Randomized double-blind controlled study with sublingual carbamylated allergoid immunotherapy in mild rhinitis due to mites
Randomized double-blind controlled study with sublingualcarbamylated allergoid immunotherapy in mild rhinitis due tomites
Background: The clinical eﬃcacy of sublingual immunotherapy (SLIT) in mite
allergy and in mild disease is still a matter of debate, thus we performed a long-
Methods: The study was randomized, double-blind and placebo-controlled.
After a 1-year assessment, 68 patients with mild rhinitis with/without asthma
due to mites were randomized to drugs + placebo or drugs + SLIT for 2 years.
1Allergy and Respiratory Diseases, Department of
Sublingual immunotherapy was given as soluble tablets of monomeric car-
Internal Medicine, University of Genoa, Genoa;
bamylated allergoid. Clinical scores for asthma and rhinitis (0, absent to 3,
2Allergy Unit, Bordighera Hospital, Imperia; 3Allergy
severe) and drug consumption were assessed by diary card in the period
Service, Department of Internal Medicine, S. Orsola
November–February. Quality of life was assessed before and after each obser-
Hospital FBF, Brescia; 4Psychology Unit, Scientific
vation period and pharmaco-economy data were evaluated as well.
Institute of Montescano, S. Maugeri FoundationIRCCS, Montescano (PV), Italy; 5Lofarma S.p.A.,
Results: Fifty-six patients completed the study. The rate of dropouts was similar
in the two groups. No relevant side eﬀect was reported. There was a signiﬁcantreduction of total clinical scores (P < 0.05) in the active group vs placebo at theﬁrst year, but not at the second whereas nasal obstruction signiﬁcantly improvedin both years (P < 0.05). The reduction of drug intake score was signiﬁcant only
Key words: asthma; carbamylated allergoid; mite
at the ﬁrst year. No change was observed concerning most of the Short Form-36
allergy; rhinitis; sublingual immunotherapy.
items, because at baseline all patients displayed a normal proﬁle. A signiﬁcant
change in SLIT group was seen for the item Ôchange in health statusÕ. The need
for extra visits was signiﬁcantly lower in the active group (25% vs 43%).
Conclusions: Sublingual immunotherapy was clinically eﬀective and safe in mite-
Allergen-speciﬁc immunotherapy (IT) is a cornerstone in
that SLIT was a viable alternative to the injection route
the management of respiratory allergy (1), and its clinical
(1). These conclusions were subsequently conﬁrmed in the
value is nowadays well recognized. In general, the clinical
recent ARIA (allergic rhintis and its impact on asthma)
eﬃcacy (reduction of symptoms and need for medica-
guidelines that extended the indication of SLIT to
tions) of IT seems to be greater in pollen than in mite-
children also (8). Also in the case of SLIT, the eﬀects in
induced allergy (1–4). This is probably due to the fact that
mite respiratory allergy were quantitatively less relevant
in the case of dust mite allergy the continuous, although
than in pollen allergy, and statistically signiﬁcant results
variable, exposure to an allergen sustains a chronic
were often obtained only with long-term treatments (9–
inﬂammation where the role of immunoglobulin E (IgE)
11). Moreover, in children, SLIT proved eﬀective only in
and mast cells is less relevant than in pollinosis.
those subjects with more severe rhinitis symptoms (12).
Starting from the earliest attempts, IT has been
Therefore, there are still some concerns about the
administered subcutaneously but due to safety aspects
indications and eﬃcacy of SLIT in mild disease.
(5, 6) in the last 20 years new routes of administration
To date, it is recognized that the simple measurement
have been investigated (7) and developed. Among these,
of objective parameters or symptomatic changes does not
the sublingual route (sublingual immunotherapy, SLIT)
provide a full evaluation of the eﬀects of a given
appeared to be the most promising alternative to the
treatment, but the patientsÕ perception also plays a
traditional IT. In 1998, the World Health Organization
relevant role. This is the reason why the assessment of
based on an extensive review of the literature, concluded
quality of life (QoL) is assuming a more and more
important role in clinical trials, especially in allergy (13,
in the Mediterranean area); (vii) any speciﬁc IT course in the last
14). In association with the patientsÕ perception of the
5 years and (viii) major psychiatric disorders. All patients signed an
impact of disease on his/her life, there is an another
informed consent at the time of enrollment. A physician was alwaysavailable at each centre for phone contact. All patients were
parameter that can provide further information about the
instructed, as routinely done, to carry on allergen avoidance: use of
subject’s well-being: the so-called ÔsatisfactionÕ that is the
impermeable mattress and pillow covers, removal of moquettes,
cognitive product of the comparison between expecta-
carpets and curtains, hot water washing of bedding once weekly.
tions and reality (15, 16). In the case of IT in general, andSLIT in particular, there are few data concerning the QoLaspects (11). Aim of the present study was to evaluate the
Immunotherapy and concomitant medications
clinical eﬃcacy and the safety of SLIT over a 2-year
Sublingual immunotherapy was a monomeric carbamylated aller-
period in patients suﬀering from mild rhinitis due to dust
goid (LaisÒ) kindly provided by Lofarma S.p.A. (Milan, Italy)
mites. The eﬀects on QoL were assessed as well.
biologically standardized (9, 19) in allergenic units (AU), and pre-pared as soluble tablets. The tablets had to be taken in the morningon an empty stomach, and kept under the tongue for 1–2 min untildissolution before swallowing. During the build-up phase of about
1 month, tablets with increasing dosages (25, 100, 300 and1000 AU) were used in order to gradually achieve the maximum
dose of 1000 AU. Subsequently, that maintenance dose of 1000 AUwas administered two times a week for 2 years continuously. Con-
This was a multicentre, randomized, placebo-controlled, two par-
cerning the content of major allergen, it is not reported on the
allel-arm trial of SLIT to mites. Outpatients suﬀering from mild
product label because the chemical modiﬁcation of the allergen does
allergic rhinoconjunctivitis with/without mild intermittent asthma
not allow its titration in micrograms. Placebo tablets contained the
were enrolled. All patients underwent a 1-year run-in observation in
same excipients without the allergoid and were undistinguishable
order to establish their baseline clinical conditions. After the run-in,
in aspect, ﬂavour and dissolution time from the active treatment.
patients were randomized to receive, in addition to drug treatment,
Patients were randomly allocated to SLIT or placebo according to a
either SLIT in tablets or matched placebo. Clinical scores (symp-
toms and drug intake) were recorded each year by diary card from
During the study, all patients were allowed to use rescue medi-
November through February. Quality of life and satisfaction were
cations for symptom control: cetirizine tablets (10 mg; once daily),
assessed at regular intervals during the study. The study plan is
inhaled albuterol (100 lg; 2–4 puﬀ on demand), intranasal ﬂutica-
shown in Fig. 1. The trial was approved by the ethical committees
sone (50 lg; 1 spray per nostril once daily on medical prescription).
In the case of severe rhinitis unresponsive to the standard treatment,a short course of systemic steroid was given (prednisone 50 mg daily
Adult patients (18–50 years) of both sexes were enrolled. They had
to suﬀer from mild persistent rhinitis according to ARIA guidelineswith/without mild intermittent asthma according to Global Initiative
Patients were required to record daily on a speciﬁc form the pres-
on Asthma (GINA) guidelines (17) since at least 2 years. They had to
ence and severity of symptoms and the amount of medications used.
have a skin positivity to house dust mite (wheal diameter > 5 mm)
The diary had to be ﬁlled from November to February, when the
(18) and a CAP-radioallergosorbent class II or greater. Exclusion
exposure to indoor mites is expected to be greater, for 3 years
criteria were: (i) systemic immunological disorders; (ii) malignancies;
(1 year run-in and 2 years of double-blind study). The following
(iii) diabetes; (iv) chronic heart failure or chronic obstructive pul-
symptoms were considered: nasal itching, obstruction, rhinorrhea,
monary disease; (v) pregnancy or lactation; (vi) skin test positivity to
sneezing, ocular itching, cough and shortness of breath. A score
cat/dog dander or Parietaria (this latter allergen is almost perennial
ranging from 0 (absent) to 3 (severe) was attributed daily to each ofthe mentioned symptoms. A mean daily score was calculated foreach 4-month period. The drug intake was scored 1 point for eachactuation of salbutamol, 2 points for each dose of antihistamine,nasal or inhaled steroid, 3 points for each dose of systemic steroid,and a cumulative drug intake score was obtained.
All patients were also required to record on a separate diary any
untoward eﬀect, possibly related to the intake of SLIT. Adverseevents were subdivided into local (oral itching, swelling of tongue)and systemic: asthma, rhinitis, urticaria, abdominal pain/diarrhoeaand anaphylaxis. Finally, patients had to record the number of extravisits (other than the scheduled ones) attended, and the working(school) days missed because of their allergy problems.
At the beginning and the end of each observation period (Novemberand February), patients had to ﬁll two generic questionnaires, oneassessing the health status and the other one assessing the subjective
satisfaction. The QoL was measured by the Short Form (SF)-36Health Survey, a generic, widely used questionnaire, already valid-ated in allergic respiratory disease. It consists of 36 items corres-ponding to eight domains: physical function, role limitation(physical), bodily pain, general health, vitality, social function, rolelimitation (emotional) and mental health. An additional questioninvestigates a general evaluation of perceived changes in healthstatus in the past year. The satisfaction was evaluated by the SAT-P,a nondisease speciﬁc tool with 32 questions about several aspects ofdaily life. The patients indicate their subjective satisfaction on a10 cm visual analogue scale, from 0 (extremely dissatisﬁed) to 10(extremely satisﬁed). The SATisfaction proﬁle (SAT-P) provides ananalytic score about the 32 items and a score about the ﬁve factorsextracted: psychological functioning, physical functioning, work,sleep/eating/leisure and social functioning. The SAT-P has beenpreviously used in patients with allergic diseases (16, 20).
The nonparametric tests for two independent samples are useful for
Figure 2. Mean ± SD daily total symptom score in the active
determining whether or not the values of a particular variable (i.e.
and placebo group at baseline and after 1 and 2 years of
total symptom score) diﬀer between two groups (SLIT vs placebo).
This is especially true when the assumptions of the t-test are notmet. We used the Mann–Whitney and Wilcoxon statistics to test thenull hypothesis that two independent samples came from the samepopulation. Their advantage over the independent samples t-test isthat Mann–Whitney and Wilcoxon do not assume normality andcan be used to test ordinal variables.
Sixty-eight patients were enrolled in the trial. Their meanage was 31.28 ± 8.14 years, with an age range of 18–49,and 41.2% of them were male. Twelve patients, six ineach group, dropped out, mainly during the run-in phase.
Two subjects from the placebo group withdrew forconcomitant illness, nine patients (four placebo and ﬁveactive) retired their informed consent for personal reasonsand one active patient dropped out for major protocoldeviation (unattended visits). Fifty-six patients (mean age32.14 ± 7.97 years, 39.3% male) completed the study.
Figure 3. Mean ± SD daily obstruction score in the active andplacebo group at baseline and after 1 and 2 years of treatment.
The patients were homogeneous at baseline for demo-graphy and clinical characteristics (Table 1).
considered acceptable. Fig. 2 shows the mean daily
clinical score (all symptoms) at baseline, after 1 and
Due to the very long duration of the study, a rate of
2 years of treatment. A signiﬁcant diﬀerence between the
<15% of missing data in the clinical diaries was
two groups could be found after 1 year of treatment(P ¼ 0.027), whereas no statistical diﬀerence was found
Table 1. Demographics and clinical characteristics by treatment group
at the second year, although a trend towards improve-ment was seen. Concerning the symptom Ônasal obstruc-
tionÕ a signiﬁcant diﬀerence between groups was present
after 1 year (P ¼ 0.05) and 2 years (P ¼ 0.033) of treat-
ment (Fig. 3). No diﬀerence during the study could be
found for the other symptoms taken separately. The
global drug intake is shown in Fig. 4, being the diﬀerence
signiﬁcant at the ﬁrst year of treatment (P ¼ 0.036), but
not at the second, although a trend toward diﬀerence was
Quality of life, satisfaction profile and pharmaco-economics
There was no statistical change in all the domains of theSF-36 questionnaire at the six timepoints, and all thescores were quite high. Table 3 shows the values for eachdomain that are not diﬀerent from those of a referencehealthy population (21–23). There was indeed a diﬀerencebetween the active and the placebo group in the only itemÔoverall change in health statusÕ (P ¼ 0.05) after thesecond year of treatment (Fig. 5). No change in the itemsof the SAT-P questionnaire was found, because in thiscase also the scores were always comparable with those ofa healthy reference group ( data not shown).
There was a signiﬁcant diﬀerence between the two
groups as far as the pharmaco-economic aspects areconcerned. No working absence was reported in theactive group. In the placebo group, three patientsreported a total of 22 working days lost attributable to
Figure 4. Mean ± SD of the drug intake in the considered 4-
their allergic disease. This means a cost of 3047€ (138.5€
per day) (24) that is superior to the cost of SLIT for thesame number of patients (about 2700€). Moreover, 12
seen. Nasal steroids were prescribed only occasionally in
patients (43%) in the placebo group and six patients
both groups and a statistical analysis was not therefore
(25%) in the active group needed one or more extra visit
(P ¼ 0.01) due to illness exacerbation.
The occurrence of adverse events was not signiﬁcantly
diﬀerent between the two groups. Thirty events (11patients) in the actively treated and 43 events (16 patients)in the placebo group were reported and none was judged
possibly or certainly related to treatment. A list of those
The use and indication of SLIT in mite allergy are less
adverse events occurring at least twice is shown in
deﬁned than in pollinosis. In fact, the results of clinical
Table 2. In the active group, two patients reported
trials are less apparent in term of eﬃcacy and need longer
transient oral itching and one patient mild abdominal
times to become measurable. Some clinical trials have
provided positive results (9–11, 25), whereas in otherstudies the eﬀects were marginal (26) or absent (27, 28).
Table 2. Detail of the adverse events occurring more than one time
This may be due to the fact that with mites the allergenic
exposure is extremely variable during the course of theyear and therefore, prolonged periods of observation are
needed. Furthermore, mite-induced allergy may provoke
less severe symptoms, although long-lasting. It is diﬃcult
to carry out studies with mite allergy in adult patients. In
fact, it is objectively diﬃcult to keep many patients on a
double-blind design, recording symptoms and drug intake
Table 3. Short Form-36 domains score at the six timepoints in the active and placebo group
The last column on the right shows the mean values for a reference healthy population (19).
23), so it was not conceivable to obtain an improvementof normal values. Thus, we can deduce that a mild diseasedoes not signiﬁcantly aﬀect the QoL of patients or, inother words, patients with mild symptoms cope with theirdisease and do not perceive an impact on daily function-ing. This fact, indirectly conﬁrms the validity of theARIA classiﬁcation of the severity of rhinitis. In addition,it has been previously shown that generic questionnaires(e.g. the SF-36) may be unable to detect changes in healthstatus (29). On the other hand, a signiﬁcant change in theitem exploring the variation of the disease’s status wasfound and a statistical projection showed that this changewould have been maintained and would have becomemore and more signiﬁcant in the next years. Of note,there was also a diﬀerence in extra visits and workingabsence in the active group, this indirectly testifying thata general eﬀect on the disease severity has occurred. Itremains to be ascertained whether a continuous SLITtreatment in mild disease can be proposed to all patientsin clinical practice, although the adherence to treatmentwas shown not to represent a problem (30).
Figure 5. Short Form-36 scores Ôchange in health statusÕ meas-
The clinical eﬀect of SLIT also in mild disease should
be considered in the light of the very favourable tolerab-ility proﬁle that would also allow small children to be
continuously for years. We therefore chose to record the
safely treated (31). In this study, the safety aspect was
clinical scores only 4 months a year, from November to
further ensured by the use, as active principle, of a
February, when the exposure to allergens was expected to
monomeric carbamylated allergoid, which has a reduced
be higher. With this method, we could demonstrate that
IgE-binding capacity. The monomeric carbamylated
allergoid SLIT induced a signiﬁcant improvement of total
allergoid resulted to be very suitable for SLIT treatments
clinical symptoms and drug consumption at the ﬁrst year,
because on the one hand its low molecular size (19) allows
whereas in the second year no signiﬁcance was reached.
absorption at the mucosal level and on the other, the
This is consistent with the fact that all patients had a mild
carbamylation improves its bioavailability by increasing
disease, and were allowed to use rescue medications for
the resistance to enzymatic degradation at the gastroin-
their symptoms. On the other hand, the symptom Ônasal
testinal level, as shown by biodistribution studies per-
obstructionÕ that is the most bothering symptom of
formed with the radiolabelled Der p 2 (32). In conclusion,
persistent rhinitis, especially in patients allergic to peren-
SLIT with carbamylated allergoid exerts a measurable
nial allergens like mites, was improved in both the
clinical eﬀect even in mild rhinitis due to mites, and
observation periods. Obstruction in persistent forms is
favourably aﬀects the pharmaco-economic proﬁle of the
largely sustained by inﬂammation, and the improvement
of obstruction is consistent with the previously demon-strated anti-inﬂammatory action of the allergoid IT (9).
The nonsigniﬁcant diﬀerence between the two groups at
baseline did not aﬀect the ﬁnal results as conﬁrmed by atime-trend analysis.
This work was partially supported by ARMIA (AssociazioneRicerca Malattie Immunologiche e Allergiche). We thank biostat-
Concerning QoL, all patients had QoL proﬁles not
istician Dr Giorgio Reggiardo for his precious help.
diﬀerent from a control group of healthy subjects (15, 21–
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