Summary of Pooled Analysis

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Clinical Review Report: Halobetasol Propionate and Tazarotene (Duobrii): (Bausch Health, Canada Inc.): Indication: Psoriasis, moderate-to-severe plaque [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2020 Dec.

Cover of Clinical Review Report: Halobetasol Propionate and Tazarotene (Duobrii)

Clinical Review Report: Halobetasol Propionate and Tazarotene (Duobrii): (Bausch Health, Canada Inc.): Indication: Psoriasis, moderate-to-severe plaque [Internet].

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Appendix 4Summary of Pooled Analysis

Objective

To summarize the results of a pooled analysis of the two phase III pivotal trials, Study 301 and Study 302, for HP/TAZ (Duobrii).

Methods

All the patients who were randomized to Study 301 (N = 203) and Study 302 (N = 215) were included in the pooled analysis, for a total of 418 patients included in the ITT population used for efficacy analyses. The safety population consisted of 410 patients, which were used for the assessment of safety. The discrepancy between the two was due to a lack of post-baseline safety evaluation of eight patients.

The pooled analysis used the same primary efficacy end point as the individual pivotal trials: the percentage of patients with treatment success, defined by at least a two-grade improvement from baseline in the IGA and an IGA score of clear or almost clear at week 8. The secondary end points used the same definition of treatment success, but were reported at week 12, 6, 4, and 2. The percentage of patients with at least a two-grade improvement from baseline in the score of each of the three signs of psoriasis (erythema, plaque elevation, and scaling) were reported as exploratory end points at week 8, 12, 6, 4, and 2. A two-grade improvement of IGA scores and change from baseline in BSA were also summarized.

All pooled analyses of efficacy data were descriptive and no hypothesis testing was conducted. The MCMC multiple imputation method was used to handle missing efficacy data, as per the method used in Study 301 and Study 302. As previously described, the ITT set was used for all efficacy analyses, but the week 8 and week 12 per-protocol populations were also used.

Results

Patient Disposition

Table 48Patient Disposition (All Randomized Patients)

	Pooled analysis (Study 301 + Study 302)
	HP/TAZ	Vehicle
Screened, N	Not reported
Randomized, N (%)	276	142
Discontinued from study, n (%)	44 (15.9)	24 (16.9)
Reason for discontinuation, n (%)
Adverse event	11 (4.0)	4 (2.8)
Patient request	17 (6.2)	12 (8.5)
Protocol violation	3 (1.1)	0
Lost to follow-up	9 (3.3)	6 (4.2)
Worsening condition	3 (1.1)	2 (1.4)
Other	1 (0.4)	0
ITT, N	276 (100.0)	142 (100.0)
PP,^a n	229 (83.0)	120 (84.5)
Safety, n	270 (97.8)	140 (98.6)

: HP/TAZ = halobetasol propionate and tazarotene; ITT = intention to treat; PP = per protocol.
a: Data are for the week 8 PP population. Data for the week 12 PP population is also available (HP/TAZ = 220, vehicle = 113).
: Source: Clinical Study Report for Pooled Analysis of Study 301 and Study 302.⁴³

Table 49Summary of Baseline Characteristics (ITT Set)

	Pooled analysis (Study 301 + Study 302)
Characteristic	HP/TAZ N = 276	Vehicle N = 142
Demographic characteristics
Age, mean (SD)	50.0 (14.2)	51.0 (13.2)
Sex (% male), n (%)	175 (63.4)	97 (68.3)
Ethnicity
Hispanic or Latino	78 (28.3)	37 (26.1)
Not Hispanic or Latino	198 (71.7)	105 (73.9)
Race
White	232 (84.1)	126 (88.7)
Black or African American	18 (16.5)	9 (6.3)
Asian	16 (5.8)	5 (3.5)
Other	10 (3.6)	2 (1.4)
Baseline disease characteristics
IGA score, n (%)
3 = moderate	237 (85.9)	119 (83.8)
4 = severe	39 (14.1)	23 (16.2)
Percentage BSA affected by psoriasis
Mean (SD)	6.0 (2.86)	5.7 (2.54)
Median (range)	5.0 (3 to 12)	5.0 (3 to 12)
Size of target lesion (cm²)
Mean (SD)	36.4 (22.5)	39.7 (23.6)
Median (range)	26.5 (16 to 100)	30.0 (16 to 100)
Signs
Erythema (target lesion)
2 = mild	25 (9.1)	11 (7.7)
3 = moderate	221 (80.1)	110 (77.5)
4 = severe	30 (10.9)	21 (14.8)
Plaque elevation (target lesion)
2 = mild	30 (10.9)	14 (9.9)
3 = moderate	212 (76.8)	108 (76.1)
4 = severe	34 (12.3)	20 (14.1)
Scaling (target lesion)
2 = mild	36 (13.0)	22 (15.5)
3 = moderate	203 (73.6)	100 (70.4)
4 = severe	37 (13.4)	20 (14.1)

: BSA = body surface area; HP/TAZ = halobetasol propionate and tazarotene; IGA = Investigator’s Global Assessment; ITT = intention to treat; SD = standard deviation.
: Source: Clinical Study Report for Pooled Analysis of Study 301 and Study 302.⁴³

Exposure

Table 50Exposure to Study Drug (ITT Set)

	Pooled analysis (Study 301 + Study 302)
	HP/TAZ N = 276	Vehicle N = 142
Amount of study drug used (g)
Mean (SD)	▬	▬
Median (range)	▬	▬
Number of days exposed
Mean (SD)	▬	▬
Median (range)	▬	▬
Number of applications
Mean (SD)	▬	▬
Median (range)	▬	▬

: HP/TAZ = halobetasol propionate and tazarotene; SD = standard deviation.
: Source: Clinical Study Report for Pooled Analysis of Study 301 and Study 302.⁴³

Efficacy

Health-Related Quality of Life

HRQoL was not reported in the pooled analysis of Study 301 and Study 302.

Skin Clearance

Table 51Treatment Success in IGA (ITT Set)

Pooled analysis (Study 301 + Study 302)
Time point	Treatment outcome (% patients)	HP/TAZ N = 276	Vehicle N = 142
Week 2	Success^a	▬	▬
Week 2	Failure	▬	▬
Week 4	Success^a	▬	▬
Week 4	Failure	▬	▬
Week 6	Success^a	▬	▬
Week 6	Failure	▬	▬
Week 8	Success^a	▬	▬
Week 8	Failure	▬	▬
Week 12	Success^a	▬	▬
Week 12	Failure	▬	▬

: HP/TAZ = halobetasol propionate and tazarotene; IGA = Investigator’s Global Assessment; ITT = intention to treat; MCMC = Markov chain Monte Carlo.
: Note: Missing data were handled using multiple imputation (MCMC).
a: Treatment success was defined as at least a two-grade improvement from baseline in the IGA score and an IGA score equal to clear or almost clear.
: Source: Clinical Study Report for Pooled Analysis of Study 301 and Study 302.⁴³

Table 52Change From Baseline of Affected BSA (ITT Set)

Pooled analysis (Study 301 + Study 302)
	Total N	Baseline	End-of-treatment time point (week 8)
	Total N	Mean (SD)	Mean (SD)	Percentage change from baseline, mean (SD)
Percentage BSA^a affected by psoriasis
HP/TAZ	276	6.0 (2.9)	3.6 (2.9)	−37.6 (39.5)
Vehicle	142	5.7 (2.5)	5.3 (3.4)	−3.1 (61.1)

: BSA = body surface area; HP/TAZ = halobetasol propionate and tazarotene; ITT = intention to treat; SD = standard deviation.
a: Assessment of BSA affected by psoriasis did not include areas of the face, scalp, palms, soles, axillae, and other intertriginous areas.
: Source: Clinical Study Report for Pooled Analysis of Study 301 and Study 302.⁴³

Psoriasis-Related Signs and Symptoms

Table 53Improvement From Baseline for Each Sign of Psoriasis (ITT Set)

Pooled Analysis (Study 301 + Study 302)
Time point	Treatment outcome (% patients)	HP/TAZ N = 276	Vehicle N = 142
Week 2	Success^a	▬	▬
Week 2	Failure	▬	▬
Week 4	Success^a	▬	▬
Week 4	Failure	▬	▬
Week 6	Success^a	▬	▬
Week 6	Failure	▬	▬
Week 8	Success^a	▬	▬
Week 8	Failure	▬	▬
Week 12	Success^a	▬	▬
Week 12	Failure	▬	▬

: HP/TAZ = halobetasol propionate and tazarotene; ITT = intention to treat; MCMC = Markov chain Monte Carlo.
: Note: For all end points, Cochran-Mantel-Haenszel test was stratified by analysis centre. Values were adjusted for multiple imputation (MCMC).
a: Treatment success was defined as at least a two-grade improvement from baseline for each of the signs of psoriasis (erythema, plaque elevation, and scaling).
: Source: Clinical Study Report for Pooled Analysis of Study 301 and Study 302.⁴³

Treatment Adherence

Similar to the individual pivotal trials, the pooled analysis of Study 301 and Study 302 did not directly assess treatment adherence as an efficacy outcome, but compliance was reported. A patient who was compliant was defined as a patient who applied between 80% and 120% of the expected applications while enrolled in the respective study. Of the patients treated with HP/TAZ, ▬ were compliant. For patients receiving vehicle, ▬ were compliant.

Safety

Harms

Table 54Summary of Harms, up to Week 8 Study Visit (Safety Set)

	Pooled analysis (Study 301 + Study 302)
	HP/TAZ N = 270	Vehicle N = 140
Patients with ≥ 1 AE
n (%)	97 (35.9)	30 (21.4)
Most common AEs,^a n (%)
Contact dermatitis	20 (7.4)	0
Pruritus	8 (3.0)	4 (2.9)
Skin atrophy	5 (1.9)	0
Patients with ≥ 1 SAE
n (%)	3 (1.1)	0
SAEs by preferred term, n (%)
Cellulitis staphylococcal, asthma exacerbation^b	1 (0.4)	0
Pneumonia	1 (0.4)	0
Anemia	1 (0.4)	0
Patients who stopped treatment due to AEs^c
n (%)	17 (6.3)	5 (3.6)
AEs by preferred term, n (%)
Deaths
n (%)	0	0
Notable harms
AE of interest, n (%)
Pruritus	8 (3.0)	4 (2.9)
Thinning of skin (skin atrophy)	5 (1.9)	4 (2.9)
Folliculitis	5 (1.9)	0
Skin irritation	2	1 (0.7)
Burning sensation	2 (0.7)	2 (1.4)
Hypersensitivity events	1 (0.4)	1 (0.7)
HPA axis suppression^d	0	0
Severe dryness	0	0

: AE = adverse event; HP/TAZ = halobetasol propionate and tazarotene; HPA = hypothalamic pituitary adrenal; SAE = serious adverse event.
a: Frequency of two or more patients in any treatment group.
b: One patient reported two SAEs: cellulitis staphylococcal (1) and asthma (1).
c: Includes patients with a treatment-emergent AE leading to permanent withdrawal of study drug and/or early study discontinuation.
d: Includes: secondary glucocorticoid insufficiency, adrenal hypercorticism (Cushing syndrome, hyperglycemia, glycosuria).
: Source: Clinical Study Report for Pooled Analysis of Study 301 and Study 302.⁴³

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