Clinical trial NCT04245709
Conditions: Amyotrophic Lateral Sclerosis
Sponsor: Dwight Koeberl, M.D., Ph.D.
Start date: 2020-02-10; Completion date: 2021-03-10
Enrollment: 25 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to assess the safety and tolerability of clenbuterol (taken by mouth) in subjects with ALS (amyotrophic lateral sclerosis) and to assess the effectiveness of clenbuterol with regard to motor function in subjects with ALS. Subjects will be in this study approximately 24 weeks. The study drug, clenbuterol, is taken twice a day. As part of this study subjects will have the following tests and procedures: medical history, vital signs, physical examination, blood tests, heart and lung function tests, muscle function test, ALSFRS-R (ALS Functional Rating Scale Revised), thyroid function and for women who can become pregnant, pregnancy tests.

Detailed description:
This is an open label pilot trial in which 25 people with ALS will take clenbuterol orally at 40-80 micrograms twice daily for 24 weeks. In person visits will occur at weeks 0, 4, 12 and 24. Telephone visits will occur at weeks 1, 6, 16 and 20. During these visits several safety and efficacy outcome measures will be performed for research purposes including safety labs, thyroid functions, pregnancy testing, ALSFRS-R, FVC (forced vital capacity), and muscle strength testing (myometry). The critical test of treatment efficacy will be the comparison of the ALSFRS-R slope during treatment to the estimated pre-treatment slope. All participants will continue to have standard follow up care for their ALS at Duke (for patients followed here) or their local ALS clinic

Arms: arm 1: This is an open label pilot trial in which 25 people with ALS will take clenbuterol orally at 40-80 micrograms twice daily for 24 weeks.
Interventions: intervention 1: Clenbuterol
Intervention descriptions: intervention 1: The intervention is treatment with oral clenbuterol at 40-80 micrograms twice daily for 24 weeks. Dosage will initially be 40 mcg daily for one week, then 40 mcg BID per oral daily for the next 5 weeks. If the 40 mcg BID per oral is well tolerated in the opinion of Dr. Bedlack, the dose will be increased to 80 mcg each morning/40 mcg each evening for one week, followed by 80 mcg BID per oral for the remainder of the study. The selected target dose (80 mcg BID) is based upon the experience with the long-term administration of clenbuterol, specifically the beneficial muscle effects in a Phase I/II clinical trial that enrolled patients with late-onset Pompe disease who were previously treated with enzyme replacement therapy (Koeberl et al. 2018).

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Page 1 of 23 
 
 
 
 
 
 
 
A Clinical Investigation of the Safety and Efficacy of Clenbuterol on Motor Function in 
Individuals with Amyotrophic Lateral Sclerosis  
 
 
 
Protocol eIRB Number: Pro00103668 
  
 
Version Number 10, May 10, 2020 
 
 
 
 
 
 
 
 
 
IND Number: 145248 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
 
This document is confidential. No part of it may be transmitted, reproduced, published, or 
used by other persons without prior written authorization from the study sponsor. 


 
 
Page 2 of 23 
 
 
1 Table of Contents 
1 
TABLE OF CONTENTS .........................................................................................................................................2 
2 
LIST OF TABLES ....................................................................................................................................................3 
3 
LIST OF FIGURES ..................................................................................................................................................3 
4 
LIST OF ABBREVIATIONS..................................................................................................................................4 
5 
STUDY SUMMARY.................................................................................................................................................4 
6 
INTRODUCTION.....................................................................................................................................................5 
6.1 
Background........................................................................................................................................................ 5 
6.2 
Investigational Agent ........................................................................................................................................ 7 
6.3 
Preclinical Data ................................................................................................................................................. 8 
6.4 
Dose Rationale and Risk/Benefits.................................................................................................................... 8 
7 
STUDY OBJECTIVES ......................................................................................................................................... 10 
8 
STUDY DESIGN .................................................................................................................................................... 10 
8.1 
General Design ................................................................................................................................................ 10 
8.2 
Primary Study Endpoints ................................................................................................................................ 10 
8.3 
Secondary Study Endpoints............................................................................................................................ 10 
9 
SUBJECT SELECTION AND WITHDRAWAL ............................................................................................. 10 
9.1 
Inclusion Criteria............................................................................................................................................. 10 
9.2 
Exclusion Criteria............................................................................................................................................ 11 
9.3 
Subject Recruitment and Screening ............................................................................................................... 12 
9.4 
Early Withdrawal of Subjects......................................................................................................................... 12 
10 
STUDY DRUG........................................................................................................................................................ 12 
10.1 
Description....................................................................................................................................................... 12 
10.2 
Treatment Regimen......................................................................................................................................... 12 
10.3 
Method for Assigning Subjects to Treatment Groups .................................................................................. 12 
10.4 
Preparation and Administration of Study Drug............................................................................................. 12 
10.5 
Subject Compliance Monitoring .................................................................................................................... 12 
10.6 
Prior and Concomitant Therapy ..................................................................................................................... 13 
10.7 
Packaging......................................................................................................................................................... 13 
10.8 
Blinding of Study Drug................................................................................................................................... 13 
10.9 
Receiving, Storage, Dispensing and Return .................................................................................................. 13 
10.9.1 
Receipt of Drug Supplies...................................................................................................................... 13 
10.9.2 
Storage ................................................................................................................................................... 13 
10.9.3 
Dispensing of Study Drug .................................................................................................................... 13 
10.9.4 
Return or Destruction of Study Drug................................................................................................... 13 
11 
STUDY PROCEDURES ....................................................................................................................................... 14 
12 
STATISTICAL PLAN........................................................................................................................................... 15 
12.1 
Sample Size Determination ............................................................................................................................ 15 
12.2 
Statistical Methods .......................................................................................................................................... 16 
12.3 
Subject Population(s) for Analysis ................................................................................................................ 16 
13 
SAFETY AND ADVERSE EVENTS.................................................................................................................. 17 
13.1 
Definitions ....................................................................................................................................................... 17 
13.1.1 
Adverse Event ....................................................................................................................................... 17 


 
 
Page 3 of 23 
 
13.1.2 
Serious Adverse Event.......................................................................................................................... 17 
13.1.3 
Adverse Event Reporting Period.......................................................................................................... 17 
13.1.4 
Preexisting Condition............................................................................................................................ 17 
13.1.5 
General Physical Examination Findings.............................................................................................. 17 
13.1.6 
Post-study Adverse Event..................................................................................................................... 18 
13.1.7 
Abnormal Laboratory Values ............................................................................................................... 18 
13.1.8 
Hospitalization, Prolonged Hospitalization or Surgery ...................................................................... 18 
13.2 
Recording of Adverse Events......................................................................................................................... 18 
13.3 
Reporting of Serious Adverse Events ............................................................................................................ 19 
13.3.1 
IRB Notification by Investigator.......................................................................................................... 19 
13.3.2 
FDA Notification by Sponsor............................................................................................................... 19 
13.4 
Unblinding Procedures ................................................................................................................................... 19 
13.5 
Definitions ....................................................................................................................................................... 19 
13.5.1 
Adverse Event ....................................................................................................................................... 19 
13.5.2 
Serious Adverse Event.......................................................................................................................... 19 
13.6 
Medical Monitoring ........................................................................................................................................ 20 
13.6.1 
Internal Data and Safety Monitoring Committee................................................................................ 20 
14 
DATA HANDLING AND RECORD KEEPING.............................................................................................. 20 
14.1 
Confidentiality................................................................................................................................................. 20 
14.2 
Source Documents .......................................................................................................................................... 20 
14.3 
Case Report Forms.......................................................................................................................................... 20 
14.4 
Records Retention ........................................................................................................................................... 20 
15 
AUDITING, AND INSPECTING........................................................................................................................ 21 
15.1 
Auditing and Inspecting.................................................................................................................................. 21 
16 
ETHICAL CONSIDERATIONS......................................................................................................................... 21 
17 
STUDY FINANCES............................................................................................................................................... 21 
17.1 
Funding Source ............................................................................................................................................... 21 
17.2 
Conflict of Interest .......................................................................................................................................... 21 
18 
PUBLICATION PLAN ......................................................................................................................................... 21 
19 
REFERENCES ....................................................................................................................................................... 22 
 
 
2 List of Tables 
Table 1: Long-Term Clinical Studies with Clenbuterol ..................................................................................................... 6 
Table 2: Other Clinical Studies Using Clenbuterol ............................................................................................................ 7 
Table 3: Testing Schedule .................................................................................................................................................. 15 
Table 4: Power Percentage and Standard Deviation Assuming 25 Patients ................................................................... 16 
 
 
 
3 List of Figures 


 
 
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4 List of Abbreviations 
Adverse Event (AE) 
ALS Functional Rating Scale (ALSFRS-R)  
Alanine Aminotransferase (ALT) 
Amyotrophic Lateral Sclerosis (ALS)  
Aspartate Aminotransferase (AST) 
Creatine Kinase (CK) 
Enzyme Replacement Therapy (ERT)  
Forced Vital Capacity (FVC) 
Institutional Review Board (IRB) 
Late-Onset Pompe Disease (LOPD)  
Left Ventricular Assist Devices (LVAD) 
Left Ventricular (LV) 
Maximum Voluntary Ventilation (MVV) 
Microgram (mcg) 
Not Applicable (NA) 
5 
Study Summary 
Title 
A Clinical Investigation of the Safety and Efficacy of Clenbuterol on Motor 
Function in Individuals with Amyotrophic Lateral Sclerosis 
Short Title 
Clenbuterol in ALS 
Protocol Number 
NA 
Phase 
Phase ½ 
Methodology 
Single arm 
Study Duration 
24 weeks 
Study Center(s) 
Single-center 
Objectives 
The goals are to determine safety and efficacy with regard to motor function of 
oral clenbuterol in subjects with ALS 
Number of Subjects 
25 
Diagnosis and Main 
Inclusion Criteria 
1. Diagnosis of ALS according to the El Escorial criteria 
2. Age: 18+ years at enrollment. 
Study Product, Dose, 
Route, Regimen 
Clenbuterol (Spiropent): 40 to 80 mcgs BID per oral (up to 160 mcg per day 
maximum) 
Duration of 
administration 
24 weeks  
Reference therapy 
Standard of care at baseline 
Statistical 
Methodology 
 
The critical test of treatment efficacy will be the comparison of the ALSFRS-R 
slope during treatment to the estimated pre-treatment slope.  
   
 
 


 
 
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6 
Introduction 
This document is a protocol for a human research study. This study is to be conducted according 
to US and international standards of Good Clinical Practice (FDA Title 21 part 312 and 
International Conference on Harmonization guidelines), applicable government regulations and 
Institutional research policies and procedures.  
6.1 Background 
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that lacks 
effective treatment, proceeding to respiratory failure and premature death for affected 
individuals. The neuropathy of ALS  involves both upper motor neurons (UMN) and lower 
motor neurons (LMN) with critical secondary muscle involvement (KINSLEY AND SIDDIQUE 
1993). UMN signs include hyperreflexia, Babinski sign, increased muscle tone, and weakness. 
LMN signs include weakness, muscle wasting, hyporeflexia, muscle cramps, and fasciculations. 
Affected individuals typically present with either asymmetric weakness of the extremities 
(stumbling or poor handgrip), termed “limb onset” or bulbar findings (dysarthria, dysphagia). 
Limb onset is more frequent than bulbar onset. Once it begins, the weakness progresses, 
ultimately leading to total disability and dependence and shortened survival. The mean age of 
onset is 56 years in individuals with no known family history and 46 years in individuals with 
more than one affected family member (familial ALS or FALS). Average disease duration is 
about three years, but it can vary significantly. Death usually results from compromise of the 
respiratory muscles. Multiple confirmed genetic and suspected environmental causes have been 
described (KINSLEY AND SIDDIQUE 1993). Current ALS treatments have little effect on disease 
progression and are mainly directed at optimizing quality of life (Oskarsson and Staff 2018).  
The lack of effective therapy to reverse weakness or arrest ALS disease progression represents a 
critical unmet medical need. Clenbuterol’s ability to promote muscle hypertrophy and improve 
muscle function make it an attractive option for filling this need. Clenbuterol has been shown to 
stimulate muscle hypertrophy through inducing expression of insulin-like growth factor (Igf) -1 
and Igf-2 and their receptors (MATSUMOTO et al. 2006).  
 
Clenbuterol is a selective β2 agonist used for the treatment of asthma in Europe with a well-
established record of safety. In asthmatic patients with exercise induced bronchospasm a dose of 
20 mcg of clenbuterol given intravenously over 3-4 minutes resulted in negligible cardiac effects 
(DEL BONO et al. 1979). Subjects with asthma given 80 mcg of clenbuterol had a mild increase in 
heart rate, but no arrhythmia or significant electrocardiographic changes, tremor and headache 
has also been noted in asthma patients as well (WHITSETT et al. 1981). Multiple other studies in 
asthmatics and patients with chronic airway obstruction, found none or very mild AE (PASOTTI 
et al. 1979; TSCHAN et al. 1979; DI GIOACCHINO et al. 1987). These and other studies reassure us 
regarding the potential use of clenbuterol in ALS (BIRKS et al. 2006; KAMALAKKANNAN et al. 
2008).  
Clenbuterol has been well tolerated and had beneficial muscle effects in a Phase I/II clinical trial 
(160 mcg/day) that enrolled patients with late-onset Pompe disease who were previously treated 
with ERT (KOEBERL et al. 2018). Similar dosages have increased muscle strength or increased 
muscle mass in other studies. Patients with chronic heart failure developed increased lean muscle 


 
 
Page 6 of 23 
 
mass after taking clenbuterol at 80 mcg/day for 12 weeks (KAMALAKKANNAN et al. 2008). A 
small group of patients with Duchenne muscular dystrophy developed increased power and 
volume of well-preserved muscle following 18 months of taking clenbuterol, 30-40 mcg/day  
(OYA et al. 2001). Adverse events (AEs) associated with clenbuterol may include tremor, muscle 
cramps, nervousness, palpitations, tachycardia, and headache (Table 1), and are typically well-
tolerated. These studies demonstrated the benefits of clenbuterol’s effects on muscle, and its 
safety and tolerability in a variety of conditions other than ALS. 
A previous small open-label pilot trial of clenbuterol in patients with ALS showed very 
promising results (SORARU et al. 2006). Sixteen patients with ALS were started on 60 mcg/day, 
and fourteen completed 6 months of treatment.  Significant improvements in limb muscle 
strength and forced vital capacity (FVC) occurred in these patients, and a functional measure 
called the ALS functional rating scale score was stable over the course of the trial.  
Improvements and stability on these recognized ALS outcome measures are not typical of the 
natural history of this disease.  Again, clenbuterol was found to be safe and well-tolerated (Table 
1).  The dramatically positive results of this pilot trial need to be replicated. 
Table 1: Long-Term Clinical Studies with Clenbuterol 
Study  
Study Design  
Number of 
Subjects  
Dosage and 
Regimen  
Adverse Events  
(DI GIOACCHINO et 
al. 1987) 
Open label study of 
clenbuterol in 
exercise induced 
asthma 
14 patients 
20 mcg bid for 
60 days 
Small increase in 
heart     rate 
(ISHIKO et al. 2000) 
Randomized study 
of clenbuterol  and 
physiological  
therapy (PT)  in 
stress incontinence 
61 patients 
assigned to 
three groups 
A-clenbuterol 
only 
B- PT only 
C - both 
20 mcg bid for 
12 weeks in 41 
patients 
( group A and 
C) 
1) Two  patients 
with headache 
2) One patient with 
mild hepatopathy 
3) One patient with 
rash  
4) One patient with 
numbness 
(SORARU et al. 
2006) 
6 month open label 
dosing in patients 
with ALS  already 
on riluzole 
16 patients 
20 mcg TID for 
6 months 
Tremor, nervousness, 
cramps, fasciculations 
(details not provided) 
(KAMALAKKANNAN 
et al. 2008) 
Single site, 
randomized, double 
blind placebo 
controlled in 
subjects with class 2 
or 3 congestive 
heart failure 
19 subjects -- 
10 placebo 
9 clenbuterol 
20 mcg BID, 
increased to 40 
mcg BID after 7 
days – 12 weeks 
total 
1) Two clenbuterol 
subjects withdrew, 
one with 
asymptomatic 
ventricular 
tachycardia, and one 
with muscle cramps 
without elevated CK 
2) Six clenbuterol and 
two placebo subjects 
with muscle cramps 
3) CK elevated in 5 


 
 
Page 7 of 23 
 
subjects on 
clenbuterol, and  in 4 
on placebo 
4) Tremors in 5 
subjects on 
clenbuterol and two 
on placebo  
(KOEBERL et al. 
2018) 
52 week double-
blind, placebo 
controlled, 
prospective study in 
LOPD patients 
stably treated with 
ERT for >1 year 
13 
randomized, 
11 completed 
40 mcg for 1 
week, 40 mcg 
BID for 5 
weeks, 80 mcg 
AM + 40 mcg 
PM for 1 week, 
80 mcg BID for 
40 weeks 
4 subjects with tremor 
4 subjects with 
insomnia 
4 subjects with 
muscle spasms 
6.2  Investigational Agent 
 
ACTIONS AND MODE OR MECHANISMS OF ACTIONS 
Clenbuterol is a broncholytic agent which acts through selective stimulation of the β2-
receptors. It differs from other β2-specific sympathomimetics by its low dose, long 
biological half-life and rapid and complete absorption by oral administration. It has no 
significant effects on β1-cardiac receptors. 
 
PHARMACOLOGY 
Pharmacokinetics: Invasion half-life of clenbuterol is 1 hour, and the distribution 
corresponds to an open two compartment model with a side-compartment. Elimination from 
plasma takes place in 2 phases, the half-life of the a-phase being 1 hour and that of β-phase 
34 hours. Elimination is primarily renal (87% after 168 hours) 43% of clenbuterol is 
recovered unchanged in the urine. Dose intervals of 12 hours suffice to maintain a plasma 
level. Five metabolites have been found in humans. 
 
INDICATIONS 
Prophylaxis and therapy of bronchospasm in bronchial asthma, acute and chronic bronchitis 
associated with emphysema. 
 
CONTRAINDICATIONS 
Thyrotoxicosis, idiopathic hypertrophic subvalvular aortic stenosis, tachycardia, 
tachyarrhythmia. Known sensitivity to sympathomimetic amines. 
 
SIDE EFFECTS/ADVERSE REACTIONS 
Side effects rarely occur at the recommended doses. Some patients could have, at the 
beginning of the treatment, tremor, nervousness, extrasystoles, tachycardia, palpitations, 
vertigo, anxiety, headache and nausea. In these cases the dose should be reduced. 
 
PRECAUTIONS/WARNINGS 


 
 
Page 8 of 23 
 
Warnings: Although animal studies have shown no teratogenic effect, clenbuterol should 
not be given during the first three months of pregnancy. 
 
Precautions: Care must be exercised when additional sympathomimetic agents or IMAO 
drugs are administered. Clenbuterol should be used with caution in patients with 
hypertension, coronary heart disease, hyperthyroidism and diabetes. Caution should be used 
when treating patients with recent cardiac infarction. 
6.3 Preclinical Data 
Teng and colleagues investigated the effect of clenbuterol upon longevity in a transgenic murine 
model of familial ALS (TENG et al. 2006). Clenbuterol treated mice demonstrated improved 
neuromuscular function through better Rotarod performance, slower disease progression, and 
reduced loss of lumbar motor neurons and body weight. These benefits are attributable to 
clenbuterol’s induction of muscle Igf -1 expression and the associated muscle hypertrophy 
(MATSUMOTO et al. 2006), because the expression of Igf-1 with gene therapy in muscle has also 
improved muscle function and survival in mice with ALS (KASPAR et al. 2003). These data 
suggest that clenbuterol will have beneficial effects both through muscle hypertrophy and 
neuroprotection in ALS. The main symptoms of ALS stem from muscle weakness, and 
respiratory muscle weakness is the main cause of mortality.  
 
 
6.4 Dose Rationale and Risk/Benefits 
The selected dose (80 mcg BID) is based upon the experience with the long-term administration 
of clenbuterol, specifically the beneficial muscle effects in a Phase I/II clinical trial that enrolled 
patients with late-onset Pompe disease who were previously treated with ERT (KOEBERL et al. 
2018). 
 
The potential benefits outweigh anticipated risks for daily clenbuterol administration in patients 
with ALS. Clenbuterol treatment has been associated with specific AEs that may include tremor, 
muscle cramps, nervousness, and headache (Table 1), as observed in our Phase I/II study in 
patients with Pompe disease (KOEBERL et al. 2018). Cardiovascular adverse effects of 
clenbuterol may include palpitations associated with an increase in heart rate. However use of 
clenbuterol in conservative doses (up to 720 mcg/day) is well tolerated. In a pilot study of 
patients with congestive heart failure (CHF), clenbuterol was given at 40 mcg twice daily for 12 
weeks in 19 patients (n=10 clenbuterol, n=9 placebo) with chronic heart failure in addition to 
their standard CHF therapy. The drug was well tolerated and there were no serious AEs in that 
study. Only two patients required discontinuation of study drug (one due to asymptomatic slow 
ventricular tachycardia seen on a 24-hour electrocardiogram and the other due to muscle 
cramps). Muscle cramps occurred in 6 clenbuterol subjects; only one subject required dose 
reduction. CK was elevated in 6 clenbuterol subjects (range of peak CK was 300-664 mg/dl, 
normal range 51-294 mg/dl) and mild tremors were reported in five subjects. No subjects 
required dose reduction due to elevation of CK or tremors in that study.(KAMALAKKANNAN et al. 
2008) In our study in Pompe disease two subjects required dose reduction to 120 mcg from 160 
mcg twice daily, due to minor AEs that resolved subsequently (KOEBERL et al. 2018). 
 


 
 
Page 9 of 23 
 
In a pilot study of patients with congestive heart failure (CHF), clenbuterol was given at 40 mcg 
BID per oral for 12 weeks in 19 patients (n=10 clenbuterol, n=9 placebo) with chronic heart 
failure in addition to their standard CHF therapy. The drug was well tolerated and there were no 
serious adverse effects in any of the study subjects. Only two patients required discontinuation of 
study drug (one due to asymptomatic slow ventricular tachycardia seen on a 24- hour 
electrocardiogram and the other due to muscle cramps). Muscle cramps occurred in 6 clenbuterol 
subjects; only one subject required dose reduction. CK was elevated in 6 clenbuterol subjects 
(range of peak CK300-664 mg/dl, normal range 51-294 mg/dl) and mild tremors were reported 
in five subjects. No subjects required dose reduction due to elevation of CK or tremors 
(KAMALAKKANNAN et al. 2008). 
 
Other studies generated data about the use of clenbuterol in patients with cardiac disease (Table 
2). Clenbuterol in high doses (up to 2100 mcg/day) has been administered to 19 patients with 
end-stage HF supported with an LVAD, without significant arrhythmia or AE (YACOUB 2001; 
BIRKS et al. 2006). A study of clenbuterol in seven patients with implanted left ventricular assist 
devices (LVAD), a maximal dose of 720 mcg per day was given over 3 months. All seven 
patients were treated with and continued a maximum tolerated dose of metoprolol prior to 
initiation of clenbuterol. This dose of clenbuterol was well tolerated in all subjects. Serum 
creatine kinase (CK) was elevated in four subjects on clenbuterol, peak range (314-1497mg/dl). 
Mild tremors were seen in three subjects; mild muscle cramps were reported in four. No dose 
reduction was required for AE and there were no arrhythmic events (GEORGE et al. 2006). In 
another study of 15 patients with LVAD in heart failure were treated with clenbuterol. The first 
stage of treatment was four drugs, lisinopril, carvedilol, spironolactone, and losartan. The second 
phase of treatment was initiated when carvedilol was replaced with bisoprolol, and clenbuterol 
was started at a dose of 40 mcg three times daily and titrated to a maximal dose of 700 mcg TID 
(2100 mcg/day). Mild tremor was seen in all patients, muscle cramps in 3, but without elevated 
CK, and 1 patient had diaphoresis (BIRKS et al. 2006). A prospective study in 2011 looked again 
at this same pharmacological therapy of 20 patients with continuous flow LVAD with heart 
failure again showing that clenbuterol was well tolerated, with 4 patients developing muscle 
cramps and 2 developing mild tremor (BIRKS et al. 2011).  
 
Clenbuterol has also been shown to be well tolerated when used to treat urinary incontinence in 
Germany and Japan (Table 2). In a controlled double blind study of 39 patients with motor urge 
incontinence, 20 were treated with 10 mcg clenbuterol three times a day and the other 19 were 
treated with flavoxate hydrochloride for 6 weeks. Adverse events consisted of  4 patients with 
trembling fingers and tachycardia, 3 patients with nervousness and 1 patient stopped due to a 
drug interaction with an alpha stimulating, antihypertensive drug, clonidine which caused 
dizziness (GRUNEBERGER 1984). In a comparison study of three groups of women all with stress 
incontinence, Group A got clenbuterol only, Group B got physiological therapy and Group C got 
both. Clenbuterol was given at a dose of 20 mcg twice daily for 12 weeks. Adverse events 
consisted of 2 patients with headache, 1 patient with mild hepatopathy, 1 patient with rash and 1 
patient with numbness (ISHIKO et al. 2000). 
 


 
 
Page 7 of 23 
 
Table 2: Other Clinical Studies Using Clenbuterol 
Heart Failure Subjects 
(Reference)  
Study Design  
Number of 
Subjects  
Dosage and 
Regimen  
AEs  
(BIRKS et al. 2006) 
All received LV assist 
device and were in severe 
heart failure, primary 
pharm regiment and the 
secondary regiment of 
clenbuterol 
15  subjects 
40 mcg BID, 
titrated up to 40 
mcg TID then 
titrated up to 
700 mcg TID 
Mild tremor in all  
4 with muscle cramps without elevated CK 
Diaphoresis in 1 
(GEORGE et al. 2006) 
 
 
 
 
All  with LV assist 
devices with heart failure 
7  subjects  
Started at 40 mcg 
TID titrated up to 
720 mcg a day 
over 6 weeks, 12 
weeks of total 
treatment 
4 with elevated CPK, all had increases in 
CPK 
 3 with tremors 
4 with muscle cramps 
(BIRKS et al. 2011) 
All received LV assist 
device and were in severe 
heart failure, primary 
pharm regiment and the 
secondary regiment of 
clenbuterol 
20  subjects 
16 of the 20 made 
it to stage 2 to 
receive clenbuterol 
started at 40 mcg 
BID and increased 
to 700 mcg TID 
4 with muscle cramps  
2 with mild tremors 
2 with ventricular tachycardia that was not 
clenbuterol 
Asthma/ Chronic Airway 
obstruction  Subjects 
(Reference)  
Study Design  
Number of 
Subjects  
Dosage and 
Regimen  
AEs  
(WHITSETT et al. 1981) 
Single oral doses of 
clenbuterol compared to 
placebo, randomized 
double blind crossover in  
subjects with reversible 
obstructive airway 
disease 
13   subjects,  
10 finished 
study  
 
 
 
 
 
Multiple single 
oral doses in 40, 
60 and 80 mcg  
Tremor and headache 


 
 
Page 8 of 23 
 
(TSCHAN et al. 1979) 
 
Dose response study of 
clenbuterol in  subjects 
with obstructive lung 
disease 
12  subjects  
6,12, 24 and 48 
mcg given qd for 4 
days 
No side effects noted 
(PASOTTI et al. 1979) 
Double blind comparison 
of clenbuterol and 
salbutamol in  subjects 
with asthma   
30  subjects  
15 clenbuterol 30 
mcg BID for  
3days and  then 20 
mcg BID 
No side effects noted 
(DI GIOACCHINO et al. 
1987) 
Open label study of 
clenbuterol in exercise 
induced asthma 
14  subjects 
20 mcg BID for 60 
days 
Small increase in heart rate 
(BRUSASCO et al. 1980) 
 
 
 
Single blind cross over 
study comparing 
clenbuterol  and 
terbutaline in  subjects 
with chronic airway 
obstruction 
16  subjects 
20 to 30 mcg TID 
for  2 weeks 
5 with tremors 
(DEL BONO et al. 1979) 
Single blind placebo 
controlled cross over 
study comparing  IV 
clenbuterol and  IV 
terbutaline in asthmatic  
subjects 
9  subjects 
20 mcg daily by 
IV for 4 days 
No adverse reactions were observed with 
clenbuterol 
 
 


 
 
Page 9 of 23 
 
 
Incontinence  Subjects 
(Reference) 
Study Design  
Number of 
Subjects  
Dosage and 
Regimen  
AEs  
(GRUNEBERGER 1984) 
Controlled double blind 
study of Flavoxate vs 
Clenbuterol in motor 
urge incontinence 
39  subjects 
total 
20  subjects in 
Clenbuterol 
arm and 19 in 
Flavoxate arm 
20  subjects 
treated for 6 weeks 
with 10 mcg 
clenbuterol three 
times a day 
4  with trembling fingers and tachycardia  
3  with nervousness 
1  subject stopped due to a drug interaction 
with an alpha stimulating, antihypertensive 
drug, clonidine that caused dizziness 
(ISHIKO et al. 2000) 
Randomized study of 
clenbuterol  and 
physiological  therapy 
(PT)  in stress 
incontinence 
61  subjects 
assigned to 
three groups 
A-clenbuterol 
only 
B- PT only 
C - both 
20 mcg BID for 12 
weeks in 41  
subjects 
( group A and C) 
2   with headache 
1  with mild hepatopathy 
1  with rash 
1  with numbness 
 
 
 


 
 
Page 10 of 23 
 
7 Study Objectives 
Primary Objective 
To assess the safety and tolerability of clenbuterol in subjects with ALS 
 
Secondary Objective 
To assess the efficacy of clenbuterol with regard to motor function in subjects with ALS 
 
8 Study Design 
8.1 General Design 
This is a 24 week Phase I/II study of clenbuterol in patients with ALS (Table 3, Section 11). All subjects will be 
evaluated at Week 0 to establish a baseline and return to be evaluated for safety and efficacy during the Week 4, 
12 and 24 visits. The drug will be initiated at the Week 0 visit in a staged manner (first once daily and later 
BID), and the dose will be increased at the Week 6 visit in a similarly staged manner to minimize AEs and 
related attrition. All subjects will return for a final visit after a total of 24 weeks in the study.  
 
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 6 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 12 visit.  If 80 mcg BID is tolerated at Week 12, the subject will continue on that dose until Week 24. 
The subject will have several phone visits to evaluate safety, tolerability and ALSFRS-R score.  These will 
occur at Week 1, 6, 16, and 20.   
 
The efficacy of clenbuterol administration will be evaluated with the revised ALS Functional Rating Scale 
(ALSFRS-R) and other secondary endpoints.  
  
8.2 Primary Study Endpoints 
The primary endpoint is safety of clenbuterol at 80 mcg BID.  Adverse and serious AEs will be systematically 
gathered as described in section 8 below. 
 
 
8.3 Secondary Study Endpoints 
Secondary endpoints will include the ALSFRS-R, forced vital capacity (FVC), sniff nasal inspiratory, isometric 
muscle strength, and sub-maximum handgrip fatigue as described (SHEFNER et al. 2016). 
 
9 Subject Selection and Withdrawal 
9.1 Inclusion Criteria 
 
1. Diagnosis of possible or more definite ALS according to the El Escorial criteria 
2. FVC >50% of predicted for age, height and gender.  If FVC testing is restricted due to COVID-19, then 
a most recent FVC within the past 6 months of 80% or greater will be allowed. 
3. At least four of 12 ALSFRS-R questions scored as 2 or 3 at screening.  


 
 
Page 11 of 23 
 
4. Diminished but measurable grip strength (1) in at least one hand (females:10–50 pounds; males, 10–70 
pounds). 
5. Taking riluzole at a stable dose or not taking riluzole at screening. 
6. On Radicava at a stable dose for at least 30d or not taking this 
7. Life expectancy at least 6 months 
8. Able to swallow tablets without crushing. 
9. Age: 18+ years at enrollment. 
10. Subjects are capable of giving written consent. 
11. If sexually active, must agree to use contraceptive or abstinence for duration of treatment  
12. Females of child bearing age must have negative pregnancy test at screening 
 
9.2 Exclusion Criteria 
 
1. Concurrent illness or laboratory abnormalities that could confound the measurement of ALS progression 
or interfere with the ability to complete the study. 
2. Taking any investigational study drug within 30 days of screening or five half-lives of the prior agent. 
3. No previous exposure to clenbuterol.  
4. Pregnancy 
5. Clinically relevant EKG abnormality (arrhythmia, cardiomyopathy) 
6. Tachycardia (resting heart rate greater than 100 beats per minute) 
7. History of seizure disorder 
8. Hyperthyroidism 
9. Pheochromocytoma  
10. Pregnancy 
11. Have any other co-morbid conditions that in the opinion of the study investigator, places the participant at 
increased risk of complications, interferes with study participation or compliance, or confounds study 
objectives 
12. History of hypersensitivity to β2-agonist drugs such as albuterol, levalbuterol (Xopenex), bitolterol 
(Tornalate), pirbuterol (Maxair), terbutaline, salmeterol (Serevent). 
13. The use of the following concomitant meds is prohibited during the study:  
i. diuretics (furosemide, Lasix) 
ii. digoxin (digitalis, Lanoxin); 
iii. β-blockers such as atenolol (Tenormin), metoprolol (Lopressor), and propranolol 
(Inderal); 
iv. tricyclic antidepressants such as amitriptyline (Elavil, Etrafon), doxepin (Sinequan), 
imipramine (Janimine, Tofranil), and nortriptyline (Pamelor); 
v. MAO inhibitors such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline 
(Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate); or 
vi. other bronchodilators such as albuterol (Ventolin), levalbuterol (Xopenex), bitolterol 
(Tornalate), pirbuterol (Maxair), terbutaline (Brethine, Bricanyl), salmeterol (Serevent), 
isoetherine (Bronkometer), metaproterenol (Alupent, Metaprel), or isoproterenol (Isuprel 
Mistometer). 
 
 
 
 


 
 
Page 12 of 23 
 
9.3 Subject Recruitment and Screening 
 
Patients from Dr. Bedlack’s clinic will be approached by study staff to determine their interest in participating 
in this clinical study. The consent form will be reviewed at the subject’s routine clinic visit. Following consent, 
research study appointments will be made. No compensation is being provided for participation in this study. 
 
9.4 Early Withdrawal of Subjects 
 
When and How to Withdraw Subjects 
If the subject decides not to participate or to withdraw from the study, this action will not involve any penalty or 
loss of benefits to which the subject is entitled, and will not affect the subject’s access to health care at Duke. If 
the subject decides to withdraw, the subject will be asked to contact the investigator to notify him. In addition, 
the subject will be asked to return all unused study drug to the investigator or his staff. The subject will be told 
about any new information that may affect his or her health, welfare, or willingness to stay in this study. 
 
The investigator may decide to take any subject off this study if his or her condition gets worse, if he or she has 
serious side effects, or if the investigator determines that it is no longer in the subject’s best interest to continue. 
If the study were halted by the sponsor or a regulatory agent, the subjects will be notified and other options will 
be discussed. 
 
Data Collection and Follow-up for Withdrawn Subjects 
Subjects who withdraw from the study prior to completion of activities will be called in order to determine 
subject’s overall health status and ascertain any adverse effects, and will be asked to return to a follow-up visit 
for evaluation including medical history, vital signs, and physical examination. 
10 Study Drug  
10.1 Description  
 
The active study drug will be 20 mcg Spiropent tablets. 
10.2 Treatment Regimen 
Dosage will initially 40 mcg daily for one week, 40 mcg BID per oral daily for the next 5 weeks. 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 per oral for the remainder of the study. 
10.3 Method for Assigning Subjects to Treatment Groups 
All subjects will be assigned to the study drug. 
10.4 Preparation and Administration of Study Drug 
The drug will be stored and dispensed from the Investigational Drug Service at Duke University Health Systems 
(beth.mclendon@duke.edu). 
10.5 Subject Compliance Monitoring 
Compliance (pill counts) will be measured at the Week 4, Week 12, and Week 24 visits. The subject will have 
phone visits during Week 1, 7, 12, 16 and 20, and compliance will be discussed then.  Subjects who miss >6 
doses of the study drug, will be considered non-compliant and withdrawn from the study (Table 3). 


 
 
Page 13 of 23 
 
 
10.6 Prior and Concomitant Therapy 
The use of the following concomitant meds is prohibited during the study:  
• 
digoxin (digitalis, Lanoxin); 
• 
diuretics (furosemide, Lasix); 
• 
β-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); 
• 
MAO inhibitors such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), 
selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate); or 
• 
other bronchodilators such as albuterol (Ventolin), levalbuterol (Xopenex), bitolterol (Tornalate), 
pirbuterol (Maxair), terbutaline (Brethine, Bricanyl), salmeterol (Serevent), isoetherine 
(Bronkometer), metaproterenol (Alupent, Metaprel), or isoproterenol (Isuprel Mistometer). 
 
10.7 Packaging 
The Investigational Drug Pharmacy at Duke will package drug for this study. 
 
10.8 Blinding of Study Drug 
Not applicable. 
10.9 Receiving, Storage, Dispensing and Return 
10.9.1  
Receipt of Drug Supplies 
Spiropent (PZN#01980325) will be purchased from Boehringer Ingelheim. 
 
Upon receipt of the study treatment supplies, an inventory must be performed and a drug receipt log filled 
out and signed by the person accepting the shipment. It is important that the designated study staff counts 
and verifies that the shipment contains all the items noted in the shipment inventory. Any damaged or 
unusable study drug in a given shipment (active drug) will be documented in the study files. The 
investigator must notify study sponsor of any damaged or unusable study treatments that were supplied to 
the investigator’s site. 
10.9.2  
Storage 
Storage will be at ambient temperature in the Duke Hospital Pharmacy. 
10.9.3  
Dispensing of Study Drug 
The Investigational Drug Service will dispense study drug (clenbuterol 20 mcg) to the study team at the 
Screening/Baseline/Week 0 visit.   Subsequently, additional supply of study drug will be shipped before 
Week 18 to allow completion of the study.  The Investigational Drug Service will maintain records of 
drug dispensing. 
10.9.4  
Return or Destruction of Study Drug 
Unused drug will be destroyed by the Investigational Drug Service at the end of the study. 
 


 
 
Page 14 of 23 
 
At the completion of the study, there will be a final reconciliation of drug shipped, drug consumed, and 
drug remaining. This reconciliation will be logged on the drug reconciliation form, signed and dated. Any 
discrepancies noted will be investigated, resolved, and documented prior to return or destruction of unused 
study drug. Drug destroyed on site will be documented in the study files. 
11 Study Procedures 
1. Research Activities: Medical History: Reviewed prior to study drug initiation. 
2. Vital Signs: Completed at Screening/Baseline, Week 4, Week 12, and Week 24. 
3. Physical Examination: Performed at Screening/Baseline, Week 4, Week 12, and Week 24. 
4. AE Review: Completed at Week 4, Week 12, Week 24, and telephone visits. 
5. Blood Samples:  Blood samples will be obtained at Screening/Baseline, Week 4, Week 12, and Week 24. 
for the following analyses:  
• Safety Labs: Hematology and Chemistry (5 ml) to consist of: 
a. Complete Blood Count (CBC) 
b. Chemistry panel (including electrolytes, BUN, creatinine, glucose)  
c. Liver panel (including albumin, aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), and total bilirubin) 
d. Creatine kinase (CK) 
6. Electrocardiogram:  Performed at Screening/Baseline, Week 4, Week 12, and Week 24. 
7. Forced Vital Capacity (FVC) Testing: Performed at Screening/Baseline, Week 4, Week 12, and Week 24  
8. ALSFRS-R: Performed at Screening/Baseline, Week 4, Week 12, Week 16, Week 20 and Week 24. 
9. Muscle strength testing: Myometer testing (SORARU et al. 2006) and isometric muscle strength, and sub-
maximum handgrip fatigue (SHEFNER et al. 2016), performed at Screening/Baseline, Week 4, Week 12, and 
Week 24.  
10. Telephone visits: Performed during Week 1, 6, 16 and 20. 
11. Serum pregnancy testing at Screening/Baseline. Urine pregnancy testing at Weeks 4, 12 and 24. 
12. Thyroid function (T4, TSH) at Screening/Baseline. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Table 3: Testing Schedule 
 
Screening/ 
Baseline 
(Week 0) 
Phone 
Visit 
(Week 
1)  
Study 
Visit 
(Week 
4) 
Phone 
Visit 
(Week 
6)  
Study 
Visit 
(Week 
12) 
Phone 
Visit 
(Week 
16) 
Phone 
Visit 
(Week 
20) 
Final 
Visit 
(Week 
24)  
Medical 
History 
X 
 
 
 
 
 
 
 
Vital Signs 
X 
 
X 
 
X 
 
 
X 
Physical Exam 
X 
 
X 
 
X 
 
 
X 
Obtain 
Consent 
X 
 
 
 
 
 
 
 
Study Drug 
Dispensed 
X 
 
X 
 
X 
 
 
 
AE Review 
 
X 
X 
X 
X 
X 
X 
X 
Blood Sample 
X 
 
 
 
X 
 
 
X 
  Safety testing 
X 
 
X 
 
X 
 
 
X 
  Thyroid 
function 
testing 
X 
 
 
 
 
 
 
 
Pregnancy test 
 
 
 
 
 
 
 
 
   Blood 
X 
 
 
 
 
 
 
 
    Urine 
 
 
X 
 
X 
 
 
X 
EKG 
X 
 
X 
 
X 
 
 
X 
Pulmonary 
function 
testing  
X 
 
X 
 
X 
 
 
X 
ALSFRS-R 
X 
 
X 
 
X 
X 
X 
X 
Muscle 
strength 
testing 
X 
 
X 
 
X 
 
 
X 
 
 
 
12 Statistical Plan 
12.1 Sample Size Determination 
Due to the number of patients with ALS who are followed in Dr. Bedlack’s clinic, we estimate that 25 subjects 
can be enrolled and complete the study within 1 year.   
 
Power Analysis 
The ALSFRS-R is a rating utilized for monitoring the progression of disability in patients with ALS. The 
decline of the rating is generally linear in time and current research focuses on reducing the slope of ALSFRS-R 
with respect to time through novel treatments. Alfredo E. Farjat, Ph.D. performed a simulation study to assess 
the effectiveness for detecting specific changes in the slope of ALSFRS-R with respect to time (Table 4). The 
goal was to estimate the power for future clinical trials. 


 
 
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Table 4: Power Percentage and Standard Deviation Assuming 25 Patients 
Number of observations 
(per patient) 
Slope percentage change 
(compared to pre-trial rate of decline)  
16%  
17%  
18%  
19%  
20%  
4 
35.4 (1.5) 43.6 (1.6) 50.1 (1.6) 54.0 (1.6) 
57.7 (1.6) 
5 
70.2 (1.4) 74.7 (1.4) 81.3 (1.2) 83.4 (1.2) 
88.5 (1.0) 
6 
89.8 (1.0) 95.0 (0.7) 95.9 (0.6) 97.3 (0.5) 
98.6 (0.4) 
7 
98.8 (0.3) 99.1 (0.3) 99.6 (0.2) 98.8 (0.1) 
>99.9 (<0.1) 
 
The results indicate that a 20% change in the slope, compared to pre-trial rate of decline, can be detected with 
power >99.9 (<0.1) with 7 observations (six months trial - baseline observation plus one observation monthly). 
 
12.2 Statistical Methods 
Descriptive statistics (N, mean, median, standard deviation, and range) will be provided as appropriate.  
Continuous data will be summarized by using means, medians, standard deviations and ranges for each group 
and visit.  Categorical data, including AE analysis, will be summarized by using frequencies and distributions.   
Secondary endpoints will include the ALSFRS-R, FVC, isometric muscle strength, and sub-maximum handgrip 
fatigue as described (SHEFNER et al. 2016) and myometer testing as described (SORARU et al. 2006). 
 
The critical test for efficacy will be comparison of the slope of the ALSFRS-R during treatment compared to 
pre-treatment.  Pre-treatment slope for each participant will be estimated as follows: (48-enrollment ALSFRS-
R)/months since symptom onset. ALSFRS-R is a quickly administered (five minute) ordinal rating scale 
(ratings 0-4) used to determine patients' assessments of their capability and independence in 13 functional 
activities.  All 12 activities are relevant in ALS.  Initial validity was established in ALS patients by 
documenting that change in ALSFRS-R scores correlated with change in strength over time, was closely 
associated with quality of life measures, and predicted survival. The test-retest reliability is greater than 0.88 for 
all 13 items. The ALSFRS-R declines linearly with time over a wide range during the course of ALS. The 
minimum clinically significant change in this scale is said to be 20%.  The measure can be reliably conducted 
over the phone.  A secondary measure of efficacy will be the comparison of the change in lower limb total 
myometry  observed between Baseline and Week 24.  A statistically significant treatment effect will be 
determined by a two-tailed, paired t-test, with a critical p value < .05.   Tertiary analyses will include a mixed 
design (between and within) ANOVA of the lower limb total myometry across visits as well as a comparison of 
the slope of percent predicted FVC during treatment versus pre-treatment .  Pre-treatment slope for each 
participant will be estimated as follows: (100%-enrollment percent predicted FVC)/months since symptom 
onset. Multiple exploratory comparisons will be made to identify potential length of treatment effects.          
12.3 Subject Population(s) for Analysis 
All subjects who complete the study will be included in the analysis, providing non-compliance is not 
documented. 


 
 
Page 17 of 23 
 
13 Safety and Adverse Events 
13.1 Definitions 
13.1.1  
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study. Intercurrent illnesses or injuries should be regarded as AEs. Abnormal 
results of diagnostic procedures are considered to be AEs if the abnormality: 
• results in study withdrawal 
• is associated with a serious AE 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
13.1.2  
Serious Adverse Event 
Adverse events are classified as serious or non-serious. A serious adverse event is any AE that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance.  They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above. For example, drug overdose or abuse, a seizure that did not result in 
in-patient hospitalization, or intensive treatment of bronchospasm in an emergency department would 
typically be considered serious.  
 
All AEs that do not meet any of the criteria for serious should be regarded as non-serious adverse events.  
13.1.3  
Adverse Event Reporting Period 
The study period during which AEs must be reported is normally defined as the period from the initiation 
of any study procedures to the end of the study treatment follow-up. For this study, the study treatment 
follow-up is defined as 30 days following the last administration of study treatment.  
13.1.4  
Preexisting Condition 
A preexisting condition is one that is present at the start of the study. A preexisting condition should be 
recorded as an AE if the frequency, intensity, or the character of the condition worsens during the study 
period. 
13.1.5  
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting condition. At the 
end of the study, any new clinically significant findings/abnormalities that meet the definition of an AE 
must also be recorded and documented as an AE.  


 
 
Page 18 of 23 
 
13.1.6  
Post-study Adverse Event 
All unresolved AEs should be followed by the investigator until the events are resolved, the subject is lost 
to follow-up, or the AE is otherwise explained. At the last scheduled visit, the investigator should instruct 
each subject to report any subsequent event(s) that the subject, or the subject’s personal physician, 
believes might reasonably be related to participation in this study. The investigator should notify the study 
sponsor of any death or AE occurring at any time after a subject has discontinued or terminated study 
participation that may reasonably be related to this study. The sponsor should also be notified if the 
investigator should become aware of the development of cancer or of a congenital anomaly in a 
subsequently conceived offspring of a subject that has participated in this study.  
13.1.7  
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an AE if any one of the following conditions 
is met:  
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm the abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic investigation 
13.1.8  
Hospitalization, Prolonged Hospitalization or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be documented and reported as 
a SAE unless specifically instructed otherwise in this protocol. Any condition responsible for surgery 
should be documented as an AE if the condition meets the criteria for an AE.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an AE in the 
following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for a 
preexisting condition. Surgery should not be reported as an outcome of an AE if the purpose of the 
surgery was elective or diagnostic and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, unless it 
is a worsening or increase in frequency of hospital admissions as judged by the clinical 
investigator. 
13.2 Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on AEs by specific questioning and, as 
appropriate, by examination. Information on all AEs should be recorded immediately in the source document, 
and also in the appropriate AE module of the case report form (CRF). All clearly related signs, symptoms, and 
abnormal diagnostic procedures results should recorded in the source document, though should be grouped 
under one diagnosis. 
 
All AEs occurring during the study period must be recorded. The clinical course of each event should be 
followed until resolution, stabilization, or until it has been determined that the study treatment or participation is 
not the cause. SAEs that are still ongoing at the end of the study period must be followed up to determine the 
final outcome. Any SAE that occurs after the study period and is considered to be possibly related to the study 
treatment or study participation should be recorded and reported immediately. 


 
 
Page 19 of 23 
 
13.3 Reporting of Serious Adverse Events 
13.3.1  
IRB Notification by Investigator 
Reports of all SAEs (including follow-up information) must be submitted to the IRB within 10 working 
days. Copies of each report and documentation of IRB notification and receipt will be kept in the 
Clinical Investigator’s binder. 
13.3.2  
FDA Notification by Sponsor 
The IND sponsor shall notify the FDA by telephone or by facsimile transmission of any serious, 
unexpected and study related experience associated with the use of the drug as soon as possible but no 
later than 15 calendar days from the sponsor’s original receipt of the information. In addition, any fatal 
or life-threatening experience associated with the use of the drug shall be reported as soon as possible 
but no later than 7 calendar days from the sponsor’s original receipt of the information. 
 
If a previous AE that was not initially deemed reportable is later found to fit the criteria for reporting, 
the IND sponsor will submit the AE in a written report to the FDA as soon as possible, but no later than 
15 calendar days from the time the determination is made. 
13.4 Unblinding Procedures 
Not applicable. 
13.5 Definitions 
13.5.1  
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study. Intercurrent illnesses or injuries should be regarded as AEs.  Abnormal 
results of diagnostic procedures are considered to be AEs if the abnormality: 
 
•    results in study withdrawal 
• is associated with an SAE 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
13.5.2  
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance.  They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above. For example, drug overdose or abuse, a seizure that did not result in 


 
 
Page 20 of 23 
 
in-patient hospitalization or intensive treatment of bronchospasm in an emergency department would 
typically be considered serious.  
 
All AEs that do not meet any of the criteria for serious should be regarded as non-serious adverse events.  
13.6 Medical Monitoring 
13.6.1  
Internal Data and Safety Monitoring Committee 
The study will be monitored throughout the trial by a Data and Safety Monitoring Committee (DSMB) 
consisting of a 4 Duke University School of Medicine faculty members who are unaffiliated with the study.  
The DSMB will convene during the study at approximately 6 month intervals to review summaries of accrual 
and enrollment information, results for EKGs and PFTs, and safety (AEs, withdrawal from study). The DSMB 
will provide summaries to the PI’s. Safety will be monitored on an ongoing basis as descriptions of SAEs will 
be communicated to the DSMB Chair within 24 hours of their occurrence.  
14 Data Handling and Record Keeping 
14.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of the 
Health Insurance Portability and Accountability Act of 1996 (HIPAA). The subject will not be identified by 
name, social security number, address, telephone number, or any other direct personal identifier in study records 
disclosed outside of Duke University Health System (DUHS). Study records and samples disclosed outside of 
Duke will be identified only with the subject’s initials, date of birth and unique code number. The key to the 
research code will be kept in a locked file in Dr. Koeberl's research office. Test results will be recorded in the 
subject’s password-protected research record (located on the Division of Medical Genetics’ division website, 
maintained by Duke OIT) and medical record.  
14.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a clinical 
trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents   
Examples of these original documents, and data records include: hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded 
data from automated instruments, copies or transcriptions certified after verification as being accurate and 
complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records 
kept at the pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial. 
14.3 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study. All data requested on 
the CRF must be recorded. All missing data must be explained. If a space on the CRF is left blank because the 
procedure was not done or the question was not asked, write “N/D”. If the item is not applicable to the 
individual case, write “N/A”. All entries should be printed legibly in black ink. If any entry error has been 
made, to correct such an error, draw a single straight line through the incorrect entry and enter the correct data 
above it. All such changes must be initialed and dated. DO NOT ERASE OR WHITE OUT ERRORS. For 
clarification of illegible or uncertain entries, print the clarification above the item, then initial and date it. 
14.4 Records Retention 
The research record will be retained for 6 years following the completion of the study. Any research information 
in the subject’s medical record will be kept indefinitely.  


 
 
Page 21 of 23 
 
 
15 Auditing, and Inspecting 
15.1 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the Ethics Committee (EC) or 
Institutional Review Board (IRB), the sponsor, government regulatory bodies, and University compliance and 
quality assurance groups of all study related documents (e.g. source documents, regulatory documents, data 
collection instruments, study data etc.). The investigator will ensure the capability for inspections of applicable 
study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
16 Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical Practice (FDA Title 
21 part 312 and International Conference on Harmonization guidelines), applicable government regulations and 
Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent EC/IRB, in 
agreement with local legal prescriptions, for formal approval of the study conduct. Any protocol amendments 
will also be submitted to the FDA as per 21 CFR Part 312.30 (in addition to the IRB). 
 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study. This consent form 
will be submitted with the protocol for review and approval by the EC/IRB for the study. The formal consent of 
a subject, using the EC/IRB-approved consent form, must be obtained before that subject is submitted to any 
study procedure. This consent form must be signed by the subject or legally acceptable surrogate, and the 
investigator-designated research professional obtaining the consent.  
17 Study Finances 
17.1 Funding Source 
Departmental (Research Fund of Dr. Richard Bedlack) 
17.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain 
greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by a properly 
constituted Conflict of Interest Committee with a Committee-sanctioned conflict management plan that has 
been reviewed and approved by the IND sponsor (Dwight Koeberl, MD PhD) prior to participation in this 
study.  
18 Publication Plan 
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of the 
information provided by the sponsor for the purposes of performing the study, will be published or passed on to 
any third party without the consent of the study sponsor. Any investigator involved with this study is obligated 
to provide the sponsor with complete test results and all data derived from the study. 


 
 
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