The PARADIGMS Trial in Pediatric Multiple Sclerosis

Brenda L. Banwell, MD: The PARADIGMS trial was a double-dummy, double-blind study. In English, that means that half the enrolled children received active tablets containing fingolimod and injections that didn’t contain any biologically active substance. The other half received injections weekly of interferon beta-1a and took tablets that did not contain any active treatment. They were not told which arm they were in, so all patients were blinded to which treatment they were receiving, as were the doctors who were monitoring them.

This was a study that went up to 2 years for each person, with the primary goal to compare the number of relapses per year between the 2 groups. Subsequently, we also looked at the MRI [magnetic resonance imaging] features of the 2 groups and looked at whether disability accrual or new disability was different between the 2 groups of children.

What the study showed was that the relapse rate in the children who were treated with fingolimod was reduced by 82% compared with the children who received interferon beta-1a. Obviously, a very positive result.

On MRI studies, there was about a 53% reduction in the number of new T2, or bright, lesions in the brain in the fingolimod arm as compared with the interferon arm. The interferon arm also showed a higher rate of new enhancing lesions, which are areas of lesion that light up, if you will, when given gadolinium dye, which indicates that the lesion is very active.

When we measured brain volume and, more importantly, the change in brain volume over time, there was a reduction in the rate of brain volume loss in the children in the fingolimod arm compared with those in the interferon arm. So on fingolimod, the brain volume changed by approximately 0.48% per year and by about 0.83% negatively in the children on interferon. Both groups of children lost some brain volume during the study, but there was obviously far less brain-volume loss in the children on fingolimod.

The children receiving fingolimod also were less likely to acquire any measurable disability compared with those in the interferon arm, although across the whole 200-plus number of patients there were very few children who acquired any disability. That measurement is difficult to compare because acquiring disability in pediatric multiple sclerosis [MS] is actually quite infrequent when people are still children. Overall, the study was highly effective. It showed that fingolimod was superior to interferon beta-1a in terms of clinical benefit and MRI features.

Adverse effects between the 2 groups were also compared. Overall, both arms of the study were felt to be pretty safe. There were a few adverse effects that are noteworthy. There were a small number of children on the fingolimod treatment who experienced seizures. Most experienced only 1, and a very small number of children had seizures. I think 4 were reported in the formal study. This was not seen in the children on interferon. Whether that’s truly related to fingolimod is under study, but it is noteworthy because it was different.

In the interferon arm, as we would expect from that medication, a higher number of patients reported flu-like symptoms, which is a known adverse effect of interferon. Other than that, in both groups the frequency of infections or any other complication was infrequent and not particularly different between the 2 groups.

Lauren B. Krupp, MD: I was discussing the phase III PARADIGMS trial when I was referring to the study that showed fingolimod to be more effective than the interferon that it was compared with. The very interesting thing about that study was that the adverse-effect profile was very comparable with what’s been observed with adults. It was very well tolerated. The other thing that was noted in that study was that the reduction in relapses was dramatic with the fingolimod in contrast with the interferon beta-1a, intramuscular injection, where the relapse rate was quite a bit higher. It was in the 0.6 range, which basically means you’re having a relapse more than every other year, in contrast to having a relapse once every 8 years. That was the difference in the treatment response to the medications.

The other thing we found was that there are changes to the brain that happen with MS. So we use MRI for diagnosis, but we also use it to monitor the treatment response. In someone who’s poorly treated, new inflammatory lesions develop on the brain or spinal cord. In the PARADIGMS study, only the MRI of the brain was used to monitor the disease. And in the fingolimod-treated group, there were fewer new lesions, fewer expanding lesions, and fewer enhancing lesions compared with the group that received the interferon.

The other thing that I personally think is very concerning is that MS, if untreated, can lead to these inflammatory changes, but it also can lead to loss of brain tissue. You really don’t want to see that in a youngster. The fingolimod was better able to preserve brain volume in the treated patients compared with the interferon-treated patients. That’s yet another benefit that was observed in the study.