A comparison of topical azelaic acid 20% cream and topical metronidazole 0.75% cream in the treatment of patients with papulopustular rosacea

Background: Although it is important for physicians to have sufficient clinical data on which to base treatment decisions, little comparative data exist regarding newer treatment modalities for rosacea. Objective: The goal of the study was to compare the efficacy and safety of topical azelaic acid 20% cream and topical metronidazole 0.75% cream in the treatment of patients with papulopustular rosacea. Parameters of patient satisfaction to treatment were also assessed. Methods: Forty patients with the clinical manifestation of symmetric facial rosacea were investigated in this single-center, double-blind, randomized, contralateral split-face comparison clinical trial. Results: After 15 weeks of treatment, both azelaic acid and metronidazole induced significant, albeit equal reductions in the number of inflammatory lesions (pustules and papules). A significantly higher physician rating of global improvement was achieved with azelaic acid. Changes in the rosacea signs and symptoms of dryness, burning, telangiectasia, and itching were equal between treatments. A reduction in erythema tended toward significance with azelaic acid at week 15. A trace amount of stinging on application was noted with azelaic acid; however, such discomfort did not appear to concern patients because their overall impression of azelaic acid was superior to that of metronidazole. Conclusion: Azelaic acid 20% cream provides an effective and safe alternative to metro-nidazole 0.75% cream with the added benefit of increased patient satisfaction. (J Am Acad Dermatol 1999;40:961-5.)     

Azelaic acid in the treatment of papulopustular rosacea: a systematic review of randomized controlled trials

OBJECTIVE: To evaluate the clinical efficacy of topical 20% azelaic acid cream and 15% azelaic acid gel compared with their respective vehicles and metronidazole gel in the treatment of papulopustular rosacea. DATA SOURCES: Electronic searches of MEDLINE, EMBASE, BIOSIS, and SciSearch through July or August 2004 and the Cochrane Central Register of Controlled Trials through 2004 (issue 3). We performed hand searches of reference lists, conference proceedings, and clinical trial databases. Experts in rosacea and azelaic acid were contacted. STUDY SELECTION: Randomized controlled trials involving topical azelaic acid (cream or gel) for the treatment of rosacea compared with placebo or other topical treatments. Two authors independently examined the studies identified by the searches. Ten studies were identified, of which 5 were included (873 patients). DATA EXTRACTION: Two authors independently extracted data from the included studies, then jointly assessed methodological quality using a quality assessment scale. DATA SYNTHESIS: Because standard deviation data were not available for 4 of the 5 studies, a meta-analysis could not be conducted. Four of the 5 studies demonstrated significant decreases in mean inflammatory lesion count and erythema severity after treatment with azelaic acid compared with vehicle. None of the studies showed any significant decrease in telangiectasia severity. CONCLUSIONS: Azelaic acid in 20% cream and 15% gel formulations appears to be effective in the treatment of papulopustular rosacea, particularly in regard to decreases in mean inflammatory lesion count and erythema severity. Compared with metronidazole, azelaic acid appears to be an equally effective, if not better, treatment option.     

Azelaic acid (15% gel) in the treatment of acne rosacea

In December of 2002, the FDA approved azelaic acid 15% gel for the topical treatment of inflammatory papules and pustules of mild to moderate rosacea. Azelaic acid is a saturated dicarboxylic acid, which is naturally occurring and has been used in the treatment of rosacea, acne, and melasma. The 15% gel has a high efficacy and is generally well tolerated, with the local irritation (burning, stinging, itching, and scaling) being typically mild and transient. Azelaic acid 15% gel is considered effective and safe as a therapy for inflammatory papulo-pustular rosacea and is suitable for use on all skin types.     

Comparative study of some treatment modalities of rosacea

Background   Rosacea is a disease of complex pathogenesis and variable response to various therapeutic methods.
Aim of the work   To evaluate and compare the efficacy, safety and side effects of some topical lines of treatment of rosacea.
Patients and methods   The study included 24 patients (23 females and 1 male) with rosacea on the face. They were classified into three groups – each including eight patients (16 face sides) – and treated with one of three topical agents (azelaic acid 20% cream, metronidazole 0.75% cream or permethrin 5% cream) on one side of the face and another one on the other side twice daily for 15 weeks.
Results   There was a significant improvement of lesions after 15 weeks of topical treatment with the three agents. Azelaic acid cream was significantly more effective on inflammatory lesions but not erythema than the other two creams. Side effects – mostly transient – were observed with topical creams with no significant difference. They included itching, burning sensation, oedema and scales. Patients who used azelaic acid 20% cream were more satisfied than with other modalities.
Conclusion   Azelaic acid 20% cream provides an effective and safe alternative to metronidazole 0.75% cream or permethrin 5% cream with the added benefit of increased patient satisfaction.     

Azelaic Acid 15% Gel

Azelaic acid is a naturally occurring, straight-chain dicarboxylic acid which is effective in the treatment of rosacea, presumably on account of its anti-inflammatory properties. In randomized, double-blind, multicenter studies involving patients with moderate papulopustular facial rosacea, twice-daily topical application of azelaic acid 15% gel to the face was significantly more effective than twice-daily administration of either its vehicle (two studies) or metronidazole 0.75% gel (one study) in reducing inflammatory lesion counts and erythema severity. However, neither active treatment had a clinically discernable effect on telangiectasia. In all three studies, azelaic acid 15% gel recipients experienced continuous decreases in lesion counts and erythema throughout the 12- to 15-week treatment periods. However, the effects of metronidazole 0.75% gel plateauxed after 8 weeks. In other efficacy assessments in these studies, azelaic acid 15% gel was superior to its vehicle and metronidazole 0.75% gel in both the investigators' global assessment of rosacea and the investigators' end-of-study evaluation of overall improvement, and superior to its vehicle in the patients' end-of-study evaluation of overall improvement. The most frequent treatment-related cutaneous adverse events during administration of azelaic acid 15% gel include burning/stinging/tingling and pruritus (itching); however, these events are predominantly transient in nature and mild-to-moderate in intensity.     

A comparison of 15% azelaic acid gel and 0.75% metronidazole gel in the topical treatment of papulopustular rosacea: results of a randomized trial

OBJECTIVE: To compare the efficacy and safety of a novel formulation of 15% azelaic acid gel (Finacea; Berlex Laboratories, Inc, Montville, NJ) with 0.75% metronidazole gel (MetroGel; Galderma Laboratories LP, Fort Worth, Tex) as topical therapy for moderate, papulopustular facial rosacea. DESIGN: Multicenter, double-blind, randomized, parallel-group study. SETTING: Thirteen US centers. PATIENTS: A total of 251 patients with papulopustular rosacea with persistent erythema and telangiectasia. INTERVENTIONS: Patients were randomized to receive azelaic acid gel or metronidazole gel twice daily for 15 weeks. MAIN OUTCOME MEASURES: Nominal and percent change in inflammatory lesion count, change in erythema and telangiectasia severity ratings, investigator's global assessment of rosacea, and investigator's and patient's overall improvement ratings. RESULTS: Azelaic acid gel was superior to metronidazole gel in reduction of mean nominal lesion count (-12.9 vs -10.7, respectively) (P =.003) and mean percent decrease in inflammatory lesions (-72.7% vs -55.8%, respectively) (P<.001). With respect to erythema severity, 56% of azelaic acid gel-treated patients were rated improved vs 42% of metronidazole gel-treated patients (P =.02). The effectiveness of metronidazole gel on these variables seemed to plateau after week 8, whereas azelaic acid gel demonstrated progressive improvement through week 15. Neither treatment had a clinically appreciable effect on telangiectasia. Both the investigator's global assessment (P =.02) and overall assessment of improvement (P =.005) showed a significant therapeutic advantage for azelaic acid gel. Azelaic acid gel also scored higher on the patient's overall assessment of efficacy. Both treatments were rated as having high cosmetic acceptability. No serious or systemic treatment-related adverse events were reported in either group. CONCLUSION: Use of 15% azelaic acid gel twice daily for 15 weeks demonstrated significant superiority over using 0.75% metronidazole gel in improving principal signs of rosacea (inflammatory lesions and erythema).     

15 % Azelainsäuregel in der Behandlung der Akne. Zwei doppelblinde klinische Vergleichsstudien

Background: Topical measures are still the mainstay in the therapy of mild‐to‐moderate acne vulgaris. Azelaic acid 20 % in a cream formulation has been established as an efficacious and safe topical drug for 15 years. A new non‐alcoholic hydrogel formulation containing 15 % azelaic acid was clinically tested against two standard drugs – 5 % benzoyl peroxide (BPO) and 1 % clindamycin. Patients and Methods: In two independent, randomized, blinded comparative trials 15 % azelaic acid gel was clinically tested against 5 % benzoyl peroxide (BPO) gel in 351 patients and against 1 % clindamycin gel in 229 patients. The drugs were applied b. i. d. for 4 months. Results: Azelaic acid 15 % gel proved to be as effective as BPO and clindamycin with median % reduction of the inflamed lesion (papules and pustules) of 70 %, and 71 % respectively. The azelaic acid gel was well‐tolerated, the side effects (local burning and irritation) were distinctly less than with BPO but more pronounced than with clindamycin. Despite these side effects, the treatment was well‐accepted by the majority of patients. Conclusions: Azelaic acid gel is an effective topical monotherapy for mild‐to‐moderate acne vulgaris; its new gel form is an enrichment of acne therapy.     

(6) Azelaic acid really does work in acne—a double-blind national and international study

Azelaic acid is a natural product of Pityrosporum ovale ; used topically it has been shown to be of benefit in acne by a marked antimicrobial effect against Propionibacterium acnes. No study to date, however, has included a placebo group. We have investigated 40 patients with clinical acne in a double-blind study; half received 20% azelaic acid cream and half the base cream. Assessments were made of total acne grade, lesions counts and side-effects.
Azelaic acid was significantly better than placebo at 1, 2 and 3 months in improving overall acne grade ( P < 0·01) and inflamed lesions ( P < 0·001). Side-effects were minimal—the main drawback of the preparation was greasiness of its base.
We also collaborated in a multicentre study involving 859 patients in which azelaic acid was compared with other treatments. It was found to be as effective as benzoyl peroxide, retinoic acid and oral tetracycline over an 8-month study. It gave a significantly lower incidence of dermatitis ( P < 0·01) than either retinoic acid or benzoyl peroxide and, in contrast to the latter, it did not bleach clothes.
We conclude that azelaic acid is a safe and beneficial topical treatment for acne vulgaris.     

Comparative study of therapeutic effects of 20% azelaic acid and hydroquinone 4% cream in the treatment of melasma

Background Melasma is an irregular brown or grayish‐brown symmetric facial hypermelanosis, often affecting women, especially those living in areas with intense ultraviolet radiation. Objective Comparison of therapeutic effects of 20% azelaic acid and 4% hydroquinone cream in the treatment of melasma. Methods Twenty‐nine women with melasma were recruited. Fifteen patients were treated with 4% hydroquinone cream and 14 patients were treated with azelaic acid cream for 2 months. The cream was applied twice daily. A broad‐spectrum sunscreen was used concomitantly by both groups. The Melasma Area Severity Index (MASI) scores were determined prior to treatment and at each follow‐up. Results The mean MASI score before treatment was 7.2 ± 3.2 in the hydroquinone group and 7.6 ± 3.5 in the azelaic acid group, with no significant difference between them (t‐test, CI 95% = ?2.9 to 2.2). One month after treatment, the mean MASI score reached 6.7 ± 3.4 with hydroquinone and 6.3 ± 3.4 with azelaic acid with no significant difference between them (t‐test, CI 95% = ?2.2 to 3). After 2 months’ treatment, the MASI score was 6.2 ± 3.6 with hydroquinone and 3.8 ± 2.8 with azelaic acid, a significant statistical difference (t‐test, CI 95% = 0.03–4.9). Conclusions In conclusion, this study suggests that 20% azelaic acid cream applied twice daily may be more effective than hydroquinone 4% in reducing mild melasma. However, because this was an open trial, it is suggested that further studies involving large groups of patients be conducted to achieve a more conclusive result.     

The Treatment of Melasma 20% Azelaic Acid versus 4% Hydroquinone Cream

The efficacy of 20% azelaic acid cream and 4% hydroquinone cream, both used in conjunction with a broad-spectrum sunscreen, against melasma was investigated in a 24-week, double-blind study with 329 women. Over the treatment period the azelaic acid cream yielded 65% good or excellent results; no significant treatment differences were observed with regard to overall rating, reduction in lesion size, and pigmentary intensity. Severe side effects such as allergic sensitization or exogenous ochronosis were not observed with azelaic acid.     

Azelaic acid gel 15% in the management of papulopustular rosacea: a status report on available efficacy data and clinical application

Azelaic acid (AzA) gel 15% is approved by the US Food and Drug Administration (FDA) for the treatment of papulopustular rosacea (PPR). Its efficacy and safety as monotherapy have been demonstrated. Release of active drug from the gel formulation is superior to the cream. The combination of AzA gel 15% with oral doxycycline appears to expedite and augment response, especially in cases of PPR of greater severity, and AzA gel 15% maintains control of PPR over 6 months as compared to vehicle. Adjunctive skin care is recommended to augment the therapeutic outcome of PPR and reduce the potential for irritation that can occur with topical therapy.     

Pimecrolimus cream 1% for papulopustular rosacea: a randomized vehicle-controlled double-blind trial

BACKGROUND: Rosacea remains difficult to treat, despite many therapeutic options. OBJECTIVES: To investigate the effect of pimecrolimus cream 1% (Elidel; Novartis Pharma, Nuremberg, Germany) in the treatment of papulopustular rosacea. METHODS: Forty patients with rosacea (25 men and 15 women, mean age 58 years) were enrolled in a randomized, vehicle-controlled, double-blind study. For 4-8 weeks, patients applied pimecrolimus cream or vehicle twice daily to the involved areas on the face. Rosacea severity score, subjective severity assessment and quality of life assessment were obtained, along with photographic documentation. RESULTS: Both treatment groups of 20 patients showed an improvement after 4 weeks. The differences were not significant (P > 0 x 05) with regard to mean absolute values, mean percentage changes from baseline, or mean absolute values as differences from baseline for the total score or scores of the different clinical signs (erythema, papulation, scaling and pustules). In the subjective severity score and the quality of life assessment, there was also no significant difference between pimecrolimus and the vehicle (P > 0 x 05). CONCLUSIONS: Treatment of rosacea for 4-8 weeks with the topical calcineurin inhibitor pimecrolimus cream 1% was not more efficacious than treatment with the vehicle cream.     

A systematic review to evaluate the efficacy of azelaic acid in the management of acne,rosacea, melasma and skin aging

Background

Topical azelaic acid (AA) is indicated for acne and rosacea, but there is some evidence for its use for other dermatological conditions.

Aims

To assess the effectiveness and safety of topical AA for acne vulgaris, rosacea, hyperpigmentation/melasma, and skin aging.

Methods

RCTs of at least 6 weeks' treatment duration were eligible for inclusion. Databases including MEDLINE, Embase, CINAHL, and ClinicalTrials.gov were searched up to December 2022. Two reviewers were involved in all stages of the systematic review process.

Results

Forty-three RCTs met the inclusion criteria. Meta-analyses within 20 rosacea studies demonstrated that erythema severity, inflammatory lesion counts, overall improvement, and treatment success (achieving skin clarity) were significantly improved with AA compared with vehicle after 12 weeks. AA was more effective than metronidazole 0.75% for improved erythema severity, overall improvement, and inflammatory lesion counts. Sixteen acne studies suggest that AA is more effective than vehicle for improving global assessments and reducing acne severity. AA 20% also significantly reduced more lesions than erythromycin gel. Within seven melasma studies, AA 20% was significantly better than vehicle for both severity and global improvement. AA 20% demonstrated significantly better results compared with hydroquinone 2% for global improvement. Very few significant differences between AA and comparators were observed for commonly reported adverse events. No eligible RCTs were found that evaluated skin aging.

Conclusions

AA is more effective than vehicle for rosacea, acne and melasma. Comparisons between AA and other treatments were often equivalent. Where there is equivalence, AA may be a good option for some clinical situations. RCT evidence is needed to evaluate the effectiveness of AA on skin aging.     

A comparative study of 20% azelaic acid cream monotherapy versus a sequential therapy in the treatment of melasma in dark-skinned patients

BACKGROUND: Melasma is a commonly found hyperpigmentary disorder in dark-complexioned persons, which is rather difficult to treat. Azelaic acid (AZA) 20% is considered efficacious in the treatment of melasma, although the response is rather slow. It has also been combined synergistically with topical retinoic acid, where the results were satisfactory. OBJECTIVE: The study was done to evaluate the usefulness of a sequential therapy of potent topical steroids +20% AZA cream versus only 20% AZA cream in the treatment of melasma. METHODS: This was a prospective, single-blind, right-left comparison pilot study with (1). twice daily application of 20% AZA to one half of the face for 24 weeks and (2). a potent topical steroid, 0.05% clobetasol propionate cream, to be applied for 8 weeks only and then to be followed by 20% AZA cream only for the next 16 weeks on the other half. Concomitant use of a broad-spectrum sunscreen was also mandatory. Thirty Indian patients (25 females, 5 males), whose ages ranged from 21 to 45 years and who were not pregnant, nursing or on any concurrent therapy, completed the study. Clinical evaluation, photography and the overall response were assessed at 4, 8, 16 and 24 weeks. RESULTS: At 4, 8 and 16 weeks, the lightening of melasma was significantly more marked on the side receiving the sequential therapy rather than the side receiving only 20% AZA cream (p < 0.001). However, at 24 weeks, although the difference was still significant (p = 0.0052), as many as 96.7 and 90% of patients of each group (sequential therapy and AZA) had good to excellent responses to treatment. The side-effects noted were mostly mild and transient and mainly local irritant effects. CONCLUSIONS: A sequential therapy of topical potent steroids +20% AZA cream can be considered as another alternative treatment for melasma, which combines the beneficial effects of both besides perhaps increasing the compliance of the patients. 20% AZA monotherapy itself is also an effective and well-tolerated therapy for melasma in dark-skinned races.     

Cumulative irritation potential among metronidazole gel 1%, metronidazole gel 0.75%, and azelaic acid gel 15%

Topical therapy for rosacea aims to reduce inflammatory lesions and decrease erythema but can carry side effects such as stinging, pruritus, and burning. Metronidazole and azelaic acid gel 15% are U.S. Food and Drug Administration-approved for the treatment of rosacea. The current study was conducted to assess the cumulative irritation potential of 2 formulations of metronidazole 0.75% gel and 1% gel--and azelaic acid gel 15% over 21 days (N=36). Results of this study demonstrated a significantly greater poten tial for irritation from azelaic acid compared with metronidazole gel 0.75% (P < .0001), which had significantly greater potential for irritation compared with metronidazole gel 1% (P = .0054). Metronidazole gel 1% had a similar profile to white petrolatum.     

The management of rosacea

Rosacea is a multiphasic disease which is associated with flushing, erythrosis, papulopustular rosacea and phymas; each phase is likely to have its own treatment. Flushing is better prevented rather than treated, and its etiology investigated. Beta-blockers, atenolol in particular, are worthy of prophylactic trials examining their efficacy in treating the flushing associated with rosacea. Currently, clonidine is the only drug available for the treatment of flushing. Treatment for erythrosis includes topical and systemic therapies. Metronidazole 1% cream and azelaic acid 20% cream have been reported to reduce the severity score of erythema. The systemic treatment of erythrosis is based on the association of Helicobacter pylori with rosacea. However, this role is still being debated. Eradication of H. pylori can be achieved using a triple therapy regimen lasting 1 to 2 weeks [omeprazole and a combination of two antibacterials (a choice from clarithromycin, metronidazole or amoxicillin)]. Both the flashlamp-pumped long-pulse dye laser and the potassium-titanyl-phosphate laser may be used in the treatment of facial telangiectases. Both systemic and topical remedies may be used to treat the papulopustules of rosacea. Systemic treatment includes metronidazole, doxycycline, minocycline, clarithromycin and isotretinoin, while topical treatment is based on metronidazole cream and gel. The presence of Demodex folliculorum is important in the inflammatory reaction, whether it is pathogenetic or not. Crotamiton 10% cream or permethrin 5% cream may be useful medications for papulopustular rosacea, although they are rarely successful in eradicating D. folliculorum. Oral or topical ivermectin may also be useful in such cases. Ocular involvement is common in patients with cutaneous rosacea and can be treated with orally administered or topical antibacterials. Once rhinophyma starts to be evident, the only way to correct it is by aggressive dermatosurgical procedures. Decortication and various types of lasers can also be used. Associated conditions, such as seborrheic dermatitis and possible contact sensitizations, deserve attention.     

Efficacy and safety of serial glycolic acid peels and a topical regimen in the treatment of recalcitrant melasma

Melasma is a common acquired disorder of facial hyperpigmentation. In this study we investigated the efficacy and safety of a combined treatment regimen including serial glycolic acid peels, topical azelaic acid cream and adapalene gel in the treatment of recalcitrant melasma. Twenty-eight patients with recalcitrant melasma were enrolled in a prospective, randomized, controlled trial lasting 20 weeks. The patients of the group receiving chemical peels underwent serial glycolic acid peels in combination with topical azelaic acid 20% cream (b.i.d.) and adapalene 0.1% gel (q.i.d., applied at night). The control group received only topical treatment including topical azelaic acid and adapalene. The clinical improvement was assessed with the Melasma Area Severity Index (MASI) at baseline and monthly during the 20-week treatment period. The results showed a prominent decrease in MASI scores at the end of the treatment in both groups, although the results were better in the group receiving chemical peels (P=0.048). All patients tolerated the topical agents well with minimal irritation observed in the first few weeks of the therapy. Three patients in the glycolic acid peel group developed a mild-degree postinflammatory hyperpigmentation with total clearance at the end of the treatment period. Therefore, the present study suggests that combined treatment with serial glycolic acid peels, azelaic acid cream and adapalene gel should be considered as an effective and safe therapy in recalcitrant melasma.     

Randomized placebo-controlled trial of metronidazole 1% cream with sunscreen SPF 15 in treatment of rosacea

Background: Rosacea is a photoaggravated dermatosis responsive to treatment with topical and oral antibiotics. A formulation combining metronidazole 1% cream with sunscreen SPF 15 was developed for the treatment of rosacea. Objective: The objective of this study was to determine the safety and efficacy of a formulation combining metronidazole 1% cream with sunscreen SPF 15 in the treatment of moderate to severe rosacea. Methods: One hundred and twenty patients with moderate to severe rosacea were enrolled for a randomized, placebo-controlled (vehicle containing sunscreen with SPF 15), double-blind study. Study cream was applied twice daily to the entire face over a 12-week period. Results: Treatment with metronidazole 1% cream with sunscreen SPF 15 resulted in significant improvement (p <0.05) in inflammatory lesion count, erythema and telangiectasiae scores, and investigator and patient global assessment scores compared with baseline and placebo. Adverse reactions related to study medication were typically mild, occurred at the site of application, and were reversible. There was no difference between the safety profiles of metronidazole 1% cream with sunscreen SPF 15 and placebo. Conclusions: The combined topical formulation of metronidazole 1% cream with sunscreen SPF 15 was an effective, well-tolerated topical agent for the treatment of moderate to severe rosacea.     

Comparison of Azelaic Acid and Anthralin for the Therapy of Patchy Alopecia Areata

Background: Although topical azelaic acid has been previously used for the treatment of alopecia, no controlled trials of azelaic acid for this condition have been conducted to date. Objective: The goal of this study was to determine the efficacy, tolerability, and safety of azelaic acid treatment in patients with patchy alopecia areata (AA) in comparison with anthralin (dithranol) treatment. Subjects and methods: This study included 31 subjects with patchy AA who did not receive any treatment for at least 1 month prior to the study. Demographic and clinical characteristics of these subjects were recorded at baseline. Subjects were randomized to apply either 20% azelaic acid (15 subjects) or 0.5% anthralin (16 subjects) for 12 consecutive weeks. In a subsequent 8-week follow-up period no cream was applied. Two independent investigators performed an efficacy evaluation with clinical examination using a terminal hair regrowth score (RGS) with a scale ranging from 0 (inadequate response) to 2 (complete response) at week 20. Partial response was accepted as score 1. Results: Both groups were well matched for the relevant demographic and clinical indicators affecting treatment response at baseline. All subjects completed the trial. At week 20 the RGS was 1.27 ± 0.9 in the azelaic acid group versus 1.37 ± 0.8 in the anthralin group (p > 0.05). A complete response was observed in 53.3% of cases in the azelaic acid group (8 of 15) compared with 56.2% (9 of 16) in the anthralin group (p > 0.05). No serious adverse events were observed in either group during the study. Conclusion: The present pilot study showed that the use of azelaic acid gave similar results to anthralin with regard to hair regrowth, and that it can be an effective topical therapy for patchy AA. More extensive trials are necessary, however, to reach a definitive conclusion.