07/08/2015
Study protocol
Title: Intermediate access use of amifampridine phosphate in children with congenital
myasthenia gravis (CMS).
Principal investigator:
Sumit Verma, M.D., Assistant Professor of Pediatrics and Neurology, Emory University School
of Medicine
Introduction:
The neuromuscular junction (NMJ) is the specialized synapse between the motor nerve terminal
and the muscle fiber. Defects in NMJ function present with variable and often fluctuant
symptoms such as fatigue, muscle weakness, droopy eyelids, double vision, swallowing and
breathing difficulties. NMJ disorders are both inherited and acquired in nature. Congenital
myasthenia syndromes (CMS) are a group of heterogeneous inherited disorders caused by
mutations in genes encoding proteins essential for the integrity of neuromuscular transmission.
More than twenty different genetic mutations at the pre-synaptic, synaptic and post-synaptic
level of neuromuscular junction have been described1.
The diagnosis and management of children with CMS is challenging. Advanced
electromyography (EMG) technique and genetic testing help to confirm the diagnosis2. Response
to treatment in CMS depends upon the type of defect (pre-synaptic, synaptic and post-synaptic)
and the kinetics of the channel affected (fast vs slow). Pyridostigmine is effective in fast channel
myasthenia syndromes, however can cause worsening of symptoms in slow channel syndromes.
Salbutamol, ephedrine and fluoxetine have all been used in CMS with encouraging results3, 4.
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Amifampridine phosphate (3,4-DAP, diaminopyridine) is an agent used in treatment of disorder
of neuromuscular junction defects. It blocks the presynaptic potassium channel flux and allows
for prolonged depolarization and increases calcium influx. This leads to increased release of
acetylcholine in the synaptic terminal and improves neuromuscular transmission. This is
beneficial is both pre-synaptic and post-synaptic CMS (acetylcholine receptor defects, Rapsyn,
MUSK, DOK7 mutations) and Lambert Eaton Myasthenia Syndrome (LEMS).
Palace et al 1991 showed significant improvement in muscle strength scores on concomitant use
of 3,4-DAP with pyridostigmine in children affected with CMS. The study also included four
patients who were randomized to placebo vs 3,4-DAP and showed a significant difference in
muscle strength5. Banu et al 1996 in a double-blinded placebo-controlled trial in CMS and
juvenile myasthenia gravis failed to show significant differences in muscle strength and single
fiber EMG6. In a study by Oh et al 2009 3,4-DAP was found to be more effective than placebo in
patients with LEMS7.
The above mentioned studies did not have genetically defined CMS patients. There is also
paucity of data on use of 3,4-DAP in CMS patients younger than 10 years of age. The studies
also lacked sensitive, objective, rapid motor and electrophysiological measures to detect interval
change in motor strength and neuromuscular transmission among CMS patients. Our experience
with use of amifampridine phosphate (phosphate salt of 3,4-DAP) in a four year old girl with
well-defined CHRNE mutation CMS showed promising results8. Our preliminary work using
stim-JA has shown the technique is feasible, sensitive, and rapid in detecting neuromuscular
transmission defects in children9,
10
. In light of above mentioned advancements in field of
genetics, newer electrophysiological techniques and motor function measures, we would like to
test amifampridine phosphate use in a larger cohort of CMS patients.
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Objectives:
To study amifampridine phosphate in children with subtypes of CMS thought to be responsive.
Procedure/ methods:
All children with genetically confirmed CMS and under the age of 10 years will be eligible for
this study. Exclusion criteria will include cardiac conduction defects on electrocardiogram,
seizure disorder with abnormal electroencephalogram and abnormal baseline liver function tests.
The study will be conducted at the Children’s Healthcare of Atlanta, Scottish Rite campus from
1st April 2015 to 31st March 2016.
Institution review board (Emory and CHOA) approval will be obtained prior to initiation of the
study. Written consent form will be signed by eligible patient’s parents and family. All patient
data obtained will be safely stored with the principal investigator (S.V.) in password protected
hard drive on the CHOA computer.
Amifampridine phosphate (Firdapse®) will be provided by Catalyst Pharmaceuticals, Coral
Gables, Florida. The medication is 10mg tablet form in blister packets. The medication will be
shipped to the CHOA, Scottish Rite Pharmacy (J.C.) and dispensed to the patient and their
families at the study visits. Amifampridine will be administered by mouth in children who can
swallow the pills. In children with nasogastric or gastrostomy tube amifampridine phosphate
tablets will be crushed and diluted in 5-10cc of water and given through the tube. It is
recommended that the medication be taken with food.
Patients and their families will be evaluated in the neurology clinic at 975 Johnson Ferry Road,
Atlanta, GA at each clinic visit. Vital signs will be obtained at each visit. Amifampridine
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phosphate will be dispensed at each clinic visit. Amifampridine phosphate will be administered
at 1 mg/k/d in three divided doses. First month the patient will be monitored biweekly and
thereafter every month for two months and then once every three months for the rest of the study
period.
Concomitant use of pyridostigmine, prednisone, albuterol, ephedrine and fluoxetine, along with
the amifampridine will be permitted during the study period. However, it would be encouraged
that doses of the concomitant medications are kept unchanged as much as possible.
Table 1: Intermediate access use of amifampridine phosphate in CMS subjects
Study
Day1/
Wk#2 Wk#4
assessment
Wk#1
Consent
X
Vital signs
X
X
X
Adverse
X
X
Concomitant X
X
Wk#8 Wk#1
Wk#2 Wk#3
Wk#48
End
2
4
6
Wk#52
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X (d.e) X
X
X
X
X
events
medications
Amifamprid
X dose X
ine
escalat
dispensed
ion(d.e
(d.e)
(d.e.)
.)
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Study risks and precautions:
Adverse events such as pins and needle sensation, and gastrointestinal side effects will be
monitored at each visit. Serious adverse events including cardiac rhythm disturbance and
seizures will be recorded and reported to the FDA and Emory/CHOA IRB. In case of serious
adverse events the amifampridine phosphate will be stopped immediately.
References:
1. Rodriguez Cruz PM, Palace J, Beeson D. Congenital myasthenic syndromes and the
neuromuscular junction. Curr Opin Neurol 2014; 27(5); 566-575.
2. Kinali M, Beeson D, Pitt MC et al. Congenital Myasthenic Syndromes in Childhood:
Diagnostic and management challenges. J Neuroimmunol 2008; 201-202: 6-12.
3. Lorenzoni PJ, Scola RH, Kay CSK, et al. Salbutamol therapy in congenital myasthenic
syndrome due to DOK7 mutation. J Neurol Sci 2013; 331:155–157.
4. Sadeh M, Shen XM, Engel AG. Beneficial effect of albuterol in CMS with epsilon
subunit mutations. Muscle Nerve 2012; 44:289–291.
5. Palace J, Wiles CM, Newson-Davis J. 3,4-Diaminopyridine in treatment of congenital
(hereditary) myasthenia. J Neurol Neurosurg Psychiatry. 1991; 54(12): 1069-1072.
6. Anlar B, Varli K, Ozdirim E, et al. 3,4-Diaminopyridine in Childhood Myasthenia:
Double-Blind, Placebo-Controlled Trial. J Child Neuro 1996; 11: 458-461.
7. Oh SJ, Claussen GG, Hatanaka Y, Morgan MB. 3,4-Diaminopyridine is more effective
then placebo in a randomized, double-blind, cross over drug study in LEMS. Muscle
Nerve 2009; 40(5): 795-800.
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8. Mazell S, Verma S. Clinical and jitter change during oral amifampridine phosphate
treatment in Congenital Myasthenia Gravis. Submitted for 62nd AANEM Annual meeting
(Abstract).
9. Verma S, Lin J, Barkhaus PE. Stimulated jitter analysis in early diagnosis of infant
botulism. Muscle & Nerve 2015 (in press).
10. Lin J, Verma S. Stimulated jitter analysis (Stim-JA) for Neuromuscular Junction (NMJ)
disorders in children. The 67th AAN Annual Meeting, Washington, DC, April 2015
(Abstract).
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