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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 (including no QTc prolongation), or laboratory abnormalities with acute or 6-month open-label DAP
  • 24/25 patients had symptomatic improvement with subsequent open-label DAP (25 took open-label; only 1 had no improvement)
  • 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-day blinded phase; subsequent open-label DAP continued as long as there was symptomatic improvement, with laboratory/endocrine monitoring at 3 and 6 months on open-label DAP and periodically thereafter

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)

Baseline Characteristics

CharacteristicControlActive
N1412
Sex - Female8 (57.1%)7 (58.3%)
Age at onset (years) - Median (IQR)55.3 (47.7-63.6)56.2 (41.5-68.4)
Patients with SCLC4 (28.6%)6 (50.0%)
Baseline QMG - Median (IQR)12.3 (9.0-13.5)8.5 (7.3-17.0)
Baseline CMAP (mV) - Median (IQR)1.3 (0.8-2.2)1.5 (0.6-2.6)

Arms

FieldControl3,4-Diaminopyridine
InterventionLactose capsules identical to DAP capsules, one capsule three times daily for 6 daysDAP 20 mg capsules (in lactose), one capsule three times daily for 6 days (60 mg/day total)
Duration6 days6 days

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-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 amplitudeSecondary-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)Secondary4 better, 9 none, 1 worse9 better, 3 none, 0 worse<0.05
Perioral/digital paresthesia (blinded phase)AdverseNot reported4/14 (28.6%)
Perioral/digital paresthesia (open-label phase)AdverseN/A8/22 (36.4%)
QTc change from baseline (ms), blinded phaseAdverse-7 (IQR: -14 to 6), n=12-1 (IQR: -12 to 10), n=110.40
Liver/renal/hematologic/endocrine/EEG/EKG abnormalities (acute and 6-month open-label)AdverseNoneNone

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 of 25/26 randomized patients to open-label DAP 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

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