If the weight-loss drug Acomplia (rimonabant) is indeed the magic pill that millions of overweight and obese Americans are hoping for, one big unanswered question is why more than half of those fortunate enough to have gotten it in the big U.S. clinical trial decided to stop taking it before the end.

While almost two-thirds of the 3,045 participants who started out in the RIO-NORTH AMERICA trial quit before the study was over, what is truly remarkable is that more than half of the participants getting the highest dose of Acomplia -- the dose that clearly promotes weight-loss -- dropped out along the way.

With millions of people desperately trying to figure out how they can get Acomplia, one might wonder why those that were getting it decided to stop taking it.

It's fairly easy to understand why many of the study participants who were unlucky enough to be in the group getting a placebo, or a very low dose of Acompla that has pretty much been abandoned as ineffective, might have chosen to quit the trial. They were not, on average, losing much weight.

But of the 1,222 participants who started out on the 20 mg dose of Acomplia that Sanofi-Aventis is seeking to have approved by the U.S. FDA, only 673 were around at the end first year -- an amazing attrition rate considering that those who stuck with it had a median weight loss of almost 14 pounds.

For the second year, the group that had completed a year on a daily 20 mg dose of Acomplia was split. Half were put on a placebo, while 333 were selected to continue on Acomplia for a second full year. But of the 333 that continued getting the drug, only 257 stuck with Acomplia until the end.

Why would these individuals -- all obese or overweight with other medical problems, all desperate for a drug that could help them lose weight -- quit on the most-promising weight-loss drug of this decade?

Well, all we have at this point for an answer are the broad categories listed for dropouts in a report on the Acomplia study published in the current issue of the Journal of the American Medical Association.

Of the 549 on Acomplia who dropped out during the first year, 169 were listed as having quit due to an "adverse event" -- which the researchers said was "mainly due to psychiatric, nervous system, and gastrointestinal tract adverse events."

"Compared with patients receiving placebo, adverse events (upper respiratory tract infection, nasopharyngitis, nausea, influenza, diarrhea, arthralgia, anxiety, insomnia, viral gastroenteritis, dizziness, depressed mood, and fatigue) were reported in 5% or greater of patients receiving 20 mg of rimonabant," the researchers reported.

Another 35 of the 549 who gave up on Acomplia during the first year are listed under "lack of efficacy" (translation, it didn't work). Forty eight apparently were booted out of the trial for "poor compliance." Some 213 are mysteriously grouped under the category "patient's request" (they decided to quit, and who knows why). And 79 were listed as "lost to follow-up" (couldn't be traced). Several more dropped out for miscellaneous reasons.

Then of the 76 more who quit while still getting Acomplia during the second year, an additional 20 of the drop outs were listed as dropping out due to an "adverse event." Five quit due to "lack of efficacy," seven more were booted for "poor compliance," some 30 were listed in the mystery "patient's request" category, and 14 more dropped out of sight as "lost to follow-up."

Independent researchers not associated with the Acomplia study have been very critical of the fact this trial -- like studies of many other weight-loss drugs -- made no effort to follow-up and measure the weight at the end of the trial of all the many participants who dropped out (both those getting Acomplia and the placebo) who were not "lost to follow-up."

"It is a mystery to me why they don’t make a more concerted effort to measure the people who dropped out," said Dr. Denise Simons-Morton, Director of the Clinical Applications and Prevention Program, Division of Epidemiology and Clinical Applications at the U.S. National Heart, Lung, and Blood Institute.

Even the trial organizers concede "it must be acknowledged that the trial was limited by a high drop-out rate and that long-term effects of the drug require further study."

But some even more immediately relevant questions to ponder if you are among those hoping for early FDA approval of Acomplia may be:

• Why did so many of the participants getting the full dose of Acomplia quit taking it?
• What happened that turned people taking Acomplia off of this wonder-drug? and
• What do we know about the weight and overall health of those who started on Acomplia, and then quit, at the end of this trial?