EXAMPLE 1
Double Blind, Randomized Patient Study
A total of 35 children aged 9 to 12 years with ADHD (of which 31 were evaluable) were enrolled, at three sites, in a double-blind, randomized, placebo-controlled, crossover study consisting of nine consecutive weekly visits (i.e., a total of nine weeks duration). At each visit, serial blood samples were taken for pharmacokinetic analysis. A battery of safety and pharmacodynamic measurements were performed.
At Visit 1 (which served as the baseline visit), all subjects were given a placebo in a single-blind manner. For Visits 2-8, subjects received one of two treatment regimens and a placebo in a double blind, randomized manner. The randomization occurred within each treatment regimen. One group of subjects received three single doses of DL ethylphenidate (DL-MPWH) and then, at the crossover, received three single doses of D-MPH; while the other group received three single doses of D-MPH followed by three single doses of DL-MPH. The placebo was given at one of the visits within either treatment regimen. The D-MPH was provided in capsules of 2.5, 5, and 10 mg. The DL-MPH was matched and provided in capsules of 5, 10, and 20 mg, accounting for the equimolar presence of two isomers. A matching placebo was also provided. All capsules were administered orally.
At Visit 9, subjects were randomly given one of the treatments unless they had missed a study visit. In that case, Visit 9 was used to repeat the missed study visit. A minimum of six days separated each of the 9 visits, during which time subjects received their standard medication.
Mean Plasma Concentration
D-MPH and DL-MPH were found to have equivalent pharmacokinetics and safety profiles, and resulted in no serious adverse effects. The amount of D-MPH delivered by a 2.5 mg dose of ONLY D-MPH is approximately equal to the amount of D-MPH delivered by the 5 mg close of racemic DL-MPH. Similarly, a 5 mg dose of only D-MPH provides the same amount of the D isomer as a 10 mg dose of the racemic DL mixture. Below are listed the mean plasma concentrations of D-MPH as determined 4, 6, and 8 hours after Ingestion.
TABLE 1
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Mean plasma concentration, nanograms per milliliter (ng/ml) of D-MPH
after ingesting D-MPH or DL-MPH.
Formulation 4 hours 6 hours 8 hours
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2.5 mg D-MPH 3.00 1.82 0.67
5 mg DL-MPH 2.94 1.91 0.85
5 mg D-MPH 5.86 3.75 1.84
10 mg DL-MPH 7.66 5.20 2.66
10 mg D-MPH 11.73 7.65 3.81
20 mg DL-MPH 12.50 8.15 3.85
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Objective Measure: Math Test
A computerized math test provided a measure of attention, concentration and work output. This test was administered 30 minutes before, and 4 hours, 6 hours, and 8 hours after medication administration. Table 2 lists statistical significance (p values) for comparisons between test results obtained after administration of D-MPH or DL-MPH and test results obtained after administration of a placebo. Similar notation is used in other data tables below. Data in Table 2 were obtained 30 minutes before, and at 4, 6, and 8 hours after, administration.
Four hours following administration, 10 mg of the D isomer was as effective as 20 mg of the DL racemate, as measured by improvement on the math test. The effectiveness as measured by improvement on the math test was evident only with 10 mg D-MPH 6 and 8 hours after administration of medication, and not with its equivalent dose as contained within 20 mg of DL-MPH. Superiority in effectiveness over the placebo was not observed with doses of D-MPH of less than 10 mg, and no significant effect was observed with even twice the dose of racemic DL-MPH beyond 4 hours. At 6 hours and 8 hours after administration, superiority over placebo was not achieved with lower doses than 10 mg of D-MPD or with any dose of DL-MPH used in this study.
TABLE 2
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P values of the comparisons of math scores achieved at various time
intervals after taking placebo, with math scores achieved after taking
20 mg DL-threo methylphenidate or 10 mg D-threo methylphenidate.
Test 1 Test 4 Test 5 Test 6
(-30 min)
(4 hours) (6 hours)
(8 hours)
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placebo--DL 20 mg
NS* <0.001 NS NS
placebo--D 10 mg
NS <0.001 <0.001 0.289
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*NS, here and below, indicates no statistically significant difference. I
results of comparison are statistically significant p < 0.05), the p valu
is listed.
Connors, Loney, and Milich (CLAM) Rating
The CLAM Rating Scale is a standard, subjective measure of inattention, overactivity, aggression, and defiance. Rating was completed 6 hours after drug administration by observers who were blind as to which study medication each subject received. The scale contains 16 items:
1. Restless or Overactive
2. Disturbs other children
3. Mood changes quickly and dramatically
4. Cries often and easily
5. Demands must be met immediately
6. Teases other children and interferes with their activities
7. Fidgeting
8. Hums
9. Excitable, impulsive
10. Inattentive, easily distracted
11. Fails to finish things started
12. Quarrelsome
13. Acts smart
14. Temper outbursts
15. Defiant
16. Uncooperative
While all three doses of D-MPH significantly reduced the overall CLAM score, indicating clinical benefit over the placebo, only the 10 mg and 20 mg doses of DL-MPH remained effective six hours after drug administration.
TABLE 3
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P values for comparison of overall CLAM scores 6 hours after
administration of D-MPH or DL-MPH, with overall CLAM scores 6 hours
after administration of placebo
placebo-DL 5 mg
NS* placebo-D 2.5 mg
0.0065
placebo-DL 10 mg
0.216 placebo-D 5 mg
<0.001
placebo-DL 20 mg
<0.001 placebo-D 10 mg
<.001
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*NS, no significant difference; if statistically significant (p < 0.05),
the p value is listed
Two subscales were calculated from the CLAM: the aggression/defiance (A/D) subscale and the inattention/overactivity (I/O) subscale. All doses of D-MPH were superior to the placebo using the A/D subscale. However, only the highest dose (20 mg) of DL-MPH was superior to placebo for the A/D subscale. The highest doses of both the D-MPH and DL-MPH formulations were superior to the placebo in the I/O subscale. While the 5 mg dose of D-MPH was also superior to the placebo, the equivalent as administered in a 10 mg dose of DL-MPH was not.
Shown below are p values for the comparisons of scores on the two CLAM subscales obtained 6 hours after administration of DL or D-MPH with scores obtained 6 hours after administration of a placebo.
TABLES 4 and 5
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Comparison of scores on CLAM subscales 6 hours after
administration of DL or D-MPH or a placebo.
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Aggression-Defiance (A/D)Score
placebo-DL 5 mg
NS placebo-D 2.5 mg
0.0279
placebo-DL 10 mg
NS placebo-D 5 mg
<0.001
placebo-DL 20 mg
<0.001 placebo-D 10 mg
<.001
Inattention-Over-activity (I/O) Score
placebo-DL 5 mg
NS placebo-D 2.5 mg
NS
placebo-DL 10 mg
NS placebo-D 5 mg
<0.0097
placebo-DL 20 mg
<0.001 placebo-D 10 mg
<0.001
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Scores for the individual behaviors were also determined. According to several observed individual behaviors (fidgeting, quarrelsome and defiant), 2.5 mg D-MPH was determined to provide efficacy superior to that of a placebo, but 5 mg of DL-MPH was not similarly effective. Also, 5 mg D-MPH provided efficacy superior to that of a placebo while 10 mg of DL-MPH did not, for the following behaviors: disturbs, demands, fidgeting, excitable, inattentive, and defiant.
For two behaviors, quarrelsome and acts smart, 10 mg d-MPH provided efficacy superior to that of the placebo while 20 mg of DL-MPH did not.
Results for individual behaviors are summarized below. Shown in the tables are p values for the comparisons of the results of individual behavior rating as obtained 6 hours after administration of D-MPH and DL-MPH to the results obtained 6 hours after administration of a placebo.
TABLES 6-13
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P values for comparison of effectiveness of D-MPH and DL-MPH with
that of placebo, as indicated by individual behaviors.
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Disturbs
placebo-dl 5 mg
NS placebo-d 2.5 mg
NS
placebo-dl 10 mg
NS placebo-d 5 mg
<0.0280
placebo-dl 20 mg
<0.001 placebo-d 10 mg
<0.001
Demands
placebo-dl 5 mg
NS placebo-d 2.5 mg
NS
placebo-dl 10 mg
NS placebo-d 5 mg
0.494
placebo-dl 20 mg
0.0335* placebo-d 10 mg
0.0011
Fidgeting
placebo-dl 5 mg
NS placebo-d 2.5 mg
0.0360
placebo-dl 10 mg
NS placebo-d 5 mg
0.0067
placebo-dl 20 mg
<0.001 placebo-d 10 mg
<0.001
Excitable
placebo-dl 5 mg
NS placebo-d 2.5 mg
NS
placebo-dl 10 mg
NS placebo-d 5 mg
0.494
placebo-dl 20 mg
0.0014 placebo-d 10 mg
0.001
Inattentive
placebo-dl 5 mg
NS placebo-d 2.5 mg
NS
placebo-dl 10 mg
NS placebo-d 5 mg
0.0149
placebo-dl 20 mg
0.0016 placebo-d 10 mg
<0.001
Quarrelsome
placebo-dl 5 mg
NS placebo-d 2.5 mg
0.0115
placebo-dl 10 mg
NS placebo-d 5 mg
NS
placebo-dl 20 mg
NS placebo-d 10 mg
0.0016
Acts Smart
placebo-dl 5 mg
NS placebo-d 2.5 mg
NS
placebo-dl 10 mg
NS placebo-d 5 mg
NS
placebo-dl 20 mg
NS placebo-d 10 mg
0.001
Defiant
placebo-dl 5 mg
NS placebo-d 2.5 mg
0.0010
placebo-dl 10 mg
0.0038 placebo-d 5 mg
0.0166
placebo-dl 20 mg
<0.001 placebo-d 10 mg
<0.001
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At a dose of 5 mg, the D isomer provided efficacy for at least 6 hours following administration, as compared to the DL racemate, which required a twice that dosage to provide 6 hours of efficacy. Even more significantly, a 2.5 mg dose of the D isomer provided efficacy in controlling several behaviors, while even twice the dose of the DL racemate was ineffective against the same behaviors. For two behaviors (fidgeting and quarrelsome), even four times the dose of the racemate, i.e. 10 mg, showed no statistically significant improvement over the placebo as compared to 2.5 mg of the D isomer.
In conclusion, the data show that, according to both objective and subjective measures, D-MPH was not only more effective than a placebo in controlling subjective behaviors and in improving objective performance on a math test, but clearly provided efficacy for a significantly longer period of time than did an equivalent dose of DL-MPH.
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