Pharmacotherapeutic group: Allergen extracts, house dust mite
ATC code: V01AA03
Mechanism of action
ACARIZAX is allergy immunotherapy. Allergy immunotherapy with allergen products is the repeated administration of allergens to allergic individuals with the purpose of modifying the immunological response to the allergen.
The immune system is the target for the pharmacodynamic effect of allergy immunotherapy, but the complete and exact mechanism of action regarding the clinical effect is not fully understood. Treatment with ACARIZAX has been demonstrated to induce an increase in house dust mite specific IgG
4
and to induce a systemic antibody response that can compete with IgE in the binding of house dust mite allergens. This effect is observed already after 4 weeks of treatment.
ACARIZAX works by addressing the cause of house dust mite respiratory allergic disease, and clinical effect during treatment has been demonstrated for both upper and lower airways. The underlying protection provided by ACARIZAX leads to improvement in disease control and improved quality of life demonstrated through symptom relief, reduced need for other medications and a reduced risk for exacerbation.
Clinical efficacy in adults
The efficacy of treatment with ACARIZAX 12 SQ-HDM in house dust mite respiratory allergic disease was investigated in two double-blind, randomised, placebo-controlled trials with different endpoints and in different patient populations. Two thirds of the trial subjects were sensitised to more allergens than just house dust mite. Being sensitised to house dust mite only or to house dust mite and one or more other allergens did not impact the trial results. Supportive evidence from an allergen exposure chamber trial as well as a trial conducted with lower doses is also presented.
Allergic rhinitis
The MERIT trial (MT-06)
• The MERIT trial included 992 adults with moderate-to-severe house dust mite allergic rhinitis despite the use of rhinitis pharmacotherapy. Subjects were randomised to approximately 1 year of daily treatment with 12 SQ-HDM, 6 SQ-HDM or placebo and were given free access to standardised rhinitis pharmacotherapy. Subjects were seen by a specialist approximately every two months during the entire trial.
• The primary endpoint was the average daily total combined rhinitis score (TCRS) evaluated during the last 8 weeks of treatment.
o The TCRS was the sum of the rhinitis symptoms score and the rhinitis medication score. The rhinitis symptoms score evaluated 4 nasal symptoms (runny nose, blocked nose, itching nose, sneezing) daily on a 0-3 scale (no, mild, moderate, severe symptoms), i.e. range of scale is 0-12. The rhinitis medication score was the sum of the score for nasal steroid intake (2 points per puff, max. 4 puffs/day) and oral antihistamine intake (4 points/tablet, max. 1 tablet/day), i.e. range: 0-12. Thus the TCRS range is: 0-24.
• Additional pre-defined key secondary endpoints were the total combined rhinoconjunctivitis score and rhinoconjunctivitis quality of life (RQLQ).
• Post-hoc analyses of the days with a rhinitis exacerbation were also conducted to further illustrate the clinical relevance of the results.
o A rhinitis exacerbation was defined as a day where the subject returned to the high level of symptoms required for trial inclusion: a rhinitis symptom score of at least 6 or at least 5 with one symptom rated severe.
Table: Summary of main efficacy results in adults (allergic rhinitis)
MERIT results
12 SQ-HDM
Placebo
Treatment effect
Primary endpoint
N
Score
N
Score
Absolute difference
c
Relative difference
d
p-value
Total combined rhinitis score
FAS-MI
a
(adjusted mean)
318
5.71
338
6.81
1.09 [0.35;1.84]
-
0.004
FAS
b
(adjusted mean)
284
5.53
298
6.76
1.22 [0.49;1.96]
18%
0.001
FAS
b
(median)
284
5.88
298
7.54
1.66
22%
-
Pre-defined key secondary endpoints
N
Score
N
Score
Absolute difference
c
Relative difference
d
p-value
Rhinitis symptoms score
FAS
b
(adjusted mean)
284
2.76
298
3.30
0.54 [0.18;0.89]
16%
0.003
FAS
b
(median)
284
2.98
298
3.98
1.00
25%
-
Rhinitis medication score
FAS
b
(adjusted mean)
284
2.22
298
2.83
0.60 [0.08;1.13]
21%
0.024
FAS
b
(median)
284
2.83
298
4.00
1.17
29%
-
Total combined rhinoconjunctivitis score
FAS
b
(adjusted mean)
241
7.91
257
9.12
1.21 [0.13;2.28]
13%
0.029
FAS
b
(median)
241
8.38
257
10.05
1.67
17%
-
Rhinoconjunctivitis quality of life questionnaire (RQLQ(S)) score
FAS
b
(adjusted mean)
229
1.38
240
1.58
0.19
e
[0.02;0.37]
12%
0.031
FAS
b
(median)
229
1.25
240
1.46
0.21
14%
-
Post-hoc endpoints
N
Proportion
N
Proportion
Odds ratio
f
[95% CL]
p-value
Probability of having a day with a rhinitis exacerbation
FAS (estimate)
b
284
5.33%
298
11.14%
0.45 [0.28;0.72]
0.001
Probability of having a day with a rhinitis exacerbation despite use of rhinitis pharmacotherapy
FAS (estimate)
b
284
3.43%
298
6.50%
0.51 [0.32;0.81]
0.005
N: number of subjects in treatment group with data available for the analysis. CL: confidence limits
a
FAS-MI: full analysis set with multiple imputations. The analysis treats subjects who discontinued the trial before the efficacy assessment period as placebo subjects. For the primary analysis (FAS-MI) only the absolute difference was pre-specified.
b
FAS: full analysis set. All available data used to its full extent, i.e. subjects who provided data during the efficacy assessment period.
c
Absolute difference: placebo minus 12 SQ-HDM, 95% confidence limits.
d
Relative difference to placebo: placebo minus 12 SQ-HDM divided by placebo.
e
The difference between 12 SQ-HDM and placebo was primarily driven by differences in three domains: sleep problems, practical problems and nose symptoms.
f
Odds ratio for having a rhinitis exacerbation: 12 SQ-HDM over placebo.
Supportive evidence – allergic rhinitis
A randomised, double-blind, placebo-controlled phase II trial was conducted in an allergen exposure chamber in 124 adults with house dust mite allergic rhinitis. Before each allergen challenge, subjects were washed out of all allergy pharmacotherapy. At the end-of-trial allergen challenge after 24 weeks of treatment with 12 SQ-HDM, 6 SQ-HDM or placebo, the mean rhinitis symptoms score was 7.45 [6.57;8.33] in the placebo group and 3.83 [2.94;4.72] in the 12 SQ-HDM group, corresponding to an absolute difference of 3.62 and a relative difference of 49% (95% confidence interval [35%;60%], p<0.001). The difference between 12 SQ-HDM and placebo was also statistically significant at 16 weeks (mean scores of 4.82 and 6.90, difference of 2.08 corresponding to 30%, 95% CI [17%;42%], p<0.001) and at 8 weeks (mean scores of 5.34 and 6.71, difference of 1.37 corresponding to 20%, 95% CI [7%;33%], p=0.007).
Allergic asthma:
The MITRA trial (MT-04)
The MITRA trial included 834 adults with house dust mite allergic asthma not well-controlled by daily use of inhaled corticosteroid (ICS) corresponding to 400-1200 µg budesonide. All subjects received 7-12 months' treatment with 12 SQ-HDM, 6 SQ-HDM or placebo in addition to ICS and short-acting beta-agonist prior to ICS reduction. No titration phase to establish the lowest maintenance dose of ICS was conducted prior to randomisation. Efficacy was assessed by time to first moderate or severe asthma exacerbation under ICS reduction over the last 6 months of 13-18 months of treatment.
o The definition of a moderate asthma exacerbation was fulfilled if the subject experienced one or more of the 4 criteria below, and it led to change in treatment:
▪
Nocturnal awakening or increase in symptoms
: nocturnal awakening(s) due to asthma requiring short-acting β
2
agonist (SABA) for two consecutive nights or increase of ≥0.75 from baseline in daily symptom score on two consecutive days.
▪
Increased SABA use
: increase from baseline in occasions of SABA use on two consecutive days (minimum increase: 4 puffs/day).
▪
Deterioration in lung function
: ≥20% decrease in PEF from baseline on at least two consecutive mornings/evenings or ≥20% decrease in FEV1 from baseline.
▪
Healthcare visit
: visit to the emergency room / trial site for asthma treatment not requiring systemic corticosteroids.
o A severe asthma exacerbation was defined as experiencing at least one of the two following:
▪ Need for systemic corticosteroids for ≥3 days
▪ Emergency room visit requiring systemic corticosteroids or hospitalisation for ≥12h.
Figure: Risk of moderate/severe asthma exacerbation during ICS reduction/withdrawal phase
Table: Summary of main efficacy results in adults (allergic asthma)
MITRA results
12 SQ-HDM
Placebo
Efficacy
12 SQ-HDM over placebo
p-value
N
n (%)
N
n (%)
Hazard ratio
[95% CL]
Risk reduction
a
Primary endpoint
Any exacerbation, moderate or severe (FAS-MI)
b
282
59 (21%)
277
83 (30%)
0.69
[0.50;0.96]
31%
0.027
Any exacerbation, moderate or severe (FAS)
c
248
59 (24%)
257
83 (32%)
0.66
[0.47;0.93]
34%
0.017
Pre-defined analyses of components of the primary endpoint
Nocturnal awakening or increase in symptoms
c
248
39 (16%)
257
57 (22%)
0.64
[0.42;0.96]
36%
0.031
Increased SABA use
c
248
18 (7%)
257
32 (12%)
0.52
[0.29;0.94]
48%
0.029
Deterioration in lung function
c
248
30 (12%)
257
45 (18%)
0.58
[0.36;0.93]
42%
0.022
Severe exacerbation
c
248
10 (4%)
257
18 (7%)
0.49 [0.23;1.08]
51%
0.076
N: number of subjects in treatment group with data available for the analysis.
n (%): number and percentage of subjects in treatment group meeting criterion.
CL: confidence limits
a
Estimated by hazard ratio
b
FAS-MI: full analysis set with multiple imputations. The analysis treats subjects who discontinued the trial before the efficacy assessment period as placebo subjects.
c
FAS: full analysis set. All available data used to its full extent, i.e. including all subjects who provided data during the efficacy assessment period.
Post-hoc analyses of the asthma symptoms and symptomatic medication use in the last 4 weeks of the treatment period prior to reduction of inhaled corticosteroids were also conducted to investigate the effect of ACARIZAX as add-on to inhaled corticosteroid. The analyses looked at asthma daytime and nocturnal symptom scores, nocturnal awakenings, and SABA intake. The post-hoc analyses showed numerical differences consistently in favour of 12 SQ-HDM over placebo for all parameters investigated during the last 4 weeks prior to inhaled corticosteroid reduction. The differences were only statistically significant for the asthma daytime symptom score (p=0.0450) and the odds for no nocturnal awakenings (p=0.0409).
Supportive evidence – allergic asthma
In a double-blind, randomised, placebo-controlled phase II trial, 604 subjects ≥14 years old with house dust mite allergic asthma controlled by inhaled corticosteroids (100-800µg budesonide) and a clinical history of house dust mite allergic rhinitis were randomised to approximately 1 year of treatment with 1, 3 or 6 SQ-HDM or placebo. At the 4-week end-of-trial efficacy evaluation period, the mean change from baseline in the daily ICS dose was 207.6 µg budesonide in the 6 SQ-HDM group and 126.3 µg in the placebo group corresponding to an absolute difference of 81 µg budesonide per day (95% confidence interval [27;136], p= 0.004. Relative mean and median ICS reductions from baseline were 42% and 50% for 6 SQ-HDM and 15% and 25% for placebo. In a post-hoc analysis of a subgroup (N=108) of subjects with lower asthma control and ICS ≥400 µg budesonide, the mean change from baseline in the daily ICS dose was 384.4 µg budesonide in the 6 SQ-HDM group and 57.8 µg in the placebo group corresponding to an absolute difference between 6 SQ-HDM and placebo of 327 µg budesonide per day (95% CI [182;471], p<0.0001, post-hoc analysis).
Paediatric population
Clinical efficacy in children
The efficacy of treatment with ACARIZAX 12 SQ-HDM in house dust mite respiratory allergic disease in children was investigated in two double-blind, randomised, placebo-controlled trials. The primary objective of the trials was to investigate efficacy in allergic rhinitis in the MT-12 trial and to investigate efficacy in allergic asthma in the MT-11 trial.
Allergic rhinitis
Children 5-11 years of age
The MATIC trial (MT-12)
The efficacy of treatment with ACARIZAX 12 SQ-HDM in house dust mite allergic rhinitis in children 5-11 years was investigated in a double-blind, randomised, placebo-controlled trial (MATIC trial (MT-12)).
• The MATIC trial (MT-12) included 1458 children (5-11 years of age) with moderate to severe house dust mite allergic rhinitis/rhinoconjunctivitis (baseline mean total combined rhinitis score (TCRS) 18.3). Approximately 40% of the trial population reported concomitant asthma at baseline. Subjects were randomised to approximately 1 year of daily treatment with 12 SQ-HDM or placebo and were given free access to standardised rhinitis and conjunctivitis pharmacotherapy.
• The primary endpoint was the average daily total combined rhinitis score (TCRS) evaluated during the last 8 weeks of treatment.
o The daily TCRS is the sum of the rhinitis daily symptoms score (DSS) and the rhinitis daily medication score (DMS). The rhinitis symptoms score evaluated 4 nasal symptoms (runny nose, blocked nose, sneezing, itching nose) daily on a 0-3 scale (no, mild, moderate, severe symptoms), i.e. range of scale is 0-12. The rhinitis medication score was the sum of the score for nasal steroid intake (max. 8 points/day) and oral antihistamine intake (max. 4 points/day), i.e. range: 0-12. Thus the TCRS range is: 0-24.
• After 1 year of treatment with 12 SQ-HDM, an absolute difference in adjusted means of 0.97 (95% confidence interval [0.50;1.44]) and a relative difference of 22% (p<0.0001) compared to placebo was found. The treatment effect may vary between patients depending on their allergic disease status.
• Onset of the clinical effect was observed after 8 weeks of treatment (p=0.01).
The MATIC trial: Development over time of the total combined rhinitis score
TCRS: total combined rhinitis score (symptoms + medication score).
TCRS measured as an average over 2 weeks of assessment beginning week 8 and week 16.
The primary endpoint was the average daily TCRS during the last approximately 8 weeks of treatment (weeks ~44-52).
Adjusted means of the average TCRS over time with error bars for the difference in adjusted means. Non-overlapping intervals indicate a statistically significant difference. between the groups.
MATIC results
12 SQ-HDM
Placebo
Treatment effect
Primary endpoint
N
Score
N
Score
Absolute difference
b
Relative difference
c
p-value
Total combined rhinitis score
FAS
a
(adjusted mean)
693
3.44
706
4.41
0.97
[0.50; 1.44]
22.0%
<0.0001
Sensitivity estimator 1
e
727
f
3.45
731
f
4.42
0.97
[ 0.49 1.44 ]
21.9%
<0.0001
Pre-defined key secondary endpoints
N
Score
N
Score
Absolute difference
b
Relative difference
c
p-value
Rhinitis symptoms score
FAS (adjusted mean)
693
1.50
706
1.92
0.43
[0.23; 0.62]
22.2%
<0.0001
Rhinitis medication score
FAS (adjusted mean)
693
1.44
706
1.94
0.49
[0.18; 0.80]
25.3%
0.0016
Total combined rhinoconjunctivitis score
FAS (adjusted mean)
693
4.01
706
5.16
1.15
[0.58; 1.71]
22.2
<0.0001
Pre-defined secondary endpoints
N
Score
N
Score
Absolute difference
b
Relative difference
c
p-value
Paediatric Rhinoconjunctivitis quality of life questionnaire (PRQLQ
)
FAS (adjusted mean)
695
0.84
690
1.01
0.17
[0.08; 0.25]
16.6%
<0.0001
Pre-defined secondary endpoints
N
Proportion
N
Proportion
Odds ratio
d
[95%CL]
p-value
Rhinitis exacerbation days
FAS (estimate)
693
0.025
706
0.044
0.56 [0.42; 0.74]
<0.0001
Rhinitis mild days
FAS (estimate)
693
0.318
706
0.209
1.77 [1.27; 2.47]
0.0008
Pre-defined explorative endpoints
N
Proportion
N
Proportion
Odds ratio
d
[95%CL]
p-value
Rhinitis symptom-free days
FAS (estimate)
693
0.200
706
0.116
1.90 [1.37; 2.66]
0.0002
N: number of subjects with observations contributing to the analysis. CL: confidence limit
a
FAS: full analysis set. All available data used to its full extent, i.e. subjects who provided data during the efficacy assessment period.
b
Absolute difference: placebo minus 12 SQ-HDM, 95% confidence interval.
c
Relative difference to placebo: placebo minus 12 SQ-HDM divided by placebo.
d
Odds ratio for having a rhinitis exacerbation, rhinitis mild days and rhinitis symptom-free days: 12 SQ-HDM over placebo. Rhinitis exacerbation days (days with a rhinitis DSS of 6 or of 5 with one individual symptom scored 3 (symptom that is hard to tolerate; causes interference with activities of daily living and/or sleeping)).
e
Trial product estimand: For subjects who discontinued treatment due to lack of efficacy or treatment-related adverse events, missing endpoints were imputed from the placebo group. For treatment discontinuations due to other reasons, missing endpoints were imputed from their own treatment group.
f
For sensitivity estimator 1, N includes subjects with imputed observations.
Subgroup analysis of the primary endpoint (TCRS) by asthma status at baseline showed an absolute difference in adjusted means of 1.26 (95% confidence interval [0.46; 2.06]) in children with concomitant asthma and of 0.77 (95% confidence interval [0.19; 1.36]) in children without concomitant asthma. A pooled analysis of TCRS across 5 phase III trials in HDM allergic rhinitis patients treated with 12 SQ-HDM or placebo showed an absolute difference in adjusted means of 1.27 (95% confidence interval [0.82; 1.72]) in patients with concomitant asthma (N=1,450) and of 0.81 (95% confidence interval [0.49; 1.13]) in patients without concomitant asthma (N=2,595).
The MATIC trial: Forest plot of treatment difference of average daily TCRS in subgroups of asthma status at baseline - observed case (FAS)
CI = confidence interval, FAS = full analysis set, n = number of subjects with observations contributing to the analysis, TCRS = total combined rhinitis score
Pre-specified analyses of asthma-related endpoints evaluated asthma daily symptom score, SABA use, SABA-free days, and nocturnal awakening requiring SABA use. The results showed numerical differences consistently in favour of 12 SQ-HDM over placebo for all 4 parameters. The differences were statistically significant for the asthma daily symptom score (p=0.0259) and nocturnal awakening requiring SABA use (p=0.0279).
Children 5-17 years of age
The MAPIT trial (MT-11)
• The primary objective was to demonstrate efficacy of ACARIZAX 12 SQ-HDM versus placebo in children and adolescents (5-17 years) with house dust mite allergic asthma based on clinically relevant asthma exacerbations after at least 4 months of treatment. The ACARIZAX 12 SQ-HDM was administered as add-on treatment to asthma background treatment (low dose ICS plus long-acting β2-agonists [LABA] or high/medium dose ICS with or without LABA). The trial population also had a clinical history of house dust mite allergic rhinitis of any severity (total combined rhinitis score (TCRS) >0 at baseline; baseline mean TCRS 9.0). MT-11 was not designed to assess clinical effect in allergic rhinitis. The results of the rhinitis endpoints TCRS, rhinitis DSS, and rhinitis DMS are presented in the table below.
MAPIT results
12 SQ‑HDM
Placebo
Treatment effect
Pre‑defined additional secondary endpoints
a
N
Score
N
Score
Absolute difference
b
Relative difference
c
p-value
d
Total combined rhinitis score
FAS
e
(adjusted mean)
253
2.16
259
2.46
0.30
[-0.22; 0.81]
12.1%
0.2597
Rhinitis symptoms score
FAS (adjusted mean)
253
0.55
259
0.67
0.12
[-0.04; 0.28]
18.2%
0.1349
Rhinitis medication score
FAS (adjusted mean)
253
1.27
259
1.40
0.12
[-0.24; 0.48]
8.8%
0.5071
FAS: full analysis set. N: number of subjects with observations contributing to the analysis.
a
Rhinitis endpoints
b
Absolute difference: placebo minus 12 SQ-HDM, 95% confidence interval.
c
Relative difference to placebo: placebo minus 12 SQ-HDM divided by placebo.
d
The p‑values were not adjusted for multiplicity. Therefore, the analyses are to be considered exploratory.
e
All available data used to their full extent, i.e. subjects who provided data during the efficacy assessment period.
Adolescents 12-17 years of age
The efficacy of treatment with ACARIZAX 12 SQ-HDM in house dust mite allergic rhinitis in adolescents was investigated in two double-blind, randomised, placebo-controlled trials (P001 and TO-203-3-2). In these studies a proportion of the subjects were adolescents.
• The P001 trial included 189 adolescents (of 1482 subjects randomised in total) with moderate-to-severe house dust mite allergic rhinitis/rhinoconjunctivitis with or without asthma. Subjects were randomised to approximately 1 year of daily treatment with 12 SQ-HDM or placebo and were given free access to standardised rhinitis pharmacotherapy.
The primary endpoint was the average daily total combined rhinitis score (TCRS) evaluated during the last 8 weeks of treatment.
After 1 year of treatment with 12 SQ-HDM, an absolute difference in medians of 1.0 (95% confidence interval [0.1; 2.0]) and a relative difference of 22% (p=0.024) compared to placebo was found in the adolescent group.
• The TO-203-3-2 trial included 278 adolescents (of 851 subjects randomised in total) with moderate-to-severe persistent house dust mite allergic rhinitis. Subjects were randomised to approximately 1 year of daily treatment with 12 SQ-HDM, 6 SQ-HDM, or placebo and were given free access to standardised rhinitis pharmacotherapy.
The primary endpoint was the average daily TCRS evaluated during the last 8 weeks of treatment.
At the end-of-trial after 1 year of treatment with 12 SQ-HDM, an absolute difference in means of 1.0 (95% confidence interval [0.1; 1.9], p=0.037) and a relative difference of 20% compared to placebo was found in the adolescent group.
Table: Summary of main efficacy results in adolescents (allergic rhinitis)
Adolescent subgroups
12 SQ-HDM
Placebo
Treatment effect
Primary endpoint: TCRS
N
Score
N
Score
Absolute difference
Relative difference
d
p-value
P001
FAS
(adjusted mean)
76
3.6
84
4.8
1.2
a
[0.1;2.3]
25%
<0.05
FAS (median)
76
3.3
84
4.3
1.0
b
[0.1;2.0]
22%
0.024
TO-203-3-2
FAS (adjusted mean)
99
4.1
92
5.1
1.0
c
[0.1;1.9]
20%
0.037
FAS
(median)
99
4.2
92
5.2
1.0
19%
-
TCRS: total combined rhinitis score
a
: ANCOVA
b
: Hodges-Lehmann estimate with 95% confidence intervals (primary analysis in the P001 trial)
c
: Linear mixed-effects model (primary analysis in the TO-203-3-2 trial)
d
: Relative difference placebo: placebo minus 12 SQ-HDM divided by placebo
Allergic asthma:
Children 5-17 years of age
The MAPIT trial (MT-11) included 533 children and adolescents (5-17 years) with house dust mite allergic asthma. Subjects had a history of recent asthma exacerbations while being on asthma controller medication (low dose ICS plus LABA or medium/high dose ICS with or without LABA). Subjects were randomised to approximately 24-30 months of daily treatment with 12 SQ-HDM or placebo as add-on treatment to their asthma controller medication. The primary endpoint was the annualised rate of clinically relevant asthma exacerbations calculated as the number of exacerbations per year per subject during the efficacy evaluation period.
The adjusted rate ratio (12 SQ‑HDM divided by placebo) was in favour of 12 SQ‑HDM but there was no statistically significant difference in treatment effect between the treatment groups (rate ratio = 0.89, 95% CI [0.60; 1.31], p=0.54).
For subjects enrolled in the MAPIT trial (MT-11), the asthma exacerbation rate was generally low in both treatment groups during the trial and decreased by approximately 67% during the COVID-19 pandemic compared to the level prior to the COVID-19 pandemic, which may have had an influence on the fact that it was not possible to detect a statistically significant difference (see section 4.2 for information on paediatric use).
The Licensing Authority has waived the obligation to submit the results of studies with ACARIZAX in children under the age of 5 in house dust mite respiratory allergy (treatment of allergic rhinitis, treatment of asthma).
Elderly population
ACARIZAX is not indicated in patients >65 years of age (see section 4.2). Limited safety and tolerability data exist for elderly patients >65 years of age.
Long-term treatment
International treatment guidelines refer to a treatment period of 3 years for allergy immunotherapy to achieve disease modification. Efficacy data is available for 18 months of treatment with ACARIZAX from the MITRA trial. Long-term efficacy has not been established.
