FDA Presentation To PCNS

June 6, 2001

Ranjit Mani, M.D.

 

 

EFFECT OF GHB ON MEASURES OF DAYTIME SLEEPINESS IN NARCOLEPSY

 


MEASURES OF DAYTIME SLEEPINESS IN GHB TRIALS

 

OMC-GHB-2

·      Epworth Sleepiness Scale (Secondary)

·      Frequency Of Sleep Attacks (Secondary)

·      Duration Of Sleep Attacks (Secondary)

 

Scrima Study

·      Sleepiness Index Of Multiple Sleep Latency Test (Primary)

·      Frequency Of Sleep Attacks (Secondary)

 

Lammers Study

·      Frequency Of Sleep Attacks (Secondary)

·      Duration Of Sleep Attacks (Secondary)

 

OMC-SXB-21

None

 


 

 

Total Number Of Secondary Efficacy Measures In GHB Trials

 

OMC-GHB-2:

10

 

 

Scrima:

17

 

 

Lammers:

7

 

 

OMC-SXB-21:

0

 

 


OMC-GHB-2: Analysis Of Measures Of Daytime Sleepiness

 

Parameters

Treatment

Change in medians

P-value

P-value

 

 

from baseline to endpoint

for overall comparison *

GHB group vs placebo

Excessive Daytime Sleepiness

Placebo

-2.0

0.0006

 

(Epworth Scale)

3 g

-1.0

 

0.1137

 

6 g

-3.5

 

0.1860

 

9 g

-5.0

 

0.0001

Frequency of Daytime Sleep Attacks

Placebo

-0.26

0.0101

 

 

3 g

-0.20

 

0.1022

 

6 g

-0.48

 

0.0497

 

9 g

-0.48

 

0.0122

Duration of Daytime Sleep Attacks

Placebo

-3.10

0.0282

 

 

3 g

-5.00

 

0.9995

 

6 g

-9.75

 

0.4413

 

9 g

-7.95

 

0.0689

* based on ANCOVA


SCRIMA STUDY: ANALYSIS OF MEASURES OF DAYTIME SLEEPINESS

 

Sleepiness Index Of Multiple Sleep Latency Test

 

Treatment Group

GHB

N = 20

Placebo

N = 20

Mean Baseline Sleepiness Index

88.5

Mean Overall Sleepiness Index During Treatment

87.2

90.3

Mean Overall Change From Baseline During Treatment

-1.3

1.8

GHB-Placebo Difference For Overall Treatment Effect

-3.1

P-value for overall GHB-placebo difference

0.085

 


SCRIMA STUDY: ANALYSIS OF MEASURES OF DAYTIME SLEEPINESS

 

Frequency Of Daytime Sleep Attacks (Attacks/Day)

 

Treatment Group

GHB

N = 20

Placebo

N = 20

Mean Baseline Frequency Of Sleep Attacks

2.8

Mean Overall Frequency Of Sleep Attacks During Treatment

1.9

2.1

Mean Overall Change From Baseline During Treatment

-0.9

-0.7

GHB-Placebo Difference For Overall Treatment Effect

-0.2

P-value for overall GHB-placebo difference

0.530

 


LAMMERS STUDY: ANALYSIS OF MEASURES OF DAYTIME SLEEPINESS

 

Measure

Treatment Group

Median/Mean of Daily Score *

p-value for Change from Baseline to Endpoint (GHB vs placebo)

 

 

Baseline

Endpoint

Baseline-Endpoint Change

 

Severity of Daytime Sleepiness

Placebo

1.60

1.59

-0.01

0.034

(n =24)

GHB

1.60

1.28

-0.32

(Wilcoxon)

Frequency Of Daytime Sleep Attacks

 

Placebo

1.83

2.14

0.31

0.0008

(n =24)

GHB

2.17

1.36

-0.81

(ANCOVA*)

*Not a protocol-specified analysis

 

 


PROBLEMS WITH PROPOSED CLAIM FOR EXCESSIVE DAYTIME SLEEPINESS

 

·    Most measures for excessive daytime sleepiness were secondary

·    Only measure that was primary was “negative”

·    Majority of measures “negative” (after adjustment of Type I error for multiple comparisons)

·    Effects inconsistent across studies

·    Lack of replication of positive results on any specific measure