Results

Patients

The baseline characteristics were equal in the active and placebo group in ILIT after SCIT-10 000, except for more patients with high symptom scores (SS) being randomized to the active group. In ILIT de novo- 3000, the demographics were also balanced except for higher overall estimation of disease severity on visual analogue scale (VAS) in the placebo group. (See Table 1.)
After screening and treatment, 12 placebo and 13 active patients remained for analysis in ILIT after SCIT- 10 000. In ILIT de novo- 3000, 19 placebo and 16 active patients completed the protocol. See the supplementary information and Figure E1 for the flow of patients.

Safety

The adverse events in ILIT after SCIT- 10 000 were mostly mild. Small reactions at the injection site were common after the up-dosing injections, but also occurred after placebo injections. One active patient had rhinorrhea during 2 days after the first injection. One placebo patient suffered from pain, swelling in the groin, fever and general muscle pain 4 days after the second injection, perhaps representing a mild, self-limited infection.
In ILIT de novo- 3000, the first dose with 1000 SQ-U did not elicit any moderate or severe adverse events. After 3000 SQ-U one active patient reported tightness over the chest and head, itching in the palms, soles and at the neck without erythema, 6-12 hours after the injection. This patient was withdrawn from the study.
Four randomized patients continued to 5000 SQ-U, aiming at 10 000 SQ-U. Two patients, later confirmed having received active treatment, developed anaphylactic reactions at 5000 SQ-U. Patient number 1 had intense rhinitis and urticarial hives 15 minutes after the 5000 SQ-U injection. He received anaphylaxis treatment, the reaction resolved promptly, and he could be discharged from the hospital after 2 hours. Patient number 2 experienced an odd sensation immediately after the injection, dizziness and weakness after 5 minutes followed by abdominal pain, nausea, itching chest erythema, flush, facial angioedema and hypotension. The patient received immediate anaphylaxis treatment, was stabilized after 30 minutes and could be discharged from the hospital the same day. This patient had reported a late reaction with mild nasal obstruction, heavy breathing, increased heart rate and mild itching at the injection site already after 3000 SQ-U.
Consequently, the dose-escalation was interrupted. The protocol 1000-3000-3000 SQ-U could be performed without any serious adverse events. Two active patients had a large (>10 cm) erythema at the injections site at the last injection, both were correlated with signs of leakage of the allergen outside of the lymph node visualized with ultrasound. See Table 2 for details.

Pollen counts

According to the local pollen counts during the study periods in 2015-2017, the grass pollen levels were 17-21% lower in 2016 than in 2015 and 25-46% lower in 2017 than in 2016. See Figure 2 and Table E1.

Primary outcome measure

In ILIT after SCIT- 10 000, the median combined SMS scores (CSMS) was reduced by 31% in the active group at the pollen season after treatment compared to the season before treatment. The CSMS in the placebo group did not change (see Figure 3 and Table 3.) When comparing the active group with the placebo group there was no difference in CSMS after treatment; the active group (n=13) had median CSMS 76.3 (IQR 22.7-109.9) after treatment, and the placebo group (n=12) had median CSMS 46.2 (IQR 30.1-71.2), p=0.31. Excluding one patient that had incomplete SMS registration at the baseline season did not change the result.
In ILIT de novo- 3000, both the placebo and active groups improved the year after treatment. The active group reduced the mean CSMS with 24% and the placebo group reduced the mean scores with 28% (see Figure 3 and Table 3). Three patients had received a different up-dosing (1000-1000-3000 or 1000-3000-5000 SQ-U) but were not outliers. There was no difference between the active group versus the placebo group after treatment, the active group had mean CSMS 68.9 (SD 28.9 [95% CI 53.5-84.3]), n=16 and the placebo group had mean CSMS 74.8 (SD 34.7 [95% CI 57.5-92.0]), n= 18, p=0.60.

Secondary outcomes