Therapy
Study Type
Interventional

2. Study Status

Record Verification Date
June 2019
Overall Recruitment Status
Completed
Study Start Date
September 2013 (undefined)
Primary Completion Date
September 2, 2016 (Actual)
Study Completion Date
September 2, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Dwight Koeberl, M.D., Ph.D.

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Funding Source- FDA OOPD The purpose of this study is to investigate the safety and efficacy of clenbuterol on motor function in individuals with late-onset Pompe disease (LOPD) who are treated with enzyme replacement therapy (ERT).
Detailed Description
This is a 52 week Phase I/II double-blind, randomized, placebo-controlled study of adjunctive clenbuterol in LOPD (Table 2, Section 6). All subjects will be evaluated at Week 0 and Week 6 to establish a baseline for motor function testing. At Week 6, subjects will be randomized 3:2 to clenbuterol or placebo, and evaluated for safety and efficacy during the Week 12 and 18 visits. The Investigational Drug Service will maintain double-blinding by providing either the study drug or placebo (over-encapsulated tablets) directly to subjects. The drug (or placebo) will be initiated at the Week 6 visit in a staged manner (first once daily and later BID), and the dose will be increased at the Week 12 visit in a similarly staged manner to minimize AEs and related attrition. All subjects will return for a final visit after a total of 52 weeks in the study. In terms of standard of care, the subject will have two clinical visits (charged to the subject and/or the subject's insurance company), one at the initiation of the study drug (baseline) and one at the study completion (52 weeks). Study drug will be attempted to be initiated during the "off week", approximately one week following a dose of ERT, and ERT will continue throughout the duration of the study. Thereafter, study visits will be during the "off week". The 6, 12, and 18 week visits will be research visits (not charged to the subject and/or the subject's insurance company) in order to determine subject's overall health status and measure early signs of motor improvement. The initial dose of clenbuterol will be 40 mcg per oral each morning for one week, followed by 40 mcg BID for the next 5 weeks until the week 12 visit. If the 40 mcg BID per oral is well tolerated, the dose will be increased to 80 mcg each morning/40 mcg each evening for one week, followed by 80 mcg BID for the next 5 weeks until the Week 18 visit. If 80 mcg BID is tolerated at Week 18, the subject will continue on that dose until Week 52. Compliance will be discussed at the Week 6, Week 12, and Week 18 visits. The subject will have phone visits during Week 1, 7, 13, 36, and 52, and compliance will be discussed then. We will call subjects daily during the first week following initiation of study drug (Week 7) and dosage escalation (Week 13) to support subjects through the early adverse effects of tachyphylaxis that may lead to premature termination. An interim call will occur during Week 36 to monitor compliance. Subjects who admit non-compliance, missing >6 doses of the study drug, will be considered non-compliant and withdrawn from the study. Subjects will be called during Week 1 and Week 52, 3 days following the muscle biopsy. All phone calls will review AEs (Table). The efficacy of clenbuterol treatment during ERT in patients with LOPD will be evaluated with muscle and pulmonary function testing as the primary endpoints. A secondary endpoint, the urinary Glc4 biomarker, will be monitored when the subjects are evaluated at baseline, week 18 and week 52. The impact of enhanced CI-MPR-mediated uptake of GAA will be analyzed by comparing the muscle function, pulmonary function, and biochemical correction of muscle in subjects with LOPD treated with ERT, both prior to and during simultaneous β2 agonist therapy.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pompe Disease
Keywords
Pompe disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
17 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Clenbuterol
Arm Type
Experimental
Arm Description
Initially, 40 mcg each morning for one week. Then, increase to 40 mcg BID for the next 5 weeks. If tolerated, will increase to 80 mcg in the morning and 40 mcg in the evening for one week. Then, last dose increase will be 80 mcg BID until week 52.
Arm Title
Placebo Comparator
Arm Type
Placebo Comparator
Arm Description
Initially, one capsule each morning for one week. Then, increase to one capsule BID for the next 5 weeks. If tolerated, will increase to two capsules in the morning and one capsule in the evening for one week. Then, last dose increase will be two capsules BID until week 52.
Intervention Type
Drug
Intervention Name(s)
Clenbuterol
Other Intervention Name(s)
Spiropent
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Capsule
Primary Outcome Measure Information:
Title
Number of Participants With a Change in Creatine Kinase (CK) Reflecting Worsening of Muscle Involvement
Description
Worsening muscle involvement, as defined by >3x increase in CK from baseline that is >2x the upper limit of normal
Time Frame
Any point up to week 52
Title
Number of Participants With a Change in Aspartate Aminotransferase (AST), Alanine Transaminase (ALT), and Bilirubin Representing Liver Toxicity
Description
Liver toxicity, as defined by a >3x increase in AST or ALT from the respective baseline values and/or an increase in direct, indirect or total bilirubin of >3x the upper limit of normal
Time Frame
Any point up to week 52
Secondary Outcome Measure Information:
Title
Change in 6 Minute Walk Test
Description
Assess exercise tolerance in study patients; test administered by physical therapist. Subjects were asked to walk for 6 minutes, unassisted. The distance walked was recorded in meters.
Time Frame
Baseline, week 18
Title
Change in 6 Minute Walk Test
Description
Assess exercise tolerance in study patients; test administered by physical therapist. Subjects were asked to walk for 6 minutes, unassisted. The distance walked was recorded in meters.
Time Frame
Baseline, week 52
Title
Change in Forced Vital Capacity (FVC) in Pulmonary Function Testing
Description
Forced vital capacity (FVC) is the total amount of air exhaled during the lung function test.
Time Frame
Baseline, Week 18
Title
Change in Forced Vital Capacity (FVC) in Pulmonary Function Testing
Description
Forced vital capacity (FVC) is the total amount of air exhaled during the lung function test.
Time Frame
Baseline, Week 52
Title
Change in Urinary Glc4 Biomarker
Description
The Glc4 biomarker is measured in urine and correlates with muscle glycogen content. It is a noninvasive measurement that serves as a biomarker for Pompe disease.
Time Frame
Baseline, Week 18
Title
Change in Urinary Glc4 Biomarker
Time Frame
Baseline, Week 52
Title
GSGC (Gait, Stairs, Gowers, Arising From a Chair.)
Description
The GSGC is a criterion referenced assessment designed to measure functional status and change in gross motor function over time and, in particular, to measure clinically relevant change. Consists of 4 components: Gait, Climbing Stairs, Gower's Manuever, Arising From a Chair. Lowest score 4 = normal muscle function, highest score 27 = unable to perform motor function tests.
Time Frame
Baseline, Week 18, and Week 52
Title
Quick Motor Function Test (QMFT)
Description
The QMFT is a criterion referenced assessment designed to measure functional status and change in gross motor function over time and, in particular, to measure clinically relevant change. Consists of 16 motor function tests. Lowest score 0 = unable to perform motor function tests, highest score 64 = normal muscle function.
Time Frame
Baseline, Week 18, and Week 52
Title
Late-Life Function and Disability Instrument (LLFDI)
Description
The Late-Life Function & Disability Instrument (Late-Life FDI) is an evaluative outcome instrument for community-dwelling older adults. Highest score 240 = normal function and no disability, lowest score 0 = low levels of frequency of participating in life tasks.
Time Frame
Baseline, Week 18, Week 52
Title
Predicted Maximum Inspiration Pressure (MIP)
Description
MIP is a measurement of inspiratory muscle weakness, including weakness of the diaphragm. MIP is decreased in Pompe disease and reflects weakness of respiratory muscles.
Time Frame
Baseline, Week 18, and Week 52
Title
Maximum Expiratory Pressure (MEP)
Description
MEP reflects the strength of the abdominal muscles and other expiratory muscles.
Time Frame
Baseline, Week 18, and Week 52

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Diagnosis of Pompe disease by blood acid alpha-glucosidase assay and acid alpha-glucosidase gene sequencing, Age: 18+ years at enrollment, Receiving ERT at standard dose (20 mg/kg every 2 weeks) for at least 52 weeks, Subjects are capable of giving written consent. Exclusion Criteria: Continuous invasive ventilation (via tracheostomy or endotracheal tube) Clinically relevant illness within two weeks of enrollment including fever > 38.2 C, vomiting more than once in 24 hours, seizure, or other symptom deemed contraindicative to new therapy. Chronic heart disease (Myocardial infarction, arrythmia, cardiomyopathy) Tachycardia History of seizure disorder Hyperthyroidism Pheochromocytoma Pregnancy History of diabetes History of hypersensitivity to beta 2-agonist drugs such as albuterol, levalbuterol (Xopenex), bitolterol (Tornalate), pirbuterol (Maxair), terbutaline, salmeterol (Serevent), Patients on a non-standard schedule for ERT; for example, weekly infusions as opposed to infusions every two weeks. Treatment for asthma in the previous 12 months. The use of the following concommitant meds is prohibited during the study: diuretics (water pill); digoxin (digitalis, Lanoxin); beta-blockers such as atenolol (Tenormin), metoprolol (Lopressor), and propranolol (Inderal); tricyclic antidepressants such as amitriptyline (Elavil, Etrafon), doxepin (Sinequan), imipramine (Janimine, Tofranil), and nortriptyline (Pamelor); Monoamine oxidase inhibitors such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate); or other bronchodilators such as albuterol, levalbuterol (Xopenex), bitolterol (Tornalate), pirbuterol (Maxair), terbutaline (Brethine, Bricanyl), salmeterol (Serevent), isoetherine (Bronkometer), metaproterenol (Alupent, Metaprel), or isoproterenol (Isuprel Mistometer).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Dwight D Koeberl, MD, PhD
Organizational Affiliation
Duke University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
18374884
Citation
Kamalakkannan G, Petrilli CM, George I, LaManca J, McLaughlin BT, Shane E, Mancini DM, Maybaum S. Clenbuterol increases lean muscle mass but not endurance in patients with chronic heart failure. J Heart Lung Transplant. 2008 Apr;27(4):457-61. doi: 10.1016/j.healun.2008.01.013.
Results Reference
background
PubMed Identifier
21397538
Citation
Koeberl DD, Luo X, Sun B, McVie-Wylie A, Dai J, Li S, Banugaria SG, Chen YT, Bali DS. Enhanced efficacy of enzyme replacement therapy in Pompe disease through mannose-6-phosphate receptor expression in skeletal muscle. Mol Genet Metab. 2011 Jun;103(2):107-12. doi: 10.1016/j.ymgme.2011.02.006. Epub 2011 Feb 13.
Results Reference
background
PubMed Identifier
22154081
Citation
Koeberl DD, Li S, Dai J, Thurberg BL, Bali D, Kishnani PS. beta2 Agonists enhance the efficacy of simultaneous enzyme replacement therapy in murine Pompe disease. Mol Genet Metab. 2012 Feb;105(2):221-7. doi: 10.1016/j.ymgme.2011.11.005. Epub 2011 Nov 11.
Results Reference
background
PubMed Identifier
30025991
Citation
Koeberl DD, Case LE, Smith EC, Walters C, Han SO, Li Y, Chen W, Hornik CP, Huffman KM, Kraus WE, Thurberg BL, Corcoran DL, Bali D, Bursac N, Kishnani PS. Correction of Biochemical Abnormalities and Improved Muscle Function in a Phase I/II Clinical Trial of Clenbuterol in Pompe Disease. Mol Ther. 2018 Sep 5;26(9):2304-2314. doi: 10.1016/j.ymthe.2018.06.023. Epub 2018 Jul 5.
Results Reference
derived

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Safety and Efficacy of Clenbuterol in Individuals With Late-onset Pompe Disease and Receiving Enzyme Replacement Therapy

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