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DAP for LEMS

A randomized trial of 3,4-diaminopyridine in Lambert-Eaton myasthenic syndrome

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Year of Publication: 2000

Authors: Donald B. Sanders, Janice M. Massey, Linda L. Sanders, Lloyd J. Edwards

Journal: Neurology

Citation: Neurology 2000;54(3):603

Link: https://doi.org/10.1212/WNL.54.3.603

Clinical Question

Does 3,4-diaminopyridine (DAP) improve muscle strength and neuromuscular transmission in patients with Lambert-Eaton myasthenic syndrome compared to placebo?

Bottom Line

DAP 20 mg TID significantly improves both clinical muscle strength (QMG score) and physiologic neuromuscular transmission (CMAP amplitude) in LEMS patients with negligible side effects, confirming it as an effective and safe treatment

        Major Points
        DAP improved QMG score by median 2.0 points vs worsening of 0.25 points with placebo (p=0.01)
CMAP amplitude increased 64% with DAP vs decreased 3.2% with placebo (p<0.001)
7/12 patients on DAP improved ≥2 QMG points; no placebo patient improved >1.5 points
Side effects limited to perioral and digital paresthesia in 4/14 patients on blinded DAP
No EEG, EKG, or laboratory abnormalities with acute or 6-month open-label DAP
25/26 patients had symptomatic improvement with subsequent open-label DAP
Optimal response often obtained with 30-40 mg DAP daily, with additional benefit from pyridostigmine

      

Design

Study Type: Prospective, randomized, placebo-controlled, parallel-group trial

Randomization: 1

Blinding: Double-blind; identical capsules prepared by pharmacy, randomization code maintained by hospital pharmacy

Enrollment Period: October 1994 to May 1998

Follow-up Duration: 6 days blinded phase, then open-label follow-up to 6 months

Centers: 1

Countries: USA

Sample Size: 26

Analysis: Intention-to-treat; Wilcoxon rank sum test for continuous variables due to skewed distribution; Fisher's exact test for categorical variables

Inclusion Criteria

Age >18 years
Confirmed diagnosis of LEMS with characteristic EMG findings (small CMAPs decreasing with low-frequency stimulation, ≥twofold increase after maximum voluntary contraction)
Completion of appropriate treatment for underlying cancer
Ability and willingness to cooperate with testing procedures
Muscle weakness on examination
QMG score ≥5

Exclusion Criteria

History of cardiac arrhythmia or evidence on EKG
Seizures or epileptiform activity on EEG
Known hepatic, renal, or hematologic disease or evidence on screening blood tests
Pregnancy (women of childbearing potential tested and agreed to adequate contraception)

Arms

Field	Control	3,4-Diaminopyridine
Intervention	Lactose capsules identical to DAP capsules, one capsule three times daily for 6 days	DAP 20 mg capsules (in lactose), one capsule three times daily for 6 days (60 mg/day total)
Duration	6 days	6 days

Outcomes

Outcome	Type	Control	Intervention	P-value
Change in QMG score from baseline (average of 2 consecutive days pre-treatment) to postbaseline (average of days 5 and 6 of treatment)	Primary	+0.25 (IQR: -1.0 to 1.0)	-2.0 (IQR: -3.0 to 0.0)	0.01
Change in summated CMAP amplitude (mV)	Secondary	-0.1 (IQR: -0.1 to 0.1)	+1.3 (IQR: 0.5 to 2.5)	<0.001
Percent change in summated CMAP amplitude	Secondary	-3.2% (IQR: -13.1 to 7.5)	+64.0% (IQR: 32.6 to 301.3)	<0.001
Symptomatic response to blinded drug (Better vs None/Worse)	Secondary	4 better, 9 none, 1 worse	9 better, 3 none, 0 worse	<0.05
Perioral/digital paresthesia (blinded phase)	Adverse	Not reported	4/14 (28.6%)
Perioral/digital paresthesia (open-label phase)	Adverse	N/A	8/22 (36.4%)

Subgroup Analysis

Not performed due to small sample size; insufficient statistical power for meaningful subgroup analysis

Criticisms

Single-center study at Duke University limits generalizability
Small sample size (n=26) due to rarity of LEMS
Short blinded treatment period (6 days) may not capture long-term efficacy
Paresthesia side effect may have compromised blinding
QMG score during blinded DAP did not always predict response to optimal open-label dose
No information on teratogenicity or mutagenicity of DAP
Crossover to open-label DAP for all patients limits long-term placebo comparison

Funding

USPHS grant FD-R-001068; NIH General Clinical Research Centers Program grant M01 RR-30; 3,4-diaminopyridine provided by Jacobus Pharmaceutical Co., Inc.

Based on: DAP for LEMS (Neurology, 2000)

Authors: Donald B. Sanders, Janice M. Massey, Linda L. Sanders, Lloyd J. Edwards

Citation: Neurology 2000;54(3):603

Content summarized and formatted by NeuroTrials.ai.

DAP for LEMS

(2000)

Objective

To evaluate the effectiveness of 3,4-diaminopyridine (DAP) in patients with Lambert-Eaton myasthenic syndrome (LEMS) and determine acute and long-term side effects

Study Summary

• DAP significantly improved muscle strength in LEMS patients compared to placebo (QMG score change -2.0 vs +0.25, p=0.01)
• CMAP amplitude increased 64% with DAP vs -3.2% with placebo (p<0.001)
• Side effects were negligible, consisting of perioral and digital paresthesia

Intervention

3,4-diaminopyridine 20 mg three times daily vs placebo for 6 days

Inclusion Criteria

Age >18 years, confirmed LEMS diagnosis with characteristic EMG findings (small CMAPs decreasing with low-frequency stimulation, ≥twofold increase after maximum voluntary contraction), completed cancer treatment if applicable, QMG score ≥5

Study Design

Arms: DAP 20 mg TID vs Placebo

Patients per Arm: DAP: 12, Placebo: 14

Outcome

• QMG score improved -2.0 points with DAP vs worsened +0.25 points with placebo (p=0.01)
• Summated CMAP amplitude increased 1.30 mV (+64%) with DAP vs decreased -0.1 mV (-3%) with placebo (p<0.001)
• 25/26 patients had symptomatic improvement with subsequent open-label DAP

Bottom Line

Major Points

DAP improved QMG score by median 2.0 points vs worsening of 0.25 points with placebo (p=0.01)
CMAP amplitude increased 64% with DAP vs decreased 3.2% with placebo (p<0.001)
7/12 patients on DAP improved ≥2 QMG points; no placebo patient improved >1.5 points
Side effects limited to perioral and digital paresthesia in 4/14 patients on blinded DAP
No EEG, EKG, or laboratory abnormalities with acute or 6-month open-label DAP
25/26 patients had symptomatic improvement with subsequent open-label DAP
Optimal response often obtained with 30-40 mg DAP daily, with additional benefit from pyridostigmine

Study Design

Study Type: Prospective, randomized, placebo-controlled, parallel-group trial
Randomization: Yes
Blinding: Double-blind; identical capsules prepared by pharmacy, randomization code maintained by hospital pharmacy
Sample Size: 26
Follow-up: 6 days blinded phase, then open-label follow-up to 6 months
Centers: 1
Countries: USA

Primary Outcome

Definition: Change in QMG score from baseline (average of 2 consecutive days pre-treatment) to postbaseline (average of days 5 and 6 of treatment)

Control	Intervention	HR/OR	P-value
+0.25 (IQR: -1.0 to 1.0)	-2.0 (IQR: -3.0 to 0.0)	-	0.01

Limitations & Criticisms

Single-center study at Duke University limits generalizability
Small sample size (n=26) due to rarity of LEMS
Short blinded treatment period (6 days) may not capture long-term efficacy
Paresthesia side effect may have compromised blinding
QMG score during blinded DAP did not always predict response to optimal open-label dose
No information on teratogenicity or mutagenicity of DAP
Crossover to open-label DAP for all patients limits long-term placebo comparison

Citation

Neurology 2000;54(3):603

View Original Publication →

DAP for LEMS

A randomized trial of 3,4-diaminopyridine in Lambert-Eaton myasthenic syndrome

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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