4.1.1 Course of the study Flow chart of the study design:
4.1.2 Randomized controlled trial
Overall, 45 children from the electronic files of the hospital were assessed for eligibility for the study by calling and interviewing their parents. The study design was planned as a randomized, controlled trial (RCT), done as a placebo-controlled
trial. Some parents declined because they considered the double-blind trial too laborious, while other children were either too old for the study, passed the preceding milk challenge showing recovery from CMA, or there was no evidence that the children’s CMA was IgE-mediated.
Thirty-six patients treated for CMA when they were less than 2 years age were chosen for this study. After detailed oral and written information was provided, 28 were willing to participate, with 18 randomized to the active-treatment arm and 10 to the control arm. We assumed that the success rate would be 70% in the active cases and 10% in the controls, or a 60% case-control difference. If the probability of the type-I error is settled to 0.05, and the case-control allocation rate is 2:1, the power would be 0.9 to reject the null-hypothesis that the difference in the success rates is less than 60 %, when uncorrected chi-square statistics are used. The power calculations were made, and the conclusion was that a sample size of 36 cases is needed.
Twenty-eight school-age children with CMA from early childhood were recruited for the study. The patients were randomized by a 2:1 ratio in the blocks of six (4+2) into the two OIT arms, with 18 in the active group and 10 in the placebo group. The random allocation by block randomization was carried out by the chief pharmacist at the Tampere University Hospital Pharmacy. The study doctors opened the sealed envelopes during the six-month control visits.
4.1.3 Open trial
In the control group, the six-month OIT was followed by an open OIT with an identical protocol, including an escalation phase of six months. All 10 controls, including the two who were considered failures in the double-blind phase, participated.
4.1.4 Patients
A total of 28 children ages 6-14 years were enrolled in the study in May 2008. The patients had been treated for CMA from early childhood in the Department of Pediatrics at Tampere University Hospital in Finland. The median age of the 18 children in the active group was 10.3 years (range: 6-14), and 56% were female. The respective figures in the placebo group were 9.8 years (7-13) and 60%. Most of the patients (79%) had doctor-diagnosed asthma. Nine children (32%) were considered
to have severe CMA since they had presented with anaphylaxis to milk prior to the OIT study. All patients had a history of either pollen allergies or another food allergy besides milk, reported by parents. Other food allergies included eggs, cereals, nuts, or cross-reacting foods with pollen, such as fruits, vegetables, and spices.
Interestingly, the study included three pairs of brothers from three different families. The eligibility criteria of this OIT study, in addition to being between 6 and 14 years old, included the presence of IgE-mediated CMA, which means the diagnosis had to be proved by an immediate (< 4h) reaction in an open milk challenge test during the previous three months. In the event of recent milk anaphylaxis during the previous six-month period a challenge test was abandoned.
Additionally, either a positive ≥ 3 mm SPT reaction to CM or serum CM-specific IgE > 3.5kU/l was required.
At the first study visit, hospital records were checked, and the children and parents were interviewed to confirm that the study’s enrollment criteria were fulfilled. In addition, the threshold doses of CM that have produced induced symptoms earlier were recorded.
The children’s backgrounds included the following: 21 (75%) were asthmatics, 26 (93%) had allergic rhinitis, 26 (93%) had atopic eczema, and 26 (93%) had other food allergies: 20 to eggs, three to soy, 15 to cereal, and 20 to pollen cross-reacting foods.
4.1.4.1 Basic and outcome data of treatment group (Appendix 1)
More-specific data on the active-treatment group can be found in Appendix 1.
4.1.4.2 Basic and outcome data of placebo group (Appendix 2) More-specific data on the placebo group can be found in Appendix 2.
4.2 Oral immunotherapy
4.2.1 Daily milk-dosing schedule
The schedule of daily milk doses was modified by the first large open study, by Meglio et al., published in 2004, and the maximum dose was the same 6,400mg of
CM protein, equal to 200 mL of milk (Meglio et al. 2004). First, milk (pasteurized 2.5% fresh milk) and placebo (oat drink, rice drink, or soy drink) products were prepared by the Mother´s Milk unit of Tampere University Hospital. The placebo was chosen based on the allergy status of each child. All milk products were flavored with sugar.
The schedule started with one drop of solution containing 1 part CM and 25 parts water. For the first five weeks, patients used a milk dilution, and the rest of the time, pure milk. The CM protein amount gradually was increased from 0.006 mg to 6400 mg (equal to 200 mL of milk). The first dose and eight more doses were given at the outpatient clinic: 0.006 mg (Day 1), 0.013 mg (Day 8), 0.026 mg (Day 15), 2.0 mg (Day 36), 4.0 mg (Day 38), 8.0 mg (Day 42), 30 mg (Day 56), 60 mg (Day 64) and 130 mg (Day 78). The dosage then was increased by 0.3 mL daily for two weeks (from day 78 till day 91). Then 0.5 mL daily (day 92 to 105), 1.0 mL (day 106 to 119), 2.0 mL (day 120 to 133), 4.0 mL (day 134 to 147), and finally by 5.0 mL daily until Day 162. Most of the dose escalations occurred at home, and the amount of CM protein was doubled once a week. The OIT protocol lasted 23 weeks, consisting of 10 outpatient visits to the Department of Pediatrics at Tampere University Hospital.
These visits were supervised at the outpatient clinic for two hours by two study nurses and two study doctors. The maintenance dose of 6,400 mg after the escalation phase was given at home on Day 162. The control visit at the outpatient clinic was held within two weeks. The patients were on a maintenance dose of antihistamine during the OIT protocol, and during the control visit, antihistamine use was discontinued.
4.2.2 Symptoms during OIT
In case of any symptoms, the parents were given a phone number for the study doctors or study nurses, one of whom answered 24 hours a day. Families were required to have antihistamines, self-injectable adrenaline, and corticosteroid tablets at home if any severe symptoms occured. Parents were asked to report in a diary the 1-3 most significant symptoms from their perspectives (Thesis article I). The symptoms were reported as dermal, intestinal, oral, nasal, angioedema, or no symptoms during both blind and open phases. All 16 patients in the active group who completed the study had symptoms at some point in the study. These symptoms were mostly oral or intestinal, self-limiting, and needed no medication. There were no cases of anaphylaxis due to OIT treatment in the blind or open phases (Thesis article I).