Efficacy and safety of topical tretinoin 0.1% cream in facial skin aging in Indian subjects: A prospective open-label study

Study design and participants

A single-center, prospective, single-arm, open-label, interventional exploratory study conducted over 16 weeks across four visits (baseline, week 3, week 8, and week 16).

Eligible participants included male and female subjects aged 35–70 years with visible signs of skin aging such as wrinkles, fine lines, uneven skin tone, or mild pigmentation and Fitzpatrick skin types III–V. All subjects provided written informed consent before participation.

Subjects were excluded if they had known hypersensitivity to retinoids, were pregnant or lactating, had active facial dermatoses, recent cosmetic or dermatologic procedures, prior retinoid use within defined washout periods, or any condition that could interfere with study outcomes. Subjects with severe baseline facial irritation, defined as a score of 3 (severe) on the investigator-assessed local tolerability assessment scale (erythema, scaling, dryness, or burning/ stinging), were excluded. Individuals with uncontrolled or clinically significant systemic illness requiring active medical management, including uncontrolled diabetes mellitus, autoimmune disorders, hepatic or renal impairment, were also excluded. Subjects with prolonged sun exposure, defined as occupational or recreational outdoor exposure exceeding 2 h/day without regular photoprotection, were not eligible. In addition, subjects with a smoking history of >10 pack-years or history of substance abuse were excluded.

Sample size justification

The study sample size of 40 subjects was selected based on its exploratory, non-comparative design aimed at generating real-world clinical data. A quantitative estimation using a 95% confidence level (Z = 1.96), expected response rate of 80%, and margin of error of 10% yielded a sample size of approximately 62 subjects. However, for exploratory studies allowing a wider precision margin (±15%), the required sample size reduces to approximately 27 subjects. Accounting for an anticipated 5–10% dropout rate, a sample size of 40 subjects was considered adequate to achieve approximately 36–38 evaluable subjects.

Study products

Intervention and application procedure

Subjects were instructed to apply topical tretinoin 0.1% cream once daily at bedtime to the entire face for 16 weeks. Participants were advised to avoid the use of any additional antiaging products or dermatologic treatments during the study period.

Before application of tretinoin, the face was cleansed using the standardized sulfate-free face wash and gently patted dry. Approximately 1 fingertip unit (FTU) of moisturizer was then evenly applied over the face. After an interval of 10– 15 min, approximately half an FTU of tretinoin cream was applied as a thin, uniform layer over the facial skin, avoiding the periocular area, lips, angles of the nose, and mucosal surfaces.

The pre-application use of moisturizer was incorporated to enhance skin barrier function, reduce transepidermal water loss, and improve tolerability of high-strength tretinoin therapy, consistent with the “retinoid sandwich” approach commonly recommended for minimizing retinoid-induced irritation and dryness.¹¹

An incremental short-contact application protocol was used to minimize irritation and improve adaptation to tretinoin. Subjects were instructed to maintain contact with the tretinoin cream for approximately 30 min during week 1, 1 h during week 2, 1.5 h during week 3, and 2–4 h from week 4 onward, depending on individual tolerability. After the designated contact period, the face was rinsed using lukewarm tap water and the moisturizer was reapplied.

During daytime, subjects were instructed to apply the broad-spectrum sunscreen every 3 h between 8:30 AM and 4:00 PM and additionally before significant sun exposure.

Assessments

Standardized digital photographs were captured at baseline and follow-up visits under consistent lighting and fixed distance in frontal (0°), left (45°), and right (45°) views with neutral facial expression.

Clinical assessments

Blinded evaluation was performed by a dermatologist using standardized grading scales.

Parameters assessed included:

• Wrinkle severity: Using Modified Griffith’s/Wrinkle severity rating scale (WSRS) scale (Grades 1–5) [Supplementary Material Table 1].¹²

• Skin texture/roughness: Using the Allergan skin roughness scale (Grades 0–4) [Supplementary Material Table 2].¹³

• Photoaging: Using Glogau’s classification (Grades I–IV) [Supplementary Material Table 3].¹⁴

• Global investigator assessment (IGA): 4-point scale from none to severe (0–3) evaluating redness, dullness, oiliness, dryness, laxity, and pores.¹⁵

• Local tolerability: Graded erythema, scaling, dryness, and stinging/burning on a 0–3 scale [Supplementary Material Table 4].

Instrumental assessments

Skin biophysical properties were evaluated at baseline and study endpoint under standardized conditions. The analysis was conducted on the left cheek, right cheek, and forehead. At each site, triplicate readings were taken and averaged.

Skin hydration was measured using a digital moisture analyzer (SK-IV), sebum levels were assessed using Sebumeter^®, and pigmentation was evaluated using Dermacatch^® for melanin and erythema quantification. Wrinkle depth, pore volume, and skin texture were assessed using Antera 3D^® (Miravex Ltd., Ireland) imaging system.

Patient-reported outcomes

At study completion, subjects evaluated treatment outcomes using:

• Global esthetic improvement scale (GAIS): 7-point scale ranging from “very much improved” to “very much worse”

• Treatment satisfaction questionnaire: 5-point Likert scale (from strongly disagree to strongly agree) assessing ease of use, cosmetic acceptability, improvement in skin appearance, comfort, and overall satisfaction.

Study endpoints

The primary efficacy endpoint was the change in wrinkle severity from baseline to week 16, as assessed using the Modified Griffiths Scale/WSRS.

Key secondary endpoints included improvement in skin texture, pigmentation, and pore visibility based on IGA and instrumental analysis. Patient-reported outcomes (VAS and GAIS) and treatment satisfaction were also evaluated.

Exploratory endpoints included instrumental measurements of melanin, erythema, sebum, hydration, wrinkle depth, and skin texture using non-invasive imaging and skin analysis devices.

Safety endpoints included assessment of local skin tolerability and treatment-emergent adverse events including dryness, erythema, scaling, peeling, and stinging/burning sensations.

Statistical analysis

Data were analyzed using the Statistical Package for the Social Sciences software (version 27; IBM Corp., Armonk, NY, USA). Continuous variables were expressed as mean ± standard deviation and categorical variables as frequencies and percentages. A p < 0.05 was considered statistically significant. Normality was assessed using the Shapiro–Wilk test. Changes from baseline were analyzed using a paired t-test or Wilcoxon signed-rank test. Primary and secondary efficacy endpoints were analyzed by comparing baseline and endpoint values. Patient-reported outcomes were analyzed descriptively.

Clinical assessment

WSRS

At baseline, the majority of subjects had moderate wrinkles (61.5%), followed by severe wrinkles (20.5%), mild wrinkles (12.8%), and absent wrinkles (5.1%).

After 16 weeks of treatment, a marked improvement was observed with 38.5% of subjects demonstrating mild wrinkles, 30.8% moderate wrinkles, and 30.8% absent wrinkles, indicating a reduction in wrinkle severity across the study population [Table 1 and Figure 2].

Table 1: Clinical efficacy outcomes based on investigator assessment (n=39).

Parameter	Category	Baseline n (%)	Week 16 n (%)
Wrinkle severity rating scale	Absent	2 (5.1)	12 (30.8)
	Mild	5 (12.8)	15 (38.5)
	Moderate	24 (61.5)	12 (30.8)
	Severe	8 (20.5)	0
Skin roughness (Allergan scale)	None	7 (17.9)	21 (53.8)
	Minimal	24 (61.5)	17 (43.6)
	Moderate	8 (20.5)	1 (2.6)
Photoaging (Glogau scale)	Mild	4 (10.3)	17 (43.6)
	Moderate	24 (61.5)	20 (51.3)
	Advanced	11 (28.2)	2 (5.1)

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Figure 2: Global photography and Antera 3D assessment demonstrating changes in wrinkle depth, skin texture, and pore visibility in a representative subject at baseline (week 0) and at the endpoint (week 16) on the (a) forehead, (b) left side of the face, and (c) right side of the face.

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Global IGA

Redness

Most subjects showed no redness at baseline (92.3%), which further improved to 97.4% with no redness at study endpoint [Figure 3].

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Figure 3: Global investigator assessment.

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Local skin tolerability

The treatment demonstrated good tolerability throughout the study period. Mild erythema was observed in 17.9% of subjects, mild scaling in 12.8%, mild dryness in 30.8%, and mild stinging or burning sensations in 7.7% of participants. All reactions resolved without the need for medical intervention. Importantly, no moderate or severe local skin reactions were reported.

Instrumental assessment

Significant improvements were observed across all instrumental parameters from baseline to the study endpoint. Melanin levels showed a significant reduction with mean percentage decreases of −9.27 ± 5.62% on the forehead, −11.21 ± 6.98% on the right cheek, and −8.58 ± 6.42% on the left cheek (p < 0.001). Erythema levels also decreased, with reductions of −5.46 ± 5.74% on the forehead and −4.16 ± 5.07% on the right cheek, which were statistically significant based on the Wilcoxon test (p < 0.001) [Table 2].

Sebum production showed marked reductions, with decreases of −25.75 ± 10.57% on the forehead, −26.89 ± 11.93% on the right cheek, and −26.68 ± 12.08% on the left cheek (p < 0.001). In contrast, skin hydration significantly increased, with mean percentage improvements of +19.19 ± 13.44% on the forehead, +24.14 ± 32.76% on the right cheek, and +20.41 ± 21.45% on the left cheek (p < 0.001).

Wrinkle depth assessed using Antera 3D® demonstrated significant reductions of −14.66 ± 15.77% on the forehead, −9.98 ± 19.26% on the right cheek, and −10.67 ± 17.22% on the left cheek (p < 0.001). Skin texture analysis also revealed significant improvements, with reductions of −17.10 ± 12.36% on the forehead, −15.40 ± 19.59% on the right cheek, and −12.72 ± 15.75% on the left cheek (p < 0.001). Similarly, pore volume measurements demonstrated notable decreases of −22.96 ± 15.33% on the forehead, −20.83 ± 20.52% on the right cheek, and −17.23 ± 18.67% on the left cheek, with all improvements reaching statistical significance (p < 0.001) [Figure 2].

Patient-reported outcomes

Patient-reported outcomes indicated a generally positive treatment experience. A majority of participants agreed or strongly agreed regarding ease of application (84.7%), while 56.4% reported satisfaction with product feel and absorption. Improvement in overall skin appearance was reported by 48.7% of participants, and 61.6% agreed or strongly agreed that the treatment was comfortable to use. Overall satisfaction with the treatment was reported by 43.6% of subjects. According to the GAIS, 35.9% of participants reported improvement and 30.8% reported much improvement at the end of treatment, while 33.3% reported no noticeable change. Notably, no subjects reported worsening of skin appearance [Table 3].