Key evidence from clinical trials for calcipotriol / betamethasone dipropionate gel and ointment

What is Calcipotriol Dipropionate / Betamethasone? ointment and gel?

Calcipotriol / betamethasone dipropionate gel and ointment are current medications to treat license plate psoriasis [1–3]. Brand names of Calcipotriol / betamethasone dipropionate are Daivobet^® Ointment 50/500 and Daivobet^® 50/500 gel. Calcipotriene is called calcipotriene in some countries. An alternative brand for the combination is Dovobet®.

Betamethasone Diproprionate / Calcipotriol Ointment and Gel are available in New Zealand by prescription and are fully funded by PHARMAC. The New Zealand marketing authorization for Daivobet is in the hands of LEO Pharma.

Key phase III trials in Daivobet gel psoriasis of the scalp

Over a period of 8 weeks, multicenter, randomized, double-blind In the study, patients with psoriasis of the scalp were randomized to treatment with the formulation of two compounds of the scalp (calcipotriol 50 mcg / g plus betamethasone 0.5 mg / g, as dipropionate) (n = 541), betamethasone 0.5 mg / g (as dipropionate) in the same vehicle (n = 556), calcipotriol 50 mcg / g in the same vehicle (n = 272) or vehicle alone (n = 136) [4].

• Primary response criteria were controlled disease at week 8, defined as "clear" or "minimal disease" for patients with moderate disease in base, or "clear" for patients with mild disease at the start of the study according to the criteria of the International Global Assessment (IGA).
• More patients achieved 'absent' or 'very mild' disease at week 8 with the two compound scalp formulation (71.2%) compared to betamethasone dipropionate in the same vehicle (64.0%, P = 0.011), calcipotriene in the same vehicle (36.8%, P <0.0001), or the vehicle (22.8%, P <0.0001).

Long-term study

A long-term (52 weeks) randomized double-blind study in 869 patients with moderate to severe psoriasis of the scalp investigated effectiveness of the two-compound formulation (calcipotriol 50 mcg / g plus betamethasone dipropionate 0.5 mg / g) for psoriasis of the scalp compared to calcipotriol [5].

• Patients were randomized to a two-compound scalp formulation (n = 429) or calcipotriol (n = 440).
• The primary response criteria were the incidences of both Adverse drug reactions (ADR) of any type and adverse events of concern associated with long-term topical corticosteroid use on the scalp.
• Secondary criteria included the efficacy of treatment based on the Investigator's Global Assessment of Disease Severity ('no disease', 'very mild disease', 'mild disease', 'moderate disease', 'severe disease', ' very serious disease ') and patient evaluations of the efficacy of the treatments (' satisfactory ',' not satisfactory ').
• The percentage of patients reporting adverse drug reactions (ADRs) was significantly lower in the two-compound group compared to the calcipotriol group [172% (n = 72/419) vs. 295% (n = 127/431); oddsratio (OR ): 0595% confidence interval (CI): 036–069 [172% (n = 72/419) vs295% (n = 127/431); odds ratio (OR): 0595%confidenceinterval (CI): 036–069P <0.001.
• The proportion of ADR patients who used the drug as needed during the first 6 months of participation was lower in the two-compound group compared to the calcipotriol group. [11.4% (n = 40/350) vs. 22.4% (n = 66/295)]. This was also observed in patients who used the treatment throughout the 12-month period. [15.7% (n = 44/281) vs. 26.4% (n = 62/235)].
• Based on patient evaluations, the percentage of successful visits per patient was significantly in favor of the two compound scalp formulation (P <0.001). A total of 76.2% of the patients evaluated the response to treatment as satisfactory at each visit in the group of two compounds versus 50.2% in calcipotriol.

According to the Investigator's Global Assessment of Disease Severity, the number of patients who achieved 'satisfactorily controlled disease' ('no disease,' 'mild disease,' or 'very mild disease') was higher in the two-compound group. than in the group of two compounds. calcipotriol group.

• The median number of visits per patient with "satisfactorily controlled disease" was higher in the group of two compounds. Patients in this group were rated as having satisfactorily controlled disease in the 92.3% of the evaluations, which was significantly higher than in the calcipotriol group (80.0%; P <0.001).

Key phase III trials in body psoriasis

• The efficacy of once-daily use of calcipotriol / betamethasone diproprionate gel in non-scalp regions of the body was investigated in an 8-week, randomized, double-blind clinical study involving 364 patients with chronic psoriasis plaque of the trunk or extremities [6].
• The comparators were betamethasone dipropionate in the gel vehicle, calcipotriol in the gel vehicle, and the gel vehicle alone, all used once daily.
• The results of the primary response criterion showed that the percentage of patients whose disease was clear or very mild and who had at least a two-step improvement in the Investigator's Global Assessment of Disease Severity (IGA) at week 8, was significantly higher with calcipotriol plus betamethasone dipropionate (27.2%) than with betamethasone dipropionate (16.9%, P = 0.027), calcipotriol (11.4%, P = 0.006) or gel vehicle (0.0%, P <0.001).

Calcipotriol / betamethasone dipropionate gel compared to tacalcitol

• A separate comparative trial established the efficacy and safety of once-daily treatment of calcipotriol / betamethasone dipropionate gel in patients with chronic plaque psoriasis, relative to tacalcitol ointment and the gel vehicle alone [7].
• 458 patients with at least moderately severe disease were randomized into 3 treatment arms over a period of 8 weeks. The treatment was blinded by the investigator, and the success of the treatment was defined as patients with an overall Investigator evaluation of “clear” or “almost clear” at week 8.
• Once daily treatment with the 2-compound calcipotriol / betamethasone diproprionate gel was safe and effective therapeutic regimen for people with psoriasis on the body.
• The proportion of patients who were "clear or nearly clear" was significantly higher in the 2-compound gel group (39.9%) compared to 17.9% in the tacalcitol group and 5.5% in the gel vehicle group: P <0.001 in both comparisons.
• The proportion of patients with at least one adverse drug reaction was significantly lower in the 2-compound gel group compared to tacalicitol ointment and the gel vehicle alone.

Calcipotriol / betamethasone effectiveness in real life studies

Several largescale, real life studies have evaluated the efficacy of calcipotriol / betamethasone gel in plaque psoriasis of the body and scalp. In addition to demonstrating antipsoriatic efficacy in tightly controlled clinical trials, confirmation of effectiveness in the real-life setting, where factors such as patient preference, satisfaction, and adherence to treatment become increasingly relevant.

• In the largest of these studies (optimization of PSoriasis treatment [PSO-TOP] study; n = 1,795), 4 after 8 weeks of topical calcipotriol / betamethasone gel treatment, more than a third of patients who had failed prior to treatment with powerful topical steroids, they had documented the success of treatment with PGA (Patient Global Assessment) or PhGA (Physician Global Assessment) ('clear' 34.2% or 'near clear' lesions 36.5%; p <0.0001 vs base) [8].
• Importantly, the 48% of the patients had received a failed treatment with a potent topical steroid during the 8 weeks prior to calcipotriol / betamethasone.
• The Patient Preference Questionnaire revealed that calcipotriol / betamethasone gel was highly preferred by patients (> 85%) over previous topical therapy.
• Regardless of previous treatment received, most patients "agreed" or "totally agreed" that calcipotriol / betamethasone was more effective, easier to use, and associated with fewer adverse events and better tolerance than previous treatments .

Profitable analysis

Pharmacoeconomic analyzes have shown that calcipotriene dipropionate / betamethasone gel formulations are more cost-effective than other topical therapies for psoriasis [9].

Summary

• Calcipotriol / betamethasone gel formulation provides an effective first-line option for treating mild to moderate plaque psoriasis of both the body and scalp.
• The product is a once-a-day formulation and provides faster and better symptom Relief than a powerful topical steroid used alone.
• The formulation works in two ways to reduce inflammation and to treat the climbing associated with psoriasis.
• This product is fully funded in New Zealand.

Key phase III trials with calcipotriol / betamethasone diproprionate ointment

Test 1

• An international, multicenter, prospective, randomized, double-blind, vehicle-controlled, parallel group, 4-week study was performed in patients with chronic plaque psoriasis susceptible to topical treatment [3].
• Patients were randomized to one of four treatment groups: calcipotriol dipropionate / betamethasone combination formulation once daily, twice daily combination formulation, calcipotriol twice daily, or vehicle twice daily.
• There were no statistically significant differences in the mean percentage change in the area of psoriasis and the severity index (PASI) from start to finish of treatment between the two combined formulation groups, but the difference in PASI reduction was significantly greater in the combined formulation groups (68.6% once daily, 73.8% twice daily) than in both calcipotriol groups twice daily (58.8 %) and the vehicle group (26.6%).
• Safety data showed that the frequency of adverse events was lower in the combined formulation groups than in the calcipotriol group and the vehicle group.
• The proportion of patients with injuries /perilesional Adverse reactions was lower in the combined formulation groups and vehicle group than in the calcipotriol group (9.9% of combined formulation once daily, 10.6% of combined formulation twice daily, 19.8% of calcipotriol, 12.5% of vehicle).
• Overall, no statistically significant or clinically relevant difference in efficacy was observed between the combined formulation used once daily and twice daily. Compared to vehicle ointment or calcipotriol ointment alone, the combined formulation proved to be clearly more effective.

Test 2

• 972 patients with plaque psoriasis were randomized to one of three treatment regimens: Group 1, the two-compound calcipotriol / betamethasone diproprionate ointment once daily for 8 weeks followed by the calcipotriol once-daily ointment for 4 weeks; Group 2, the two compound ointment once a day for 4 weeks followed by 8 weeks of treatment with calcipotriol ointment once a day on weekdays and the two compound ointment once a day on weekends; and Group 3, calcipotriol ointment twice daily for 12 weeks. [4].
• Efficacy was assessed by PASI and investigators' global assessments of disease severity. The primary response criteria were the percentage reduction in PASI and the proportion of patients with absent / very mild disease according to the researchers' global evaluations after 8 weeks of treatment.
• The mean reduction in PASI from the beginning to the end of the 8 weeks of treatment was 73.3% for Group 1, 68.2% for Group 2 and 64.1% for Group 3.
• The proportion of patients with absent / very mild disease at the end of the 8 weeks of treatment was 55.3% for Group 1, 47.7% for Group 2 and 40.7% for Group 3.
• For both primary response criteria, Group 1 was statistically superior to Group 3 (P <0.001), while Group 2 did not differ significantly from Group 3. The difference between Group 1 and Group 2 was statistically significant with respect to PASI but not with respect to the proportion of patients with absent / very mild disease.
• Patients who received initial therapy with the two-compound product achieved the fastest treatment response, with the maximum treatment effect seen after 5 weeks. This effect was maintained with continuous treatment with the two compound product for up to 8 weeks.
• After 12 weeks of treatment, no significant difference was observed between the three groups with respect to PASI reduction, while the proportion of patients with absent / very mild disease in Group 2 was higher than in Group 3.
• Patients receiving therapy with the two-compound product experienced fewer adverse reactions to perilesional injuries / lesions than patients treated with calcipotriol (P <0.001): 10.9% in Group 1, 11.5% in Group 2, and 22.3% in Group 3.

Long-term study

The primary objective was to investigate the safety of two treatment regimens involving the use of the two-compound calcipotriol / betamethasone dipropionate product for 52 weeks. [5].

Six hundred and thirty-four patients were randomized double blind for treatment (once daily, when necessary) with:

• 52 weeks product of two compounds (group of two compounds)
• 52 weeks of alternate periods of 4 weeks of product of two compounds and calcipotriol (alternate group)
• 4 weeks of two compound product followed by 48 weeks of calcipotriol (calcipotriol group). There was a trend towards the efficacy of the two-compound product used for up to 52 weeks, being better than the 4-week efficacy of the two-compound product followed by 48 weeks of calcipotriol.

Results

• Adverse drug reactions (ADRs) occurred in 45 (21.7%) patients in the two-compound group, 63 (29.6%) in the alternate group, and 78 (37.9%) in the calcipotriol group. The odds ratio for ADR in the two-compound group relative to the calcipotriol group was 0.46 (95% confidence interval: 0.30-0.70; P <0.001).
• Troubling adverse reactions associated with long-term topical corticosteroid use occurred in 10 (4.8%) patients in the two-compound group, six (2.8%) in the alternate group, and six (2.9%) in the calcipotriol group; those with the highest incidence they were skin atrophy, which occurs in four (1.9%), one (0.5%) and two (1.0%) patients, respectively, and folliculitis, in three (1.4%), one (0.5%) and no patient, respectively.
• Calcipotriol / betamethasone dipropionate ointment once daily leads to 2% fewer patients withdraw (95% CI: 0% to 4% P = 0.03) due to adverse events and 11% fewer patients who have at least one adverse event (95% IC: 6% to 16%, P = 0.00001) than calcipotriol ointment once daily.
• Treatment with the two-compound product for up to 52 weeks appears to be safe and well tolerated, whether used alone or alternated every 4 weeks with treatment with calcipotriol.

Calcipotriol / betamethasone dipropionate ointment compared to calcipotriol and betamethasone alone

• 1106 patients with psoriasis were randomized to double-blind treatment with betamethasone / calcipotriol ointment, betamethasone dipropionate alone, or calcipotriol for 4 weeks. Then, patients received calcipotriol twice daily, without blinding, for another 4 weeks. [6].
• The mean percentage change in PASI at the end of the double-blind phase was -74.4 (combination group), -61.3 (betamethasone group), and -55.3 (calcipotriol group).
• In the combination group, the mean PASI at the end of the double-blind phase was 2.5 and 3.6 at the end of the unblinded phase compared to 3.9 and 4.1, respectively for betamethasone alone and 4.4 and 3.7 for calcipotriol.
• In the double-blind phase, 8.1% of the patients (combination) reported lesional / perilesional adverse reactions compared to 4.7% (betamethasone alone) and 12.0% (calcipotriol).

The calcipotriol / betamethasone combination was more effective and had a faster onset of action than either active. Constitution used alone, and was well tolerated. It is safe to transfer patients from betamethasone / calcipotriol to calcipotriol alone, with maintenance of the clinical effect.

Calcipotriol / betamethasone diproprionate ointment in elderly patients

• A total of 1,534 patients who participated in four randomized double-blind studies included 357 patients aged ≥ 60 years with psoriasis who received a two-compound calcipotriol / betamethasone diproprionate ointment once daily. [7].
• After 4 weeks of treatment, the mean PASI reduction was 67.8% in patients <60 years compared to 72.6% in patients ≥ 60 years.
• 52.1% of patients <60 years and 58.2% of patients ≥ 60 years of age achieved "controlled disease" according to an overall evaluation of "no disease" or "very mild disease" according to the researchers.
• Patients in both age groups reported a similar number of lesional / perilesional adverse drug reactions; 6.4% in patients <60 years vs 5.0% in patients ≥ 60 years confirming that the two compound ointment is effective and well tolerated in the treatment of plaque psoriasis, regardless of age.

Profitable analysis

A cost-benefit analysis from the perspective of a Swedish healthcare payer used a decision tree model with a 12-week time horizon to assess the cost-effectiveness of calcipotriol / betamethasone foam versus calcipotriol / betamethasone ointment [8].

• 376 patients with plaque psoriasis were treated with two 4-week cycles of topical calcipotriol 50 μg / g and betamethasone 0.5 mg / g as dipropionate foam (Cal / BD) or Cal / BD ointment as needed before proceeding to treatment second line with phototherapy / methotrexate.
• The superior efficacy of Cal / BD foam over the ointment led to fewer office visits, a lower risk of advancing to second-line therapy, and lower total costs.
• Although Cal / BD foam costs more than Cal / BD ointment, this was offset by lower phototherapy / methotrexate costs and fewer office visits.

Summary

• Two-compound ointment with calcipotriol 50 μg / g and betamethasone dipropionate 0.5 mg / g should be considered as the first-line treatment of choice for chronic plaque psoriasis subject to topical treatment
• The product is a once-a-day formulation and provides quicker and better symptom relief than a powerful topical steroid used alone.
• Its formulation works in two ways to reduce inflammation and to treat the scale associated with psoriasis.
• This product is fully funded in New Zealand. Please note that foam formulation is not yet funded in New Zealand (January 2020).