.
`
`A randomized, double-blind, placebo-controlled trial
`of the combined effect of doxycycline hyclate ZO-mg
`tablets and metronidazole 0.75% topical lotion V
`. in the treatment of rosacea
`‘
`
`Jorge Sanchez, MD,“ Aida Lugo Somolinos, MD,“ Pablo I. Almodévar, MD,fl Guy Webster, MD,b
`Mark Bradshaw, Pth and Christopher Powala, BSd
`Rio Pieavas, Puerto Rico; Philadelphia, Pennsylvania; Princeton, New jersey;
`and Newton, Pennsylvania
`
`Background: Subantimicrobial doses of doxycycline may improve outcomes in rosacea when combined,
`with topical metronidazole and used as maintenance monotherapy.
`
`Objective: The purpose of this study was to evaluate the safety and efficacy of doxycycline hyclate 20 mg
`(subantimicrobial dose doxycycline) administered twice daily as an adjunct to metronidazole 075% topical
`lotion in the treatment of rosacea.
`
`Methods: Patients received. subantimicrobial doses of doxycycline twice daily plus metronidazole (n = 20)
`or placebo plus metronidazole (n = 20) for 12 weeks. Subantimicrobial—dose doxycycline or placebo
`monotherapy continued for 4 weeks. The primary efficacy measure was change from baseline in total
`inflammatory lesions at weeks 2 and 16.
`
`Results: Total inflammatOIy lesions were reduced significantly (P =.O48) by week 4 and by all subsequent
`visits
`in the
`subantimicrobial—dose doxycycline/metronidaZole group compared with placebo/
`metronidazole. Changes from baseline increased over time and were maintained during subantimicrobial~
`dose doxycycline monotherapy.
`
`Conclusion: Adjunctive use of subantimicrobial dose doxycycline significantly reduced the clinical signs
`of rosacea compared with metronidazole alone and may be useful maintenance monotherapy. (I Am Acad
`Dermatol 2005;55:791-7.)
`
`osacea is a common, Chronic skin disease.
`The National Rosacea Society estimates that
`approximately 14 million persons in the
`United States are afflicted with some form of the
`disorder, although many may not be aware of it.1
`
`
`
`From the University of Puerto Rico, Rio Piedrasa; Jefferson Medical
`College, Philadelphiab; Covance,
`Inc, Princeton“; and Colla—
`Genex Pharmaceuticals, inc, Newton.d
`Supported by CollaGenex Pharmaceuticals, inc.
`Conflicts of interest: None identified.
`Accepted for publication April 6,2005.
`Reprint requests: Jorge Sanchez, MD, Department of Dermatology,
`Puerto Rico Medical Center, Medical Sciences Campus, Pharmacy
`Building, 5th Floor, Rio Piedras, PR 00935. E—mail: rcmdermatol@
`rcm.upr.edu.
`Published online September 7, 2005.
`0190—9622/$30.00
`© 2005 by the American Academy of Dermatology, Inc.
`doi:10.1016/j.jaad.2005.04.069
`
`in fair—skinned adults
`Rosacea is most prevalent
`between 30 and 50 years of age and is diagnosed
`nearly 2 to 5 times more frequently in women tha
`in menz’3
`‘
`
`Variously termed a condition, typology, or syn—
`drome, rosacea is typified by a range of signs and
`symptoms that can include one or more primary
`features (facial flushing, erythema,
`telangiectasia,
`papules, and pustules), usually in the central area of
`the face/1'6 Rosacea presents a therapeutic challenge
`because of its chronic nature, progression, potential
`for disfigurement, and. psychosocial impact.
`Traditionally, doxycycline at usual and reduced
`antimicrobial doses has been used. to treat rosa—
`
`cea.2’7’8 Such a strategy, though effective, can in—
`crease the risk of the development of various
`adverse events, such as photosensitivity and vagini—
`tis. These antimicrobial doses alsocan lead to the
`development of antibiotic~resistant organisms.9 The
`
`Amneal 1063
`Amneal v. Supernus
`IPR2013-00371
`
`791
`
`

`

`792 Some/.762 et all
`
`I AM ACAD DERMATOL
`NOVEMBER 2005
`
`anti—inflammatory effects of doxycycline at subanti—
`microbial levels suggest that lowered doses would
`be of value in inflammatory skin conditions such as
`rosacea. Indeed, a recent study of subantimicrobial~
`dose doxycycline hyclate 20 mg, administered twice
`daily for moderate acne, showed the lower dosage
`to be effective in reducing inflammatory and non—
`inflammatory lesions without
`increasing resistant
`flora of the skin.10 Extensive studies of the oral, gastro~
`intestinal, genitourinaiy,
`and skin microflora of
`patients treated with subantimicrobial—dose doxycy—
`Cline administered. twice daily for 6 to 18 months
`showed no red.uctions in the microflora, no develop—
`ment of resistant organisms, and no cross—resis—
`tance to 6 commercially available antimicrobial agents,
`including vancomy'cin. “’12
`Therapy for rosacea usually consists of a com—
`bination of
`topical
`and oral
`antimicrobials.6
`Metronidazole in various formulations is approved.
`by the Food and Drug Administration as topical
`therapy for the inflammatory papules and pustules of
`rosacea.15 There is some evidence that remissions
`
`may be maintained longer after concurrent therapy
`with an oral tetracycline than when metronidazole is
`used. as monotherapy.14 It was thus hypothesized
`that a combination of topical metronidazole and oral
`doxycycline at a subantimicrobial dose would. im—
`prove clinical outcomes in patients with rosacea, and
`the improvement would then be maintained. by use
`of subantimicrobial~dose doxycycline as monother-
`apy. Therefore a controlled trial was conducted to
`evaluate the safety and efficacy of doxycycline
`hyclate 20 mg administered twice daily as an adjunct
`to metronidazole 0.75% topical lotion for the treat—
`ment of rosacea.
`
`A total of 180 subjects were evaluated, of which
`40 met the inclusion criteria. For those who did. not
`
`meet the inclusion criteria, the diagnosis was not
`rosacea (seborrheic dermatitis and acne vulgaris
`mostly),
`the number of inflammatory lesions was
`less than 8 or the subject had two or more nodules, or
`the subject was receiving laser therapy.
`
`METHODS
`Patients
`
`Healthyfmale and female adult outpatients (>18
`years of age) with rosacea, presenting with 8 to 50
`papules plus pustules and no more than 2 nodules,
`were eligible for the trial. Other inclusion criteria
`were a score of 2 to 4 on the Clinician’s Global
`
`Severity Score, presence of moderate to severe
`erythema (score of 2 to 4) in a least one of the facial
`areas, a total score of 5 to 20 on the Clinician’s
`
`Global Erythema Assessment, and the presence of
`telangiectasia. Women of childbearing potential
`
`had to be using a reliable method of contraception.
`Women who were pregnant or
`lactating were ,
`excluded as were those who initiate l, changed,
`or discontinued. hormonal contraception within
`4'months of baseline. Systemic antibiotics or topical
`acne/rosacea treatments within 4 weeks of baseline
`
`were prohibited. Concomitant medications pro~
`hibited. during the study included long—term use
`(>14 days) of sulfa drugs, erythromycin, cephalo—
`sporins, quinolones, nonsteroidal anti—inflammatory
`drugs, acne treatments,
`tetracycline and penicillin
`antibiotics, and. antacids containing aluminum, cal—
`cium, or magnesium.
`
`Study design
`This study was a 16—week, outpatient, random—
`ized, double—blind, placebo~controlled trial. Patients
`meeting entry criteria were assigned randomly to
`one of two treatment arms (Fig 1):
`
`1. Subantimicrobial dose doxycycline/metronida—
`zole: Metronidazole 0.75% topical lotion (Metro—
`Lotion, Galderma Laboratories, Ft Worth, TeX) for
`twice—daily application plus doxycycline hyclate
`20—mg tablets (Periostat, CollaGeneX Pharmaceu—
`ticals, Newtown, Pa) administered. twice daily for
`12 weeks followed. by 4 weeks of monotherapy
`with doxycycline hyclate 20—mg tablets.
`2. Placebo/metronidazole: Metronidazole 0.75% top—
`ical lotion plus placebo tablets administered twice
`daily for 12 weeks followed. by 4 weeks of placebo
`monotherapy. All study tablets were identical
`in size, shape, and. color (white).
`
`Randomization was accomplished. by assigning
`numbers to the subantimicrobial dose doxycycline
`and placebo bottles based. on the SAS statistical
`software randomization procedures. Each patient
`entering the study received the next sequentially
`numbered bottle.
`
`Patients were informed verbally and. in writing
`of the details of the study and its potential risks
`and benefits. Intent—to—treat informed. consent was
`
`obtained. from each patient before the prestudy
`screening and. baseline evaluations, which were
`undertaken within 1 month before randomization
`
`into the study. Evaluations comprised a complete
`medical history, Vital signs,
`total inflammatory le—
`sions (total number of facial lesions and number
`of papules, pustules, and nodules, the Clinician’s
`Global Severity Score (Table I), and the Clinician’s
`Global Eiythema Assessment (Table II). Full—face
`photographs were taken at baseline and at
`the
`week 12 and 16 visits. Follow—up clinical and safety
`assessments took place at weeks 4, 8, 12, and. 16.
`Number and types of
`lesions we're evaluated.
`
`

`

`Some/062 81' all 793
`
`FLOW DIAGRAM
`
`Registered or Elegible Patients
`(n=40)
`
`R
`
`Received
`Intervention as Allocated (n=20)
`
`
`
`
`Followed-up (n=20)
`Weeks 4,8, 12 and 16
`Evaluate: total inflammatory
`lesions; erythema, adverse
`effects, photographs, drug count
`
`
`
`
`Withdrawal (n=5)
`Personal reasons (n=2)
`Protocol violation (n=1)
`Illness no related to protocol
`.
`(n=1)
`Elythema at application site
`(n=1)
`
`'
`
`m C
`
`ompleted trial (n- 15)
`
`
`
`
`
`Received Standard
`Intervention as Allocated (n=20)
`
`
`
`Followed-up (n=20)
`
`Weeks 4,8, 12 and 16
`Evaluate: total inflammatory
`lesions; erythema, adverse
`effects, photographs, drug count
`
`
`
`
`
`withdrawal (n=0)
`
`Completed trial (n=20)
`
`
`
`Fig 1. Flow diagram.
`
`RESULTS
`
`Demographics
`Forty patients met eligibility criteria and 20 were
`assigned randomly to each treatment arm. Demo—
`graphic and. baseline characteristics are shown in
`Table 111. There were no significant differences bet—
`ween treatment groups in any of these characteristics,
`including disease severity based. on total inflamma—
`tory lesions or either of the global assessments.
`
`Efficacy
`In the primary
`Total inflammatory lesions.
`end—point analysis, patients who received. metroni—
`dazole 0.75% topical lotion plus doxycycline hyclate
`20 mg experienced a significant reduction from
`baseline in total inflammatory lesions at week 12
`(P < .01). This difference was maintained at week 16
`
`when doxycycline had been given as monotherapy
`for 4 weeks (P < .01). Additional analyses revealed
`that total inflammatory lesions were reduced. signif—
`icantly (P = .048) by week 4 in patients receiving
`doxycycline/metronidazole and at week 8 (P < .01).
`The magnitude of change from baseline increased
`over time and was maintained during monotherapy
`with doxycycline. Mean changes from baseline for
`each of the two groups are depicted. in Fig 2.
`clinician’s Global Severity Score. Clinical
`differences
`in clinician’s Global Severity Score
`values relative to baseline began to emerge between
`
`J AM ACAD DERMATOL
`VOLUME 53, NUMBER 5
`l)
`
`clinician’s Global Severity Score and Clinician’s
`Global Erythema Assessment values were obtained
`at each visit. The evaluations also included study
`drug accountability, use of concomitant medications,
`adverse events, vital signs, and a full—face photo—
`graph. Urine pregnancy tests for women of child.—
`bearing potential were undertaken at baseline and. at
`the 16—week exit visit.
`
`Efficacy evaluations
`The primary measure of efficacy was the change
`from baseline in the total inflammatory lesion count
`(papules plus pustules plus nodules) at the 12 and
`16—week visits. Secondary measures of efficacy were
`the changes from baseline at weeks 12 and 16 in the
`Clinician’s Global Severity Score and clinician’s
`Global Erythema Assessment.
`
`Safety evaluations
`At each study visit, adverse events were recorded,
`vitafsigns were monitored, and concomitant medi—
`cations were reviewed. Adverse events were evalu—
`
`ated for duration, intensity, and relationship to study
`medication and were characterized as mild, moder—
`ate, or severe. Serious (fatal, life—threatening, or per-
`manently disabling) or unexpected adverse events
`(those not included in current prescribing informa—
`tion for either metronidazole 0.75% topical lotion or
`doxycycline hyclate 20—mg tablets) were to be re—
`ported immediately to the Institutional Review Board.
`
`Statistical analyses
`In addition to descriptive statistics for compari—
`sons between groups,
`inferential
`tests were per—
`formed. using one—way analysis of variance models.
`Fisher’s exact test was used to compare categorical
`variables between groups. All statistical tests were
`two—tailed, and P < .05 was considered statistically
`significant. Results in the range .05 < P s .10 were
`considered indicative of trends toward statistical
`
`significance and deemed eligible for evaluation.
`Efficacy analysis was based on the intent to treat.
`Patients in the intent—to—treat population received
`doxycycline or placebo and attended at least one
`postbaseline visit. The analysis was based on the last
`observation carried forward, by using values from
`the most recent visit with nonmissing data to replace
`missing data for a particular visit. Analyses for effi—
`cacy. were based. on individual patient changes from
`baseline values and were performed at each post—
`baseline Visit, although the primary efficacy analysis
`was at weeks 12 and 16. Additional analyses of
`subgroups according to baseline disease severity
`were undertaken to provide additional information
`on treatment effectiveness (see “Results”).
`
`

`

`794 Some/062 et all
`
`I AM ACAD DERMATOL
`NOVEMBER 2005
`
`Table I. Clinician’s Global Severity Score*
`
`
`
`DefinitionScore/Grade Guideline
`
`(0) None to very mild
`
`No signs or symptoms present; at most,
`mild erythema
`
`(1) Mild
`
`(2) Moderate
`
`(3) Severe
`
`Mild erythema present; none to few
`papules/pustules
`
`Moderate erythema; moderate number
`of pa pules/pustules
`
`Severe erythema; papules/pustules common
`
`0-3 papules/pustules
`Erythema Assessment Score
`Total score <1; Area—specific score: Ger 1
`4—9 papules/pustules
`Erythema Assessment Score
`Total score <5; Area-specific score: 0 or 1
`10—14 papules/pustules'
`Erythema Assessment Score
`Total score 6—10; Area-specific score: 2 or 3
`15—19 papules/pustules
`Erythema Assessment Score
`Total score 16—20; Area—specific score: 3 or 4
`>20 papules/pustules
`Erythema Assessment Score
`Total score 16—20; Area—specific score: 3 or 4
`
`(4) Very severe
`
`Fiery red erythema; numerous papules/pustules
`
`*One score to be selected for each patient at each evaluation.
`
`Table II. Clinician’s Erythema Assessment Scale*
`Definition
`Score/Grade ‘
`
`(0) None
`(1) Mild
`(2) Moderate
`
`No redness present
`Slight pinkness
`Definite redness
`
`Marked erythema
`(3) Significant
`
`(4) Severe
`Fiery redness
`
`*Total score based on all areas of face evaluated (forehead, chin,
`nose, right cheek, left cheek). Each of the 5 areas could be scored
`from 0 to 4. Maximum total score was 20.
`
`trended
`treatment groups by week 4 (P = .108),
`toward statistical significance at week 8 (P = .075),
`and were statistically significant (P = .046) at week
`12. At each Visit,- patients receiving subantimicrobial—
`dose doxycycline had a greater mean change from
`baseline in their Clinician’s Global Severity Score
`results than did patients receiving placebo/metroni—
`dazole (Fig 5).
`clinician’s Erythema Assessment Scale. A
`review of patients’ erythema locations at baseline
`revealed that most patients presented with erythema
`at certain facial
`locations but not at others. This
`
`mirrors thecharacteristics of typical rosacea patients,
`but it makes the clinician’s Global Erythema Assess—
`ment, which assigns equal weights to facial areas
`regardless of the presence or absence of erythema at
`baseline, relatively insensitive. Because of the dispar—
`ity in location and number of affected facial sites, the
`standard analysis failed to demonstrate a change in
`clinician’s Global Erythema Assessment from baseline
`in the treated. groups, although the absolute changes
`in the scores favored the subantimicrobial—close
`
`doxycycline/metronidazole regimen through week 12.
`
`'\
`
`Additional efficacy analyses targeting loca-
`tions with erythema at baseline.
`In this study,
`inclusion criteria for moderate to severe erythema
`were defined relatively broadly as a score of 2 to 4 in
`at least one of the 5 facial areas and a total score of 5
`
`to 20 on the clinician’s Global Erythema Assessment.
`Additional analyses indicated that the effect of sub—
`antimicrobial~dose doxycycline/metronidazole was
`most evident when sites evaluated. for erythema
`were excluded if the baseline score for that area
`
`was less than 2, For example, patients receiving
`subantimicrobial—dose doxycycline had clinically
`lower scores on the Clinician’s Global Erythema
`Assessment at week 4 (P = .06). The differences
`
`between the two treatment arms were statistically
`significant at week 12 (P = .04). When sites with
`scores less than 3 on the clinician’s Global Erythema
`Assessment were excluded from the analysis, pa—
`tients receiving subantimicrobial—dose doxycycline
`had a statistically significant reduction from baseline
`in their clinician’s Global Erythema Assessment
`scores at week 4 (P = .027). Overall, the greater the
`degree of severity at baseline,
`the greater
`the
`changes that were observed with subantimicrobial—
`dose doxycycline/metronidazole treatment (Fig 4).
`
`Discontinuations
`
`Five patients discontinued the study, all from
`the placebo/metronidazole arm. Of these, two pa~
`tients discontinued for personal reasons, one was
`eliminated because of a protocol Violation, one had
`illness not related. to treatment, and one experienced
`pruritus and erythema at the application site after
`the first
`treatment with placebo/metronidazole.
`There were no statistically significaht differences
`
`

`

`1 AM ACAD DERMATOL
`VOLUME 53, NUMBER 5
`)
`
`1
`
`SaflCbGZ at [/71 795
`
`Table III. Demographic characteristics of patients
`
`Placebo plus
`Subantimicrobial
`inetronidazole
`(lose doxycycline plus
`Characteristic
`(11 = 20)
`metronidazole (11 = 20)
`P value
`
`
`Mean age (+ subantimicrobial dose)*
`Gender (no.)
`Male
`Female
`Race (no.)
`Hispanic
`White
`Black
`
`41.6 (11.7)
`
`38.8 (7.2)
`
`3
`17
`
`15
`5
`0
`
`NS
`
`NS
`NS
`
`NS
`
`i
`
`NS
`27.3 (3.6)
`25.9 (3.7)
`Total inflammatory lesions (mean + SEM)
`NS
`2.7 (0.17)
`2.6 (0.17)
`Clinician’s Global Severity Score (mean + SEM)
`NS
`9.5 (0.69)
`9.8 (0.71)
`Clinician’s Global Erythema Assessment
`(mean total score + SEM)
`
`V
`
`NS, no statistical significance; SE/Vl, standard error of the mean.
`*Age not available for 1 placebo— and 3 subantimicroblal-dose doXycycline—treated patients.
`
`between treatment groups for the mean number of
`days on medication (placebo/metronidazole: 108
`days;
`subantimicrobial—dOse doxycycline/metroni—
`dazole: 118 days).
`
`Adverse events
`
`tolerated, with no
`Both treatments were well
`between—group differences observed in adverse
`events. A total of 33 adverse events occurred, 19 in
`the placebo/metronidazole group and 14 in subanti—
`microbial—dose doxycycline/metronidazole—treated
`patients. Facial dryness, burning, irritation, and ery—
`thema accounted. for 6 of the 19 events in the
`
`placebo/metronidazole group and for 3 events in
`the subantimicrobial—dose doxycycline/metronida—
`zole group. Gastrointestinal events were more com—
`mon in patients receiving subantimicrobial—dose
`doxycycline/metronidazole (5 vs 2). No instances
`of vaginitis or photosensitivity were reported. No
`treatment—related severe adverse events occurred. in
`
`either treatment group.
`
`DISCUSSION
`
`This study is the first controlled trial of a sub—
`antimicrobial regimen of doxycycline, in combina—
`tion with topical metronidazole, to treat rosacea. The
`results demonstrated that adjunctive use of doxycy—
`cline hyclate 20 mg twice daily significantly reduced
`the clinical signs of rosacea in comparison with
`monotherapy with topical metronidazole. The com—
`bination treatment resulted in a statistically signifi—
`cant reduction in the total inflammatory lesion count
`(papules plus pustules plus nodules) from baseline
`at the 12— and 16—week visits, which was the primary
`efficacy end point. In addition, total inflammatory
`lesions were reduced significantly at all other Visits,
`
`including as early as 4 weeks after the start of
`therapy. Moreover, the reduction in total inflamma—
`tory lesions was maintained during monotherapy
`with subantimicrobial—dose doxycycline.
`_
`Over the course of the trial, the secondary end
`points of global severity and erythema also were
`reduced. significantly by the combination treatment.
`Differences between groups on the clinician’s
`Global Erythema Assessment showed statistically
`significant differences favoring subantimicrobial—
`dose doxycycline during the monotherapy phase of
`the trial when the analysis focused on those facial
`locations presenting with erythema at baseline, an
`observation aligned. with typical therapeutic goals
`for the treatment of most patients. The degree of
`change from baseline appeared to be maintained by
`low—dose doxycycline monotherapy for facial sites
`with the highest degree of baseline severity. These
`findings may be complicated by observations that 9
`patients overall experienced facial adverse events
`such as dryness and irritation. Five of these patients
`were switched to topical metronidazole cream at
`week 4 or 8. Additionally, the analyses of erythema
`according to baseline severity underscore the diffi—
`culty of assessing an effect when the baseline
`erythema score is weighted toward. the low end by
`facial areas having mild or no erythema. It is likely
`that a study comprising a larger number of patients
`at various baseline levels of erythema severity would
`provide additional data to clarify these findings.
`Overall, both treatment regimens were well tol—
`erated, and there were no between—group differ—
`ences in adverse events. lmportantly, no instances of
`vaginitis or photosensitivity occurred, confirming the
`safety and advantages of oral subantimicrobial—dose
`doxycycline in the treatment of rosacea.
`
`

`

`796 Sanchez et all
`
`J AM ACAD DERMATOL
`NOVEMBER 2005
`
`Weeks
`Week 16
`Week 8
`Week 12
`Week 4
`I | l |
`
`
`
`
`
`
`
`0
`
`
`
`
`
`Totalinflammatorylesrons lll3‘F33
`
`—16
`
`—o—- P/TM
`«aw so DOXY/TM
`
`2'
`
`WW“
`
`Fig 2. Change from baseline in mean total inflammatory
`lesions.
`
`Weeks
`Week 4
`Week 8
`Week 12
`Week 16
`
`.L.
`I
`I
`I
`
`0
`:3
`‘2 0
`Q m
`E E ~02
`
`.53 35‘ —0.4 M3 5no 01>) —0.6
`,D0
`—o— P/TM
`g g _0,8
`man- s0 DOXY/TM
`“EMMA!
`g 77”
`~1
`—1.2
`Fig 3. Meangchanges from baseline in Clinical Global
`Severity Score.
`
`is
`The origin of rosacea is not known, but it
`speculated that some individuals are genetically
`, predisposed for development of the condition be—
`cause of a wide variety of circumstances and. trig—
`gers.15’16 The pathologic process itself appears to be
`initiated by dermal vascular changes (small—vessel
`dilation) associated with flushing and. telangiectasia.
`As the pathophysiologic processes underlying pro—
`gression of rosacea have becomebetter understood,
`treatment strategies also are evolving. These include
`the recognition that the tetracyclines can exert anti—
`inflammatory effects that are distinct from their
`antimicrobial effects. 17
`
`For example, telangiectasia may result from the
`reduction of mechanical integrity of the upper der—
`mal connective tissue as a result of perivascular
`inflammatory cell infiltration as well as neovascular—
`ization.6’18’19 These processes may be mediated by
`type IV collagenases, which are shown to be in—
`hibited by doxycyclinezo’21
`edema may
`Vasodilatation and subsequent
`contribute to progressive inflammatory processes
`that may underlie the inflammatory manifestations
`of rosacea/1”16 Neutrophils recruited. to the sites of
`inflammation produce several proteases, including
`elastase and collagenases, that can contribute to the
`degradation of elastin and. type IV collagen. This
`can lead to the separation of the elastin from the
`lymphatic vessels, thereby impairing the removal of
`the extravascular fluid, which results in flushing/
`
`u
`a) 8
`v)
`g g
`g g 0
`E E E
`g) Q ”’
`A. ii0 ‘1)El
`
`Weeks
`Week 8
`Week 12
`
`Week 16
`
`Week A
`
`
`
`+ TM: Baseline z 2
`“mu-w SD DOXY: Baseline 2 2
`"vi-n TM: Baselineaa
`u-x— so DOXY/TM: Baseline 2 a
`
`Fig 4. Changes from baseline in Clinical Erythema As—
`sessment Scale scores according to baseline severity.
`
`blushing. This lymphatic failure ultimately results
`in a sustained. inflammatory response that exacer—
`bates the condition.6 Doxycycline has been shown
`to inhibit elastase as well as type IV collagenases,
`thereby maintaining the integrity of the capillary
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