Volume 79 ' Number 3
`
`Modified-Release Subantimicrobial
`Dose Doxycycline Enhances Scaling
`and Root Planing in Subjects With
`Periodontal Disease
`
`Philip M. Preshaw,* M. John l‘lovak,T James Mellonig,1F lngvar Magnusson,§ Alan Poison,ll
`William V. Giannobiieffl Randal W. Rowlandfll John Thomas,M Clay Walker,§ Dolphus R. Dawsonfl
`Dennis Sharkey,“ and Mark H. BradshawTT
`
` |_
`Background: Previous studies showed that adjunctive subantimicrobial dose doxycycline (SDD; 20 mg,
`twice daily) provides significant clinical benefits to scaling and root planing (SRP). A modified-release SDD
`formulation containing 40 mg doxycycline (EDD—40} to be taken once daily has been developed. The aim of
`this study was to investigate the efficacy ofSDD-4O when used as an adjunct to SRP for the treatment ofperi-
`odontitis.
`Methods: A 9-month. double-masked. randomized. placebo-controlled. rnulticenter study was con—
`ducted to test the efficacy of adjunctive 813040 in 266 subjects with periodontitis. Subjects were treated
`by SRP and randomized to receive SOD-40 or placebo for 9 months with evaluations at 3. 6, and 9 months.
`Results: Adjunctjve SOD-4O provided significantly greater clinical benefits than placebo at all time
`points. At month 9. at sites with baseline probing depths (PD) 26 mm. 72% to 76% of sites in the SDD-4O
`group demonstrated clinically significant PD reductions and clinical attachment level (CAL) gains 22 mm
`compared to 56% to 58% oisites in the placebo group (P<0.DOO] }; 48% to 52% of sites in the EDD-40 group
`demonstrated PD reductions and CAL gains 23 mm compared to 32% of sites in the placebo group
`(P (0.000 i ). in moderate sites (baseline PD 4 to 6 mm). adiunctive SUD-40 provided significant clinical
`benefits compared to placebo for mean CAL [all time points: P<0.05). PD (3 months: P: 0.002; 6 and 9
`
`
`
`group.
`Conclusion: SDD-4O used as an adjunct to SRP resulted in significantly greater clinical benefits than SRP
`alone in the treatment of periodontitis. J Periodontol 2008;79:440-452.
`KEY WORDS
`
`Double-masked method; doxycycline/therapeutic use; multicenter; periodontitis/drug therapy.
`
`
`Department of Periodontology. University at Florida. Gainesvliie. FL.
`Department oi Periodonloiogy. University of Pennsylvania School of Dental Medicine. Philadelphia. PA.
`Department of Iteriodontoiogy. Michigan Center for Oral Health Research. University at Michigan. Ann Arbor. MI.
`Private practice. San Francisco. CA.
`'* Department oi Pathology. West Virginia University. Mnrgantown. WV.
`T 1' Global Consulting Partners — Medical Biometrics. Princeton. NJ.
`
`Amneal 1039
`Amneal v. Supernus
`
`

`

`j Periodontol - March 2008
`
`Preshaw, Novak, Mellonig, et al.
`
`Subantimicrobial dose doxycycline” (SDD;
`
`doxycycline, 20 mg, twice daily) has become
`widely established as an effective adjunctive
`systemic therapy in the management of periodontitis.
`Clinical studiesl'5 confirmed that when used as an
`
`adjunct to scaling and root planing (SRP) for the
`treatment of periodontal disease, SDD results in
`statistically and clinically significant improvements
`over those achieved by SRP alone. in addition, the
`long-term use of SDD has been shown to be safe, and
`it is not associated with the development of antibiotic
`resistance in the periodontal microflora,6 the skin
`microflora (when used long-term for the management
`of inflammatory conditions, such as acne),7 or the
`flora of the gastrointestinal or genitourinary tracts.8
`The clinical benefits of SDD derive from the ability
`of doxycycline to inhibit the activity of matrix metal-
`loproteinases (MMPs).9 MMPs play a key role in peri-
`odontal pathogenesis and are secreted by a variety
`of resident and infiltrating inflammatory cells in dis—
`eased periodontal tissues. MMP levels are increased
`pathologically in inflamed periodontal tissues and in
`gingival crevicular fluid (GCF) from deep periodontal
`pockets.” Administration of SDD was shown clearly
`to result in statistically significant decreases in GCF-
`derived MMPs and bone breakdown components; it
`also promoted concomitant improvements in the clin-
`ical measurements of periodontal status.4'“'12 SDD
`was shown to improve clinical outcomes when used
`as an adjunctto periodontal flap surgery and to reduce
`GCF concentrations of markers of alveolar bone re-
`
`sorption.13 SDD, by virtue of its anti-inflammatory
`and anti-MMP effects, was also shown to be of poten-
`tial benefit in the management of systemic conditions
`such as coronary artery disease,14 rheumatoid arthri-
`tis,15 and adult acne and rosacea.16
`The decision whether to use a systemic adjunct to
`conventional periodontal therapies must be made af-
`ter consideration of many factors including the di-
`agnosis, the desired treatment outcomes, and the
`patient’s wishes following full explanation of all treat-
`ment options. Clearly, the use of a systemic medica-
`tion over 3 to 9 months requires a commitment on the
`part of the patient, and poor compliance with a twice-
`daily medication may affect clinical outcomes. in dis-
`orders such as hypertension, it has been shown that
`compliance with medication is increased as the fre-
`quency of daily dosing is decreased”,18 Thus,
`in
`terms of compliance, once-daily dosing is preferred
`to twice-daily (or more) dosing whenever possible.
`Although reducing the frequency of dosing en-
`hances compliance and usually is preferred by pa-
`tients,19 this can create challenges in maintaining
`circulating drug concentrations at the correct thera-
`
`lease and subsequent absorption of a medication is
`prolonged, thereby ensuring the correct therapeutic
`dose for an extended period of time. A modified-
`release formulation of SDD has been developed
`containing doxycycline monohydrate 40 mg in con-
`trolled-release capsules§§ to be taken once daily
`(SDD-40). Therefore, the objective of this study was
`to evaluate the efficacy of SDD-40 when used as an
`adjunct to SRP compared to placebo for the treatment
`of periodontitis. Furthermore, the effect, if any, of a
`9-month regimen of SDD-40 on the subgingival flora
`was evaluated compared to the placebo control.
`
`MATERJALS AND METHODS
`
`Study Design
`This was a randomized, multicenter, double-masked,
`placebo-controlled parallel group study to evaluate
`the efficacy of SDD-40 when used as an adjunct to
`SRP in the treatment of periodontitis. The duration
`of the study was ~9.5 months, consisting ofa 2—week
`screening process and a 9-month treatment period.
`Subjects were assigned randomly to treatment with
`SDD-40 or placebo once daily for 9 months. The study
`was conducted between May 2004 and August 2005
`at seven clinical investigational sites (Universities of
`Kentucky, Texas at San AntOnio, Florida, Pennsylva-
`nia, Michigan, and Newcastle upon Tyne and a private
`practice in San Francisco), with all microbiologic as-
`says conducted at West Virginia University. Approval
`was granted by the respective institutional review
`boards or ethics committee of the study centers prior
`to study initiation. Written informed consent was ob-
`tained from all subjects. Subjects were screened to
`confirm eligibility and then underwent full-mouth
`SRP at the baseline visit. Following this, subjects were
`allocated randomly to receive adjunctive SDD-40 or
`adjunctive placebo for the treatment period of the
`study (9 months) commencing at baseline. Subjects
`returned to their respective study center for evalua—
`tions at 3, 6, and 9 months after baseline.
`
`Study Population
`Eligible subjects were male or female, 218 years old,
`with evidence of untreated periodontitis manifested
`by four periodontal sites in each of two quadrants,
`i.e., eight qualifying periodontal sites, with a minimum
`of two affected teeth per quadrant, with all eight qual—
`ifying sites demonstrating probing depth (PD) 25 mm,
`attachment loss 25 mm, and bleeding on probing
`(BOP) score20 21 , with at least two sites having bleed-
`ing scores 22. Exclusion criteria included pregnant
`or nursing females; serious medical conditions, e.g.,
`kidney or liver disease; systemic infection; dental
`prophylaxis within the last 30 days; requirement for
`
`

`

`Modified-Release SDD (SUD—40) Enhances SRP
`
`Volume 79 ° Number 3
`
`antibiotic prophylaxis prior to dental procedures; use
`of non-tetracycline antibiotics within 6 weeks of base-
`line; use of tetracycline antibiotics within 3 months
`of baseline; hypersensitivity to tetracyclines; a re-
`quirement for chronic (22 weeks) antibiotic therapy;
`surgery to bypass or exclude the duodenum; and
`achlorhydria.
`
`Procedures
`Written informed consent was obtained at the screen-
`
`ing examination. A health history was recorded, and
`an oral pathology examination was undertaken. Full-
`mouth clinical attachment level (CAL) and PD mea-
`sures were recorded by trained examiners using
`manual University of North Carolina 15 periodontal
`probes at six sites per tooth. BOP was recorded at
`six sites per tooth using a bleeding index (0 = no bleed-
`= single bleeding point or fine line of blood; 2 =
`interdental triangle or direct margin fills with blood;
`and 3 = profuse bleeding immediately after prob-
`ing).20 Venous blood samples were obtained, and a
`pregnancy test was performed when appropriate to ex-
`clude pregnancy. Radiographs taken within 12 months
`of screening (including any taken at the screening ap-
`pointment itself) were used to confirm the periodontal
`diagnosis and identify any underlying conditions that
`might exclude a subject from participation in the
`study. Demographic information, details of oral hy-
`giene practices, and smoking histories were recorded.
`The screening examination also served as the
`baseline examination for those subjects who immedi-
`ately qualified for the study. Otherwise, subjects re-
`turned for the baseline examination 14 days after
`screening. In either case, following the baseline exam—
`ination, full-mouth SRP was undertaken commencing
`immediately after the baseline examination and com-
`pleted within a maximum of 24 hours. SRP was per-
`formed by supra- and subgingival use of ultrasonic
`instruments followed by hand instruments for removal
`of plaque and calculus deposits until tooth surfaces
`were smooth and calculus could not be detected, with
`a time limit of 1 hour per quadrant. Ultrasonic and uni-
`versal or area-specific curets were used, as was local
`anesthesia, based on operator preference.
`At baseline, subjects were randomized to receive
`SDD-4O or placebo once daily (1:1 randomization).
`Randomization was carried out at each investigational
`site based on a randomly generated predefined
`schedule with fixed block size. Subjects were in-
`structed to take study medication with water 21 hour
`before or 2 hours after meals. Subjects were instructed
`that antacids and nutritional supplements containing
`Al, Ca, or Mg may impair drug absorption and that
`these were to be taken 21.5 hours before or 3 hours
`
`dispensed in 3-month quantities. All personnel in-
`volved in the study were masked to study medication
`allocation. Subjects returned for full-mouth clinical
`assessments at 3, 6, and 9 months and were con-
`tacted monthly by telephone for the recording of ad-
`verse events (AEs) and for ensuring compliance. At
`month 9, a dental prophylaxis was performed, and
`the subjects were exited from the study.
`Assessments
`
`Prior to the study, all examiners were trained and
`practiced in each of the clinical measurements. To
`minimize the impact of interexaminer variability, the
`same examiner assessed a given subject for the dura-
`tion of the study. Prior to the primary statistical ana-
`lyses, sites were stratified by the degree of PD at
`baseline: sites with PD of 1 to 3 mm were considered
`normal; sites with PD of 4 to 6 mm were considered
`mild-moderately diseased; and sites with baseline
`PD 27 mm were considered severely diseased.”
`Full-mouth PD, BOP, and CAL were recorded at
`baseline and months 3, 6, and 9. Efficacy parameters
`included the mean changes in PD, BOP, and CAL
`score from baseline. AEs and the use of concomitant
`
`medications were documented in subject diaries and
`recorded at each study visit and during monthly tele-
`phone contacts. Compliance with study drug therapy
`was recorded by counting the number of tablets dis-
`pensed and returned. Laboratory tests (blood chemis-
`try and complete blood cell count and differentiation)
`were conducted at the screening/baseline visit and
`month 9. Vital signs, oral soft tissue examinations,
`and examinations of the head and neck were per-
`formed at screening/baseline and at months 3, 6,
`and 9. The pregnancy test was repeated at month 9
`when appropriate.
`
`Microbiologic Assessments
`At two preselected investigational centers (University
`of Kentucky and University of Florida), subgingival
`plaque samples were collected using sterile paper
`points at baseline and month 9 and analyzed for mi-
`croflora and antibiotic susceptibility. Plaque was col-
`lected from four of the eight selected qualifying sites
`with PD 25 mm and £8 mm. Obvious supragingival
`plaque was removed and discarded. Subgingival
`samples were collected by inserting a single sterile
`endodontic paper point into the pocket until resis-
`tance was felt. The paper point was moved laterally
`parallel to the long axis of the tooth and left in place
`for ~10 seconds as described previously.6 The point
`was removed and immediately placed in modified
`Amies transpOrt medium.22 A separate paper point
`was used to sample each site, but the sites were
`pooled by subject for processing.
`
`

`

`] Periodontol - March 2008
`
`Preshaw, Novak, Mellnnig. et al.
`
`sonication and vortexing for 10 seconds using anaer-
`obic techniques. Ten-fold serial dilutions were made
`under anaerobic conditions using prereduced anaer-
`obically sterilized (PRAS) Ringers solution, and 0.1-
`ml aliquots were dispensed onto the surface of agar
`plates and spread with sterile glass rods. Following
`the prescribed incubation period, plates were exam~
`ined for colony forming units (CFLl). Counts for the
`enumeration of total anaerobic and total facultative
`
`counts were performed on the plate dilutions that gave
`rise to 20 to 200 CFU. Counts on selective media were
`
`performed using the plate dilutions that yielded 20 to
`200 CFU.
`To determine the effect of SDD-4O on the total cul-
`
`tivable flora, 0.1-ml aliquots of the diluted samples
`were spread onto trypticase-soy blood agar supple—
`mented with hemin and menadione (TSBA-HK) me-
`dium containing 4 pg doxycycline per milliliter of
`medium (TSBA + doxycycline). These plates were in-
`cubated anaerobically along with the TSBA-HK plates
`for the determination of total anaerobic bacterial
`
`counts. Following 5 to 7 days of incubation, both sets
`of plates (TSBA-HK doxycycline containing and non-
`doxycycline containing) were examined for CH]. The
`colonies on the countable TSBA + doxycycline plates
`were examined; colonies belonging'to'each of the
`most numerous colony types present (up to three dif-
`ferent colony types per sample when present) were
`counted, and a representative isolate of each was sub-
`cultured to TSBA—HK. Each isolate that survived sub—
`
`culture was identified to genus and species level. The
`minimal inhibitory concentrations (Mle) of doxycy-
`cline, minocycline, tetracycline, erythromycin, clin-
`damycin, and amoxicillin were determined by agar
`dilution or by the E-test for each isolate that survived
`the characterization and identification process.6v23
`This procedure yielded the following: percentage of
`the cultivable flora resistant to doxycycline, the iden-
`tity of the predominant doxycycline-resistant flora,
`and the presence or absence of multiantibiotic re-
`sistance and the particular antibiotics to which the
`microorganism was resistant. The percentage of cul-
`tivable flora resistant to doxycycline was calculated
`from the total counts on doxycycline-containing me-
`dium as a percentage of the total anaerobic counts on
`non-doxycycline—containing medium.
`
`Statistical Analyses
`The study was designed to detect a difference 20.2
`mm in mean change from baseline CAL between
`treatment arms (two-tailed tests) with 80% power, as-
`suming that 72 subjects would complete the study in
`each group. An intent-to-treat analysis strategy was
`used for all subjects who were randomized to study
`
`carried-forward (LOCF) algorithm was used to impute
`missing data at each time point.
`Changes in mean CAL, PD, and BOP were calcu-
`lated at each time point from subject means catego-
`rized according to PD at baseline. Comparisons
`between the treatment groups were made using anal-
`ysis of covariance (ANCOVA). The ANCOVA model
`analyzed the subject-level mean changes from base-
`line; included factors for treatment group, investiga—
`tional site, and the treatment by investigational site
`interaction; and included the baseline value of the pa-
`rameter for each subject as covariate. All tests of sig-
`nificance were two-sided; differences were considered
`statistically significant when P<0.05.
`For sites requiring additional periodontal therapy
`during the course of the study (those sites that dem-
`onstrated 22 mm attachment loss at any point during
`the study), the post-baseline observations recorded
`immediately prior to the local therapy were analyzed
`using the LOCF strategy to ensure analyses were con-
`servative and not biased. Differences between the
`
`groups for threshold changes indicating disease pro-
`gression, i.e., 22 mm attachment loss, were analyzed
`using a generalized estimating equations (GEE) anal-
`ysis for the repeated measures across visits.
`To assess the clinical significance of any improve-
`ments in periodontal status as a result of treatment,
`the number of sites achieving clinically significant re-
`ductions in PD, i.e., reductions 22 and 23 mm, and
`clinically significant gains in CAL, i.e., gains 22 and
`23 mm, were determined. Separate analyses were
`done for all sites with baseline PD 24 mm and for
`
`deeper sites with baseline PD 26 mm. The proportion
`of sites achieving such improvements in each group
`was expressed as a percentage of the total number
`of sites, and comparisons between the two treatment
`groups were made using a GEE model with adjust-
`ment for within-subject correlations among sites.
`Compliance with study medication was defined as
`the number of medication doses taken as a percent-
`age of the number that should have been taken based
`on the number of days between study visits. Non-
`compliance was defined if compliance was 380%.
`The microbial data from both clinical centers that
`
`collected plaque samples were combined and ana-
`lyzed as a single data set. lnferential analyses of doxy-
`cycline resistance were based on the per-subject
`mean percentage of colonies at each visit that showed
`resistance to doxycycline and the change from base-
`line in the mean percentage of resistant organisms. In-
`ferential analyses of species-specific colony counts
`were based on log (10)-transformed counts, where
`the log (10) transformation of a count of zero was
`set to zero. The primary analyses sought to determine
`
`

`

`Modified-Release SDD (SDD-40) Enhances SRP
`
`Volume 79 0 Number 3
`
`baseline to month 9 with regard to the mean percent-
`age of doxycycline-resistant organisms. Separate
`analyses were conducted for each of the visits and
`for the changes from baseline to month 9 using the
`Wilcoxon two-sample test. This non-parametric test
`was chosen because distributions of the per-subject
`percentage of resistance data did not meet the re-
`quirements for parametric analyses. It is a conserva-
`tive test that provides unbiased probability estimates
`under these circumstances. The secondary analyses
`were performed to determine whether colony counts
`for specific species were different between the two
`treatment groups at either visit and whether the
`changes from baseline in mean log (10) counts dif—
`fered between treatment groups. As in the case of
`the primary analyses, separate analyses were con-
`ducted for each of the visits and for the changes from
`baseline using the Wilcoxon two-sample test. In all
`cases,
`two-tailed P values £0.05 were considered
`statistically significant. All analyses were performed
`using a software program."“
`
`RESULTS
`
`A total of 266 subjects were enrolled into the study;
`133 were randomized to receive adjunctive SDD-40,
`and 133 were randomized to receive adjunctive pla-
`cebo. A total of 110 subjects (82.7%) in the SDD-40
`group and 117 subjects (88.0%) in the placebo group
`completed the study. The primary reasons for discon-
`tinuing participation were loss to follow-up (SDD-4O
`group: 10 subjects; placebo group: four subjects),
`AEs (SDD-40 group: seven subjects; placebo group:
`four subjects) or lack of compliance (SDD-40 group:
`two subjects; placebo group: four subjects). There
`were no statistically significant differences between
`the SDD-40 and placebo groups with respect to the
`numbers of subjects who did not continue the study
`or the reasons for discontinuation.
`
`There were no statistically significant differences
`between the treatment groups regarding demo-
`graphic characteristics (Table 1). Similarly,
`there
`were no significant differences between the study
`groups with respect to oral hygiene practices. On av-
`erage, subjects brushed their teeth twice per day and
`flossedjust over three times per week. Eighteen of 266
`(6.8%) subjects had diabetes; one subject had type
`1 diabetes mellitus (this subject was randomized to re-
`ceive placebo), and 17 had type 2 diabetes mellitus
`(nine subjects in the SDD-40 group and eight subjects
`in the placebo group). There were no statistically sig-
`nificant differences in diabetes status between the
`treatment groups (P = 0.59). The treatment groups
`also were similar with regard to other baseline vari-
`ables, including medical history, medication history,
`
`Table l.
`
`Demographic Characteristics of
`Study Population
`-—-—————___._____
`
`Characteristic
`
`Age (years)
`Mean i SD
`Range
`
`Gender (n [%])
`Male
`Female
`
`Race/ethnicity (n [%])
`White
`Black
`Asian
`Other
`
`SRP + SDD-40 SRP + Placebo
`
`(n 2 I33)
`
`(n = I33)
`
`P
`
`48.5 i I I4
`24 to 8|
`
`49.9 i- I I0
`23 to 82
`
`0.34
`
`58 (43.6)
`75 (56.4)
`
`62 (46.6)
`7| (53.4)
`
`0.62
`
`87 (65.4)
`28 (2|.I)
`8 (6.0)
`|0 (7.5)
`
`0.90
`
`IOO (75.2)
`2| (l5.8)
`7 (5.3)
`5 (3.7)
`
`Tobacco use (n [%])
`0.95
`84 (62.2)
`82 (62.6)
`E><— or current smoker
`——————________
`Current smoker
`45 (34.4)
`32 (23.7)
`0.06
`P values were determined using the X2 test for discrete variables and the
`two»samp|e I test for continuous variables.
`
`Table 2.
`
`Baseline Clinical Characteristics
`(mean i SEM) of Study Population
`————__________
`
`P
`Baseline PD Parameter SRP + SDD-40 SRP + Placebo
`—————.________
`
`4 to 6 mm PD (mm)
`CAL (mm)
`BOP
`
`4.9I i 0.02
`4.8I i 0.09
`I89 i 0.04
`
`4.89 i— 0.02
`4.82 i 0.09
`I88 1- 0.04
`
`0.46
`0.78
`0.8l
`
`27 mm
`
`0.62
`7.47 i 0.06
`7.43 i 0.06
`PD (mm)
`0.60
`7.30 i- 0.l5
`7.I8 i 0.l6
`CAL (mm)
`0.5I
`2.|O i 0.05
`2.|4 i 0.04
`BOP
`—————————_—_____
`
`pliance in the SDD-40 group and 95% compliance
`in the placebo group.
`Baseline clinical parameters are shown in Table 2.
`There were no statistically significant differences in
`the baseline clinical characteristics between the two
`treatment groups.
`
`Clinical Outcomes
`
`The mean per-subject changes in CAL from baseline
`to month 9 are shown in Figures 1 and 2. Attachment
`gains were demonstrated in both groups, which was
`expected following SRP. However, gains in CAL were
`significantly greater at all time points in the subjects
`treated with SDD-40 compared to the subjects who re—
`ceived placebo (P<0.05) whether considering moderate
`
`

`

`J Periodontal ' March 2008
`
`Preshaw, Novak, Mellonig, et 31.
`
`Baseline PD 4 to 6 mm
`
`Baseline PD 4 to 6 mm
`2
`1.8
`
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`
` 1.6
`
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`1
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`
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`|
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`
`-
`
`0
`
`r
`Month 3
`
`+ SRP + SDD—40
`-<>— SRP +Placebo
`.- — —.
`Month 8
`Month 9
`
`Figure 1.
`Mean attachment gains in sites with baseline PD of4 to 6 mm. The
`mean per—subject changes from baseline and standard errors are
`presented. *P <0.05 versus placebo.
`
`Figure 3.
`Mean PD reductions in sites with baseline PD of 4 to 6 mm. The mean
`per—subject Changes from baseline and standard errors are presented.
`TP <0.0l versus placebo
`
`Baseline PD 27 mm
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`2.20:0.31
`
`-
`2 07:027
`
`
`
`o L.
`0
`
`—
`-
`Month 3
`
`-I- SRP + sob—40
`-<>- SRP +Placebo
`-
`Month 6
`
`-
`Month 9
`
`Figure 2.
`Mean attachment gains in sites with baseline PD 27 mm. The mean
`per-subject changes from baseline and standard errors are presented.
`*P <0.05 versus placebo; 7P <0.0l versus placebo.
`
`Figure 4.
`Mean PD reductions in sites with baseline PD 27 mm. The mean
`per—subject changes from baseline and standard errors are presented.
`TP <0.00l versus placebo.
`
`(baseline PD 4 to 6 mm) or deep (baseline PD 27 mm)
`sites. In moderate sites at month 9, mean CAL gains
`from baseline were 11% greater with adjunctive SDD-
`40 than with placebo (1.66 mm versus 1.49 mm, re-
`spectively; P= 0.02). In deep sites at month 9, mean
`CAL gains from baseline were 19% greater with ad-
`junctive SDD—4O than with placebo (2.62 mm versus
`2.20 mm, respectively; P<0.01).
`The mean per-subject changes in PD from baseline
`to month 9 are shown in Figures 3 and 4. Again, as was
`expected following SRP, PD reductions were observed
`in both groups. These were significantly greater at all
`time points, at moderate and deep sites, in the sub-
`
`at month 9, mean PD reductions from baseline were
`16% greater with adjunctive SDD-4O than with placebo
`(1.63 mm versus 1.41 mm, respectively; P<0.01). In
`deep sites at month 9, mean PD reductions from base-
`line were 22% greater with adjunctive SDD-40 than
`with placebo (2.74 mm versus 2.25 mm, respectively;
`P <0.001 ).
`Although mean changes in PD and CAL are useful
`summary statistics, they do not lend themselves eas-
`ily to interpretation of whether improvements are clin-
`ically significant. Therefore, a threshold analysis was
`undertaken to determine the proportion of sites un-
`dergoing PD reductions and CAL gains 22 and 23 mm
`
`

`

`Modified-Release SDD (SDD—40) Enhances SRP
`
`Volume 79 - Number 3
`
`Table 3.
`
`Threshold Analyses of Sites Demonstrating Clinically Significant CAL Gains and PD
`Reductions at Month 9
`
`Deep Sites (baseline PD 26 mm)
`All Sites (baseline PD 24 mm)
`————————____._.—_—___
`SRP + SDD—4O
`SRP + Placebo
`SRP + SDD—40
`SRP + Placebo
`Threshold Change
`(n : 8,260) (% [n])
`(n = 8.046) (% [n])
`(n = 2,748) (% [n])
`(n = 2,630) (% [n])
`From Baseline
`—————-——-—__________________
`CAL gain 22 mm
`573* (4,732)
`45.8 (3,688)
`7i.8‘i (i973)
`55.9 (i,469)
`CAL gain 23 mm
`283* (2,337)
`i9.5 (i569)
`47.3’r (i299)
`3i.6 (83 I)
`P3 reduction 22 mm
`577* (4,769)
`45.i
`(3.626)
`75.9t (2,086)
`57.8 (LSZO)
`P3 reduction 23 mm
`25.4%E (2,069)
`i6.5 (i,324)
`5i.7’r (i,420)
`32_i (845)
`* P<0.0] compared to placebo (determined using GEE model with adjustment for within-subject correlations among sites).
`T P<0.0001 compared to placebo (determined using GEE model with adjustment for within-subject correlations among sites).
`
`instance, a substantial and
`
`Table 4.
`
`highly statistically significant
`benefit of SDD-40 was ap-
`parent. For example, when
`considering the most dis-
`eased sites (baseline PD 26
`mm); ~48% to 52% of sites
`in the SDD-4O group dem-
`onstrated highly clinically
`significant PD reductions
`and CAL gains 23 mm com-
`pared to ~32% of sites in the
`
`placebo group (P<0.0001).
`Similarly, ~72% to 76% of
`sites with baseline PD 26
`
`mm in the SDD-40 group
`demonstrated clinically sig-
`nificant PD reductions and
`
`CAL gains 22 mm compared
`to 56% to 58% of sites in the
`
`placebo group (P <0.000] ).
`Mean changes
`in BOP
`d . T
`scores are Prejsent‘? m a'
`ble 4- RedUCtlons 1“ mean
`BOP scores were observed
`
`Changes (mean i SEM) in BOP From Baseline
`——————__—___________
`
`SRP + Placebo
`SRP + SDD—40
`SRP + Placebo
`SRP + SDD—4O
`—_—————__—________
`
`Deep Sites (PD 27 mm)
`Moderate Sites (PD 4 to 6 mm)
`————————___—__________
`3
`—l.l9i—Ol3*
`~l.07i0.l3
`—|.20i0.l6Jr
`—l.03i0.l6
`
`6
`
`—l.26i0.l3Jr
`
`~|.l6i0.l3
`
`—|.3|i0.l3
`
`~l.l6:0.|3
`
`—l.|5i0.l4
`—|.3li—O.l41L
`—|.l9i0.l2
`—l.27i0.l2Jr
`9
`—-—————-—_—__________
`‘ P<0.01 compared to placebo.
`T P<0.05 compared to placebo.
`Negative numbers indicate reduction in BOP.
`
`Table 5.
`
`Per-Subject Percentage (mean i SEM) of Sites Demonstrating
`Attachment Loss 22 and 23 mm From Baseline
`——————__.________________
`SRP + SDD—40
`SRP + Placebo
`SRP + SDD—4O
`SRP + Placebo
`—————____________
`
`Deep Sites (PD 27 mm)
`Attachment Loss Month Moderate Sites (PD 4 to 6 mm)
`"————————__._________
`22 mm
`3
`i2 2 0.5
`i4 2 0.5
`0.8 i- 0.5
`L9 i 0.5
`6
`i2 i 0.5
`L5 i 0.5
`0.9 :r 0.6
`L9 i 0.6
`9
`L4 i 0.6
`L7 2 0.5
`2i i 0.9
`2i i 0.9
`
`3
`6
`9
`
`23 mm
`
`in both treatment groups f0].
`lowing SRP, as was expected.
`However, reductions in BOP
`were significantly greater in
`the SDD-40 group than the placebo group at all time
`points in moderate and deep sites (with the exception
`of deep sites at month 6, at which there was no signif—
`icant difference betWeen SDD-40 and placebo).
`The percentage of sites demonstrating progressing
`disease manifested by attachment loss 22 or 23 mm
`from baseline are presented in Table 5. There was a
`
`0.3 e 0.2
`0.3 i 0.2
`0.6 i 0.3
`
`0.4 i 0.2
`0.6 i 0.2
`0.9 i 0.3
`
`0.4 i 0.3
`0.5 i 0.4
`0.3 i 0.4
`
`0.9 :r 0.3
`l.0 i 0.4
`i2 2 0.4
`
`ment loss 22 and 23 mm from baseline compared to
`the placebo group, but these differences were not
`statistically significant.
`
`Safety Data
`In the SDD-40 group, 88 subjects (66.2%) reported a
`total of217 AEs; 94 subjects (70.7%) reported a total
`
`

`

`j Periodontol - March 2008
`
`Preshaw, I‘Iovak, Mellonig, et al.
`
`headache (13 subjects; 9.8%) and influenza and naso-
`pharyngitis (each seven subjects; 5.3%). In the pla-
`cebo group, the most frequently reported AEs were
`sensitivity of teeth (13 subjects; 9.8%) and headache
`and nasopharyngitis (each 10 subjects; 7.5%). AEs
`were ranked as mild, moderate, or severe in intensity,
`with the most common being mild or moderate. Se—
`vere AEs were recorded for nine (6.8%) subjects in
`the SDD-40 group and 18 (13.5%) subjects in the pla—
`cebo group. No AE was considered to be probably re-
`lated to the study medication in either group. Serious
`AEs (SAEs) were reported for six (4.5%) subjects in
`the SDD-40 group and three (2.3%) subjects in the
`placebo group, and no SAE was considered to be re-
`lated to treatment. Adjunctive SDD-40 was tolerated
`well, and there were no clinically meaningful differ-
`ences in the numbers of AEs between the treatment
`
`groups, including any associated with the gastrointes-
`tinal tract or genitourinary tract.
`No clinically meaningful differences between the
`placebo and SDD groups were found for any labora-
`tory tests (complete blood cell count and blood chem—
`istry), and there were no notable mean changes from
`baseline to month 9 in either treatment group for any
`laboratory parameter. No positive pregnancy tests were
`recorded, and there were no differences between the
`treatment groups in changes in vital signs or weight.
`
`Microbiologic Outcomes
`Data from 70 subjects (34 in the SDD-40 group and
`36 in the placebo group) were available for microbio-
`Iogic analysis. It was immediately apparent that an
`imbalance existed between the two treatment groups
`in the percentage resistance to doxycycline at the
`baseline visit, and subjects randomized to SDD-40
`presented with a three—fold greater load of doxycy-
`cline-resistant bacteria (12.69%) than did subjects
`randomized to placebo (3.95%) (Table 6). A similar
`imbalance also was present at month 9 when twice
`as many subjects in the SDD-40 group demonstrated
`resistance to doxycycline compared to the placebo
`group. However, when considering the change in doxy-
`
`Table 6.
`
`Percentage (mean i SD) of Recovered
`Flora Resistant to Doxycycline (4 pug/ml)
`for Each Treatment Group
`
`Baseline
`
`Month 9
`
`SDD—40
`
`Placebo
`
`I269 i 23.l6
`
`3.95 i- 7.39
`
`I779 i 20.85
`
`9.33 i 2049-1
`
`Change fiom baseline
`
`5.09 i 3|.l7
`
`5.311 .4; 22.02
`
`cycline-resistant counts over the course of the study,
`the two groups were very similar, with an increase of
`just >5% in each treatment group. There were no sta-
`tistically significant differences by parametric or non-
`parametric analysis overtime (P: 0.965, analysis of
`variance; P: 0.156, Wilcoxon).
`The effect of treatment, i.e., SDD-40 versus pla-
`cebo, on the specific microbial taxa also was enumer-
`ated. The microbial counts were log transformed (log