Trial Pains Secondary to Placebo Effect?


An interesting report has just been published showing that Naloxegol is beneficial in OIC [i].  Naloxegol is a µ opioid receptor (MOR) antagonist which – by virtue of pegylation – acts peripherally and not centrally.  Hence, the analgesic effects of opioid therapy are unaffected while the very bothersome side effect of constipation can be overcome.

Overcome?  Not really when you look at the numbers.  After all, only patients in the higher-dose treatment arms had an increase of 1 (sic!) more SBM / week than controls.  Hardly a normalization of bowel activity (but better than nothing, presumably).

However, some other information provided in the Naloxegol article merits attention.

#1 – A consistently high placebo effect:

In the Naloxegol trials, exactly 29% of study participants in the placebo arm were ‘responders’.  In an earlier Phase 2 trial, the placebo success rate was even higher, at 35%[ii].  This despite rather tough endpoint criteria for ‘response’ which require ≥ 3 SBMs during ≥ 9 of 12 weeks of observation, plus several other measures of improvement.  Now these were the same patients that consistently had < 3 SBMs during their 4-wk run-in period, and no response to laxatives.  One would think only severely constipated patients were selected in the screening process.  Nonetheless, some 30% obviously had spontaneous improvement in bowel function whilubiprostle receiving only placebo.

Actually this does not come as a total surprise.  Other well-controlled OIC trials have come up with similar data.  For instance, patients on placebo in Alvimopan (Entereg®) studies showed a positive response in approx. 40%.[iii]  While endpoints and FDA stipulated criteria for ‘responders’ have changed very dramatically in recent years, high placebo responses have remained a consistent finding in OIC drug trials.  Only in the lubiprostone (Amitiza®) 12-wk studies a lower placebo response rates of approx. 19% was found.

What does this mean?  Clearly it shows that we are unable to select true non-responders with any kind of predictive accuracy.  Even rigorous enrollment criteria are unable to identify those patients that would only respond to an MOR antagonist.  Should we raise the bar further when selecting patients?  Should we require complete normalization of bowel function as an endpoint?  I think a sensitivity analysis that better defines true non-responders and a better understanding of the natural course of OIC and its presentation over time would help reduce the number of placebo responders.  This is a testable hypothesis.

We have certainly made enrollment very difficult by implementing criteria that are not of much value.  This looks like an effort driven by what makes sense conceptually but turns out to be just burdensome.

Case in point, the Phase 3 trial program for naloxegol.

#2 – A huge effort to find the ‘right’ patients:

Why did it take 257 study sites and 19 months to find 1352 ITT-evaluable OIC patients?  This amounts to a yield of only 5 patients per center, on average, during the entire trial.  Admittedly, 2 out of 3 patients screened did not meet entry criteria after the run-in period and therefore did not get randomized.  As discussed above that screening effort did not buy much reduction in background noise but surely created much work for the sponsor and CRO.

Still for a condition as common as OIC any screening process should be easy and fast, right?

I guess this is a wrong assumption, too.  Logical assumptions can be so misleading in the real world.


UPDATED 8/14/2014:
– Naloxegol’s PDUFA date was originally set for June 11, 2014, but is now Sept. 16, 2014
– Naloxegol brand name =  Movantik ®



ITT         intent-to-treat population
OIC        opioid-induced constipation
SBM       spontaneous bowel movement



[i]  Chey, NEJM 2014; Online First, June 4, 2014
[ii] Webster, Pain 2013; 154: 1542
[iii] Ford, Am J Gastroenterol 2013; 108:1566

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