Supplementary material Supplementary methods Adverse event management



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Supplementary material
Supplementary methods
Adverse event management

Adverse events were monitored throughout the trial, at every visit during sirolimus treatment, and through monthly telephone calls in the standard-care period. Parents were instructed to contact the investigator if their child became ill, or when they thought their child might have developed an adverse event.

Adverse events were classified according to the WHO adverse reaction terminology and graded according to the National Cancer Institute common terminology criteria for adverse events. For most types of adverse events, sirolimus was stopped in case of a grade two adverse event, and after the event was resolved or reached grade one, was restarted on the same dose. In case of a grade three adverse event, sirolimus was stopped until the event resolved or reached grade one, and was restarted at a lower dose. In case of a grade 4 adverse event, sirolimus was discontinued. For mouth ulcers, the sirolimus treatment schedule was more strict, as these can be very debilitating for young children. In case of grade one mouth ulcers, sirolimus was discontinued if necessary until the ulcer subsided, the dose was not changed when sirolimus was restarted, and parents were instructed to use non-alcoholic mouth-wash. In case of grade two or three mouth ulcers, sirolimus was discontinued until the ulcers were resolved or reached grade one, a lower dose was restarted, and non-alcoholic mouth wash and lidocaine oral gel was advised. In case of grade four mouth ulcers, sirolimus was discontinued.

If surgery was needed during the trial, sirolimus was stopped one week in advance should the surgeon wish, or earlier if needed. Sirolimus would then be started again at two weeks post-surgery or after wound healing, at the last dose that did not cause adverse events.



Sirolimus dosing

Patients received a 1 mg/ml oral solution of sirolimus (Rapamune, Pfizer), monitored and released through the Erasmus MC pharmacy. Starting dose was based on the normal starting dose of 2 mg daily for an adult of >50 kg or a body surface area of 1.73 m2. This corresponds with a dose of 0.033 mg/kg/day, which was used as starting dose for participants. Participants using CYP3A4-inducing AEDs (carbamazepine, fenobarbitone, phenytoin) were started on a 25% higher dose. No loading dose was used. Sirolimus levels were originally titrated to blood trough levels of 10-15 ng/ml, but the target trough was lowered to 5-10 ng/ml after two serious adverse events, after deliberation with the DSMB. To ensure that participants reached this trough level as quickly as possible, trough levels and consequent dose adjustments were done after one week, two weeks and four weeks of starting sirolimus treatment. If dose increases were needed after the appointment at four weeks, blood was taken an additional time two weeks after the dose increase. Administration of sirolimus was once a day, at a set time, always at the same time relative to a meal (for example always before breakfast). Parents were instructed to administer sirolimus by letting the child drink a solution of the sirolimus dose with at least 100 ml of liquid (water or juice), and rinse the glass with another 40 ml of liquid to ensure the entire dose was administered. During the sirolimus treatment period, the use of strong inhibitors or inducers of the CYP3A4 enzyme was to be avoided. These included ketoconazole, voriconazole, itraconazole, telithromycin, clarithromycin, rifampin, rifabutin, nicardipine, clotrimazole, fluconazole, troleandomycin, bromocriptine, cimetidine, danazol, protease inhibitors. Intake of grapefruit juice was also to be avoided during the trial. Parents and physicians of the participant were instructed to contact the investigators if the participant was to be prescribed one of these drugs, so an alternative could be found.


Supplementary table e-1

Summary of literature on mTORC1 inhibitor treatment for epileptic seizures in patients with Tuberous Sclerosis Complex.




Study

Study type

Number of patients

Age of patients

Drug

Dose

Duration of treatment

Control group?

Outcome

Muncy et al. 20091

Case report

1

9 years

Sirolimus

0.15 mg/kg/day

10 months

No

Seizure clusters stopped, 1-5 seizures per day remained

Krueger et al. 20102
Krueger et al. 20133

Prospective open-label trial into SEGA treatment, with epilepsy as secondary outcome
Long-term follow up of patients in prospective open-label study

16

26 at baseline,23 at end of follow-up



Median 11 years (range 3-34)

in total study population of 28 patients


Same as above

Everolimus

Everolimus



Median 5.6 mg/m2/day (range 1.5-10.5)

in total study population of 28 patients


Median 5.3 mg/m2/day (range 2.1-12.3)

in total study population of 25 patients


6 months

Median 34.2 months (range 4.7-47.1) in total study population of 25



No

No


Frequency decrease in 9, no change in 6, increase in 1
Percentage of patients who reported no seizures since their last visit increased from 38.5% to 65.2% at 24 months. Patients reporting at least one seizure per day decreased from 26.9% to 13.0% at 24 months

Perek-Polnik et al. 20124

Case report

1

10 years

Everolimus

4.5 mg/m2/day

12 months

No

Seizures ceased completely within first six weeks of treatment

Franz et al. 20135

Kotulska et al. 20136





Randomized controlled trialĀ into SEGA treatment, with epilepsy as secondary outcome
Long-term follow up of a selection of patients from randomized controlled trial

117

8


Median 9.5 years (range 1.0-23.9) in 78 patients receiving everolimus

Median 24.5 months (range 12-35)



Everolimus

Everolimus



4.9 mg/m2/day (range 2.3-11.8)

Median 4.5 mg/m2/day (range 2.53-8.0)



24 weeks

Median 35 months (range 33-38)



Yes, placebo

No


Change from baseline in seizure frequency was 0 in the everolimus and the placebo groups
Three patients seizure free at baseline, 1 complete and permanent cessation after two months treatment

Two patients more than 50% reduction in the first six months

One patient decreased markedly in the first year, then increased requiring a new AED

One patient no impact on seizure frequency



Moavero et al. 20137

Case report

1

20 years

Everolimus

Not reported

7 months

No

Seizure frequency decreased, generalized seizures stopped, patient continued to have focal-onset seizures

Krueger et al. 20138

Prospective open-label trial

20

Median 8 years (range 2-21)

Everolimus

8.4 mg/m2/day (range 3.4-13.7)

12 weeks (4 weeks titration, 4 weeks early maintenance, 4 weeks final maintenance)

No

12 patients >50% reduction of seizure frequency

Three patients 25-50% reduction

Five patient <25% reduction

Significant improvement only in the final maintenance period



Wiegand et al. 20139

Case series

7

Median 5 years (range 2-12)

Everolimus

Median 3.5 mg/day (range 2.9-7.0)

36 weeks

No

Reduction of seizures in 4 patients, no alteration of seizures in 2 patients

Canpolat et al. 201410

Case series

7

Median 13 (range 4-16)

Sirolimus

Median 2 mg/day (range 1.25-3)

12 months

No

All patient were seizure free after 0-9 months

Wiemer-Kruel et al. 201411

Case report

1

13.5 years

Everolimus

5 mg

37 days

No

Clusters of severe seizures requiring hospitalization

Cardamone et al. 201412

Case series


7

Median 6 years (range 3-17)

Sirolimus (6 patients) and

Everolimus (1 patient)



Sirolimus: median 2.5 mg daily (range 1-5)

Everolimus: 5 mg



Median 18 months (range 6-36 months)

No

One patient >90% reduction of frequency

Four patients 50-90% reduction



Two patients <50% reduction

AED anti-epileptic drug

References

1. Muncy J, Butler IJ, Koenig MK. Rapamycin Reduces Seizure Frequency in Tuberous Sclerosis Complex. J Child Neurol 2009;24:477-477.

2. Krueger DA, Care MM, Holland K, et al. Everolimus for Subependymal Giant-Cell Astrocytomas in Tuberous Sclerosis. New Engl J Med 2010;363:1801-1811.

3. Krueger DA, Care MM, Agricola K, Tudor C, Mays M, Franz DN. Everolimus long-term safety and efficacy in subependymal giant cell astrocytoma. Neurology 2013;80:574-580.

4. Perek-Polnik M, Jozwiak S, Jurkiewicz E, Perek D, Kotulska K. Effective everolimus treatment of inoperable, life-threatening subependymal giant cell astrocytoma and intractable epilepsy in a patient with tuberous sclerosis complex. Eur J Paediatr Neuro 2012;16:83-85.

5. Franz DN, Belousova E, Sparagana S, et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 2013;381:125-132.

6. Kotulska K, Chmielewski D, Borkowska J, et al. Long-term effect of everolimus on epilepsy and growth in children under 3 years of age treated for subependymal giant cell astrocytoma associated with tuberous sclerosis complex. Eur J Paediatr Neuro 2013;17:479-485.

7. Moavero R, Coniglio A, Garaci F, Curatolo P. Is mTOR inhibition a systemic treatment for tuberous sclerosis? Ital J Pediatr 2013;39.

8. Krueger DA, Wilfong AA, Holland-Bouley K, et al. Everolimus Treatment of Refractory Epilepsy in Tuberous Sclerosis Complex. Ann Neurol 2013;74:679-687.

9. Wiegand G, May TW, Ostertag P, Boor R, Stephani U, Franz DN. Everolimus in tuberous sclerosis patients with intractable epilepsy: A treatment option? Eur J Paediatr Neuro 2013;17:631-638.

10. Canpolat M, Per H, Gumus H, et al. Rapamycin has a beneficial effect on controlling epilepsy in children with tuberous sclerosis complex: results of 7 children from a cohort of 86. Child Nerv Syst 2014;30:227-240.

11. Wiemer-Kruel A, Woerle H, Strobl K, Bast T. Everolimus for the Treatment of Subependymal Giant Cell Astrocytoma Probably Causing Seizure Aggravation in a Child with Tuberous Sclerosis Complex: A Case Report. Neuropediatrics 2014;45:129-131.

12. Cardamone M, Flanagan D, Mowat D, Kennedy SE, Chopra M, Lawson JA. Mammalian Target of Rapamycin Inhibitors for Intractable Epilepsy and Subependymal Giant Cell Astrocytomas in Tuberous Sclerosis Complex. J Pediatr-Us 2014;164:1195-1200.









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