Phase II Clinical Trial of Clenbuterol in Adult Patients With Pompe Disease

Study Overview
=================
Brief Summary
-----------------
The goals of this study are to determine safety and efficacy with regard to motor function of oral clenbuterol in combination with ERT in subjects with LOPD

Official Title
-----------------
Phase II Clinical Trial of Clenbuterol in Adult Patients With Pompe Disease Stably Treated With Enzyme Replacement Therapy

Conditions
-----------------
Pompe Disease (Late-onset)

Intervention / Treatment
-----------------
* Drug: Clenbuterol
* Drug: Placebos


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of Pompe disease by blood Acid alpha-glucosidase (GAA) assay and GAA gene sequencing, Age: 18+ years at enrollment, Receiving enzyme replacement therapy (ERT) at a stable dose for >104 weeks, FVC >15% of expected (supine). Subjects are capable of giving written consent. Able to walk at least 100 meters on the 6 minute walk test (6MWT) (with assistive devices permitted). Exclusion Criteria: Continuous invasive ventilation (via tracheostomy or endotracheal tube) 6MWT distance >90% of expected performance (% expected) FVC >90% of expected (upright). Clinically relevant illness within two weeks of enrollment including fever > 38.2o 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 β2-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. Renal insufficiency (elevated serum creatinine). Having started respiratory muscle strength training in the last 6 months prior to study day 1 or having discontinued respiratory muscle strength training in the 6-month period preceding study day 1, or having started respiratory strength training greater than 6 months prior to study day 1 and unwilling to continue for the first year of study participation. Received an investigational drug or participated in another interventional study within 90 days of Study Day 1. Anti-rhGAA IgG with sustained titer >1:25.600 for >6 months at time of enrollment. 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 (MAO) 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).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: clenbuterol<br>The initial dose of clenbuterol will be 40 mcg per oral each morning for one week, followed by 40 mcg twice per day (BID) for the next 5 weeks until Week 6. 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 12 visit. If 80 mcg BID is tolerated at Week 12, the subject will continue on that dose until Week 52. | Drug: Clenbuterol<br>* 20 mcg spiropent tablets will be overencapsulated (two 20 mcg tablets per capsule)<br>* Other names: Spiropent;|
| Placebo Comparator: placebo<br>Initially, one capsule each morning for one week, followed by one capsule BID for the next 5 weeks until Week 6. If tolerated, the dose will be increased to two capsules each morning and 1 capsule each evening for one week, followed by two capsules BID for the next 5 weeks until the Week 12 visit. If two capsules BID is tolerated at Week 12, the subject will continue on that dose until Week 52. | Drug: Placebos<br>* dextrose-filled capsules<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in 6 minute walk test (MWT) distance |  | Baseline (week 0) through 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in pulmonary function tests: forced expiratory volume in 1 second (FEV1) |  | Baseline (week 0) through 52 weeks | 
| Changes in pulmonary function tests: forced vital capacity (FVC) |  | Baseline (week 0) through 52 weeks | 
| Changes in pulmonary function tests: maximum expiratory pressure (MEP) |  | Baseline (week 0) through 52 weeks | 
| Changes in pulmonary function tests: Maximum inspiratory pressure (MIP) |  | Baseline (week 0) through 52 weeks | 
| Changes in graded functional test: Gait, Stairs, Gower, Chair (GSCS) |  | Baseline (week 0) through 52 weeks | 
| Changes in graded functional test: Quick Motor Function Test (QMFT) |  | Baseline (week 0) through 52 weeks | 
| Changes in the concentration of alanine transaminase (ALT) in serum | Avoidance of liver toxicity as defined by a a persistent (sustained >2 weeks) >3x increase in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) from the respective baseline values and/or an increase in direct, indirect or total bilirubin of >3x the upper limit of normal (no liver toxicity has been reported in association with clenbuterol administration and therefore repeat testing should be acceptable) | Baseline (week 0) through 52 weeks | 
| Changes in the concentration of creatine kinase (CK) in serum | Avoidance of Worsening muscle involvement (i.e. muscle weakness, cramping, or fatigue) accompanied by a persistent (sustained >2 weeks) >3x increase in CK from baseline that is >2x the upper limit of normal (elevated CK is associated with LOPD and minor elevations of CK have been reported in association with clenbuterol administration, therefore repeat testing should be acceptable). | Baseline (week 0) through 52 weeks | 
| Changes in the concentration of urinary glucose tetramer (Glc4) |  | Baseline (week 0) through 52 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Pompe disease, LOPD, Late-onset Pompe Disease