Just the abstract
An Open-Label, Stepwise Dose-Escalating Pilot Study
to Evaluate the Safety, Tolerance, & Efficacy of
Low-Dose Thalidomide in the Treatment of
Chronically-Active, Steroid-Department Crohn's Disease (CD)
AGA
Research Forum G3637
Eric A Vasiliauskas, Cedars-Sinai IBD Ctr, D4063,
Los Angeles, CA; L Y Kam, M T Abreu-Martin,
K A Papadakis, Cedars-Sinai Med Ctr, Los Angeles,
CA; J B Zeldis, Celgene Corp., Warren, NJ; S R Targan,
Cedars-Sinai Med Ctr, Los Angeles, CA
BACKGROUND: The pivotal role of tumor necrosis factor
alpha (TNF-a) in CD is highlighted by the favorable
response of refractory CD patients to monoclonal
antibody therapy directed against TNF-a. THalidomide
decreases the production of the proinflammatory
cytokines TNF-a & IL-12. Clinically,
thalidomide has shown beneficial effects in RA &
in a CD case.
AIMS: To evaluate the safety, tolerance, and efficacy of
low-dose thalidomide (50-100 mg/day) (Celgene Corp.,NJ)
in patients with moderate to severe chronically-active,
steroid-dependent CD.
METHODS: 9 out of 12 adult male patients with moderate
to severe CD (CDAI Ž250 & £500) despite Ž20 mg
prednisone/day for Ž1 month were enrolled and have completed
the first 4 of a 12 week study. 4/9 had previously been
treated with cyclosporine A. All were either intolerant
of or had an incomplete response to 6MP or azathioprine
(AZA). The first 6 patients were treated with 50mg of
thalidomide qhs & next 3 with 100mg qhs. The primary
endpoint was measured at 4 weeks & included clinical
response: a decrease in the CDAI score of Ž100 points
from baseline & clinical remission: a drop in the CDAI
score of Ž100 points from baseline and an absolute CDAI
score of <150. The secondary endpoint measured the
absolute DCDAI at 4 weeks from baseline. Steroids
& other concurrent medications were continued
at stable doses during the first 4 weeks of treatment.
RESULTS: The mean age was 45±13yrs. (range: 27-61 yrs.);
mean disease duration was 17±9 yrs. (range: 3-30yrs).
The mean prednisone dose at initiation was 24±9 mg
(range: 20-40mg). The mean pre-thalidomide CDAI score
was 350±66 (range: 257-470). Results of the first 4
weeks of therapy: The mean DCDAI at 4 weeks in the 6
responders was -150±37 (range: -110 to -216) and in
the 3 non-responders was -76±8 (-61,-79,-83). Transient
peripheral neuropathy was seen in 4, spontaneously
resolving in 3 despite continuation of thalidomide
at the same dosage. In one patient the dose was
temporarily held and then resumed at the previous
dosage once symptoms resolved. There were no
opportunistic infections or significant dermatitis.
3 experienced transient drowsiness.
CONCLUSIONS:
1) Consistent improvement in disease
activity was seen in all patients with a mean decrease
in the CDAI score of 125 points. Two thirds of patients
responded using the predetermined primary endpoint
criteria.
2) Treatment was generally well tolerated.
3) Low-dose thalidomide appears to be safe
& effective over a 4-week treatment period
in patients with chronically-active, s
teroid-dependent or unresponsive CD.
4) These findings provide the rationale
for a larger placebo-controlled trial.
The response of a further 3 patients that have been
screened and the complete 12-week trial, including the
results of the effect of thalidomide on steroid
withdrawal will be presented.
Dose Response Remission Change (and range)
50 mg 67% (4/6) 33% (2/6) -130 (+ or -55)
(-67 to - 216)
100 mg 67% (2/3) 0% (0/3) -115 (+ or - 35)
(-83 to -153)
Total 67% (6/9) 22% (2/9) -125 (+ or - 47)
(-67 to -216)
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