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1186

A Phase Wl Clinical Trial to Evaluate


a Combination of Recombinant Human
Platelet-Derived Growth Factor-BB and
Recombinant Human Insulin-Like
Growth Factor-I in Patients with
Periodontal Disease
T. Howard Howell* Joseph P. Fiorellini, David W.
William V. Giannobile, * and Samuel E. Lynch*
'

Paquette,f Steven Offenbacher,'*

primary objective- of this study was to assess the safety of recombinant human
(rh) platelet-derived growth factor-BB (PDGF-BB) and (rh) insulin-like growth factor-I
(IGF-I) when applied to periodontal osseous defects in humans; a secondary objective
was to begin to accrue data on the therapeutic dose of these growth factors (GFs) required
to stimulate periodontal regeneration. Thirty-eight human subjects possessing bilateral os-

The

seous periodontal lesions were assigned to one of two treatment groups in a split-mouth
design. Following full-thickness flap reflection, test sites received local application of the
therapeutic drug delivered in coded syringes by a "masked" investigator. Two dose levels
were tested, 50 p,g/ml each of rhPDGF-BB and rhIGF-I in a gel vehicle (LD-PDGF/IGFI) and 150 g/ml each of rhPDGF-BB and rhIGF-I plus vehicle (HD-PDGF/IGF-I). Control treatment consisted of either conventional periodontal flap surgery or surgery plus
vehicle. Safety analyses included physical examination, hematology, serum chemistry,
urinalysis, antibody titers, and radiographie evaluation of bony changes. The primary
therapeutic assessment was bone fill measured at re-entry 6 to 9 months after treatment.
No local or systemic safety issues were found as a result of GF administration. No patients
developed antibodies to the rhGF proteins. In subjects treated with LD-PDGF/IGF-I, there
were no enhancements in periodontal regeneration compared to controls. However, in
patients treated with HD-PDGF/IGF-I, statistically significant increases in alveolar bone
formation were noted as measured by surgical re-entry 9 months following drug delivery
(P < 0.05). This corresponded to an increase of 2.08 mm of new vertical bone height
and 42.3% osseous defect fill in the HD-PDGF/IGF-I subjects versus only 0.75 mm and
18.5% gains in new bone height and osseous fill, respectively, in the controls. Furcation
lesions, although limited in number, responded most favorably to treatment, with 2.8 mm
horizontal osseous fill. The results from this study suggest that the local application of
rhPDGF-BB and rhIGF-I to periodontal lesions is safe at the dose levels studied. LDPDGF/IGF-I did not elicit increased defect fill compared to the control; however, HDPDGF/IGF-I resulted in a significant promotion in bone regeneration. Additional studies
are warranted to more fully characterize the effects of PDGF/IGF-I on periodontal regen-

eration in humans. J Periodontol

1997;68:1186-1193.

Key Words: Periodontal diseases/surgery; periodontal diseases/regeneration; growth factors/platelet-derived; growth factors/insulin-like; clinical trials.

*Department of Periodontology, Harvard School of Dental Medicine, Boston, MA.


'Department of Periodontics, University of North Carolina-Chapel Hill, Chapel Hill, NC.
Previously, Department of Periodontology, Harvard School of Dental Medicine; currently, Osteohealth Company, Shirley,

NY.

Volume 68
Number 12

HOWELL, FIORELLINI, PAQUETTE, OFFENBACHER, GIANNOBILE, LYNCH

Traditional methods of treating periodontal disease have


focused on the elimination of bacterial pathogens and the
modulation of the host response in an effort to arrest or
slow disease progression. With continued success of these
forms of therapy and a clearer understanding of the disease process, the regeneration of the periodontium, composed of alveolar bone, ligament, and tooth root surface
cementum, is one of the major goals of therapy. Examples
of current periodontal regenerative therapies include bone
autografts, allografts, and guided tissue regeneration using cell-occlusive barrier membranes. While these treatments can, under certain conditions, lead to partial restoration of the periodontium, there remains a need for
development of new therapies with greater predictability,
ease of use, and magnitude of efficacy.
Polypeptide growth factors are a class of natural biological mediators which regulate key cellular events in
tissue repair including cell proliferation, Chemotaxis, differentiation, and matrix synthesis via binding to specific
cell-surface receptors.1 Growth factors possess pleiotropic
effects on wound repair and are potent modulators of cells
residing within the periodontium.2-3 Preclinical animal
studies by several investigational groups have demonstrated that the combination of two such growth factors,
namely platelet-derived growth factor-BB (PDGF-BB)
and insulin-like growth factor-I (IGF-I), has the capacity
to stimulate new bone, periodontal ligament, and cementum formation in periodontal lesions in dogs and nonhuman primates.4-8
The primary objective of this Phase I/II clinical trial
was to determine the safety of a single application of a
combination of recombinant human (rh) PDGF-BB and
rhIGF-I in a gel carrier when placed into osseous defects
during periodontal flap surgery in humans. A secondary
objective was to evaluate the biological response of
growth factor therapy on the promotion of periodontal
tissue regeneration.

MATERIALS AND METHODS


Enrollment and Randomization
Thirty-eight patients with moderate to severe periodontal
disease and corresponding bone destruction were selected
for this randomized, double-masked, paired design clinical trial. Patients were entered into the trial at two test
centers, the Harvard School of Dental Medicine and the
University of North Carolina-Chapel Hill School of Dentistry. The mean age of the patients entered was 46.1
years (range 38 to 62 years). Sixty-six percent (66%) of
the patients were male and 34% female. Subjects entered
into the study protocol met inclusion and exclusion criteria outlined in Tables 1 and 2. Patients signed informed
consent according to the approved human studies protocols at Harvard University and the University of North
Carolina. Treatment and control sites were randomized

1187

Table 1. Inclusion Criteria


1. Males and females between 21 and 62 years of age.
2. If female, practicing adequate birth control, negative pregnancy test within 3 days of dosing, post-menopausal, and/or
surgically sterilized.
3. Scaling and root planing of the 4 quadrants completed within
4 weeks prior to surgery.
4. At least one tooth in contralateral quadrants with similar angular or Class II furcation osseous defects.
5. Angular osseous defects must be &3 mm in depth as assessed
by radiographie evaluation.
6. For interproximal defects, radiographie evidence of 30% to
70% bone loss around study teeth. For furcation defects, radiographie evidence of furcation involvement at baseline.
7. Patients demonstrate acceptable oral hygiene prior to surgical
therapy. Plaque score (Le and Silness)9 must be less than 2;
gingival index (Silness and Le)10 must be less than 2.
8. Involved teeth are vital and asymptomatic.
9. Patients are willing and able to give informed consent.
10. Patients are willing and able to return for multiple follow-up
visits.
'

Table 2. Exclusion Criteria

positive pregnancy test within 3 days of dosing or


practicing adequate birth control.
Patients taking drugs which are known to interfere with
wound healing such as corticosteroids, anticancer agents, or
immune modulators or who have received such drugs within
4 weeks prior to application of the study medication.
Allergies to yeast-derived products.

1. If female,
not

2.

3.
4. Current nutritional disorders.
5. Current or previous history of systemic diseases known to
interfere with adequate wound healing such as chronic liver
failure, diabetes, AIDS, chronic renal failure, malignancy,
collagen vascular diseases, and malnutrition.
6. Evidence or previous history of significant and/or unstable

cardiovascular, pulmonary, gastrointestinal, hematological, or

7.

8.
9.
10.
11.
12.
13.
14.
15.
16.

endocrine disease or other disorder which would impact on


the safety evaluations.
Current or previous history of cancer (with the exception of
squamous cell and basal cell carcinomas) within 5 years.
Lack of appropriate periodontal defects.
Unacceptable oral hygiene habits.
Grade II or greater mobility of teeth.
Endodontic involvement of study teeth.
Smoking or other use of tobacco products.
Alcohol or drug abuse as defined by criteria in Diagnostic
and Statistical Manual of Mental Disorders (DSM) III-R.
Subjects' inability or unwillingness to give informed consent.
History of juvenile or rapidly progressive Periodontitis.
Patients who have received an investigational drug or participated in a research study within 30 days prior to the first
application of study medication.

and recorded in sealed envelopes, which


the investigators at the time of surgery.

were

opened by

Therapy
Each subject possessed matching contralateral interproximal angular and/or Class II furcation bone defects. All
participants received full-mouth scaling and root planing
and oral hygiene instructions prior to drug delivery. A

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J Periodontol
December 1997

PDGF AND IGF-I THERAPY FOR PERIODONTAL DISEASE

Safety assessment
(days 2, 7,14 & 28)

Scaling and root


planing; oral hygiene
instruction

Baseline

Soft tissue

assessements

assessments

Soft tissue and

radiographie

tissue re-entry
assessments for

assessments for

assessments; hard

and surgery

with drug

application

LD-PDGF/IGF-I

subjects

Figure
over a

1. Study timeline. The axis denotes


total of 10 months of observations.

treatment assessments

and procedures

paired or split-mouth design was utilized in which all patients were randomly assigned to receive in one treatment
quadrant a control therapy consisting of either periodontal
flap surgery alone or surgery plus 4% methylcellulose gel

vehicle.5 The other contralateral bone defect within the


mouth received either a single dose of [low dose (LD)]
50 g/ml each of rhPDGF-BB and rhIGF-I (LD-PDGF/
IGF-I) or 150 g/ml [high dose (HD)] each of rhPDGF
and rhIGF-I (HD-PDGF/IGF-I) per lesion. At baseline,
surgery was performed on all study teeth in each patient
at one visit. Full-thickness mucoperiosteal flaps were elevated, the teeth were scaled and root planed, and all
granulation tissue was removed under local infiltration anesthesia. The walls of the osseous defects were perforated
approximately 3 times with a V2 round dental bur. Intraoperative hard tissue measurements were made using an
occlusal stent and calibrated periodontal probe. Approximately 70 of study medication, vehicle, or scaling and
root planing alone was administered to the bone defects.
The tissues were sutured primarily with a polytetrafluoroethylene 4-0 suture material1 and positioned at the
level of the cemento-enamel junction (CEJ). The sites
were covered with periodontal dressing. All patients received penicillin VK (1 g per day for 7 days) and 0.12%
Chlorhexidine rinses (twice daily for a period of 8 weeks).
Oral hygiene assessment and supragingival scaling were
performed on days 28 and 42 and at 3, 4.5, 6, and 9
months.
Treatment and Safety Assessments
At baseline, and periodically thereafter, safety as well as
clinical and radiographie measurements were taken (Fig.
1). All assessments were made by a masked examiner
unaware of the treatment rendered. Safety assessments included comprehensive physical examinations within 2
weeks of dosing and on day 28. Laboratory examinations
included hematology, serum chemistries and urinalysis
(baseline and on days 2, 7, 14, and 28), pregnancy testing
(baseline), and serum antibody assays to monitor antibody
5Dow Chemical Co., Midland, MI.
"Institute of Molecular Biology, Inc., Worcester, MA.
'Gore-Tex, W.L. Gore and Associates, Inc., Flagstaff, AZ.

applied to subjects

Soft tissue and

radiographie

assessments; hard
tissue re-entry

HD-PDGF/IGF-I

subjects

in LD-PDGF/IGF-I and HD-PDGF/IGF-I groups

titers to the PDGF/IGF-I drug formulation (baseline versus day 42; Table 3). All adverse events were rated mild
to severe according to the World Health Organization
(WHO) scale.
Efficacy parameters included direct bone height and fill
measures obtained during the initial treatment surgery and
re-entry surgery 6 to 9 months later." The secondary efficacy outcome included relative attachment level change
(Table 4). Clinical bone and soft tissue measurements
were made from a custom-fabricated occlusal stent. To
assure accurate placement of the fixed reference point,
positioning of the stent was recorded at each time period
using a measurement from stent to CEJ. In order to further assure the accuracy of the bone height measurements,
a second surgical procedure was performed on all study
sites to allow direct visualization of the bone margin. The
clinical hard tissue assessments performed included the
eresiai bone height, defect bone height, and defect depth
using a UNC periodontal probe. The hard tissue measurements were taken at baseline and at 6 months for the
LD-PDGF/IGF-I subjects and at baseline and 9 months
for the HD-PDGF/IGF-I subjects.
Clinical soft tissue measurements included relative attachment level made from the stent using a manual probe,
and closed horizontal furcation probing depth (furcation
lesions) taken at 3, 6, and 9 months. All clinical measurements in this trial were obtained by a single masked

Table 3.

Safety Assessments

I. Standard medical and dental histories (baseline)


II. Standard physical examination (baseline and 4 weeks post-

drug delivery)
Laboratory examinations
A. Hematology (baseline and days 2, 7, 14, and 28)
B. Serum chemistries (baseline and days 2, 7, 14, and 28)
C. Urinalysis (baseline and days 2, 7, 14, and 28)
D. Plasma sample for antibody titers to PDGF-BB and IGFI (baseline and days 28 and 84)
E. Pregnancy test (baseline)
IV. Gingival inflammation (baseline and days 2, 7, 14, and 28)
V. Radiographs (baseline and month 6 [LD-PDGF/IGF-I! and
month 9 [HD-PDGF/IGF-I])
Baseline denotes within 3 days prior to initiation of study medIII.

ication

Volume 68
Number 12

HO WELL,

examiner who

agreement (i.e.

was

FIORELLINI, PAQUETTE, OFFENBACHER, GIANNOBILE, LYNCH

calibrated prior to the study for 95%


mm) for both soft and hard tissue

outcomes.

Statistical

Analysis

The study design considered patients with comparable


disease in two quadrants to have each quadrant (containing at least one eligible site) randomly assigned to the
study medication or one of the two control treatments. Up
to two sites per quadrant were studied. The responses of
sites in the same quadrant were averaged to provide one
measurement per quadrant. Thus, the statistical design
within each dose group (n
19) consisted of two splitmouth designs: LD-PDGF/IGF-I versus standard care
(surgery alone) and LD-PDGF/IGF-I versus standard care
plus vehicle, with a similar split-mouth design for the
HD-PDGF/IGF-I patients.
Comparisons between study drugs and controls were
made within subjects, utilizing the split-mouth aspect of
the design. Wilcoxon signed rank tests were used for
paired comparisons. The first comparison involved the determination of a therapeutic effect with the vehicle versus
surgery alone. Utilizing a Wilcoxon (rank sum) test, there
were no significant differences between vehicle and standard care with respect to the primary endpoints of bone
height. Consequently, the subsequent comparisons were
made between the combined control groups versus each
of the study drug groups. All 38 patients were used for
the safety-related analysis under the intent-to-treat principle; the 36 patients completing the trial were used in
=

efficacy analyses.
RESULTS

Safety
Analysis

of the safety data indicates that both the LDPDGF/IGF-I and HD-PDGF/IGF-I drug formulations
were well tolerated. There were no serious adverse events,
discontinuations, or deaths attributed to the drug or placebo. Additionally, there were no signs of uncontrollable
tissue formation, such as gingival hyperplasia. Two patients left the study prior to completion. One patient was
non-compliant with the study protocol and the other relocated from the study center.
The most frequently observed adverse events were associated with the periodontal surgery and included pain
or discomfort at the operative site, sensitivity, and edema.
There were 18 study drug-related adverse events with a
severity rating of mild (WHO classification). However,
pain following surgery was not unexpected and no measurable differences were ascertained between treatment
and control quadrants. These events included 15 reports
of postoperative pain or discomfort, two reports of soft
tissue dehiscence, and one report of a tooth abscess. Two
adverse events, rated with a moderate severity by the in-

1189

vestigators, were noted. A 39-year-old female subject presented with an abscess of a study tooth 8 months after
receiving a single administration of HD-PDGF/TGF-I. The
second event occurred after a patient had been discontinued for non-compliance and involved a hospitalization for
alcohol rehabilitation. It was felt that the events could
have been attributable to the study medication or may
have been of endodontic or gingival origin.
Treatment-emergent abnormal laboratory events were
reported for 5 patients and included elevated liver enzymes (SGOT and SGPT), lymphocytosis, and hematuria.
All abnormalities were considered mild (WHO classification) and were found at both baseline (prior to treatment) and 28-day timepoints (i.e., the patients entered
into the study with abnormal levels prior to therapy and
continued to display altered levels at one month). Antibody titers were determined on 37 patients. No patient
developed antibodies to rhPDGF-BB or rhIGF-I after exposure to the drug.

Efficacy

Patient assessment. Data from all LD-PDGF/IGF-I and


HD-PDGF/IGF-I-treated subjects were included in all
analyses, except as follows. In LD-PDGF/IGF-I subjects,
two patients were lost to follow-up for non-drug related
reasons; one patient was excluded from analysis because
of an occurrence of a gingival abscess after treatment.
Thus, there were a total of 42 sites from 16 patients evaluated (the control therapies were evenly distributed [8
surgery alone and 8 surgery plus placebo]).
Data from all 19 HD-PDGF/IGF-I-treated subjects
were evaluated, except for two patients who were lost to
follow-up for non-drug related reasons; one patient was
excluded from analysis because of an occurrence of a
gingival abscess 8 months after treatment; one patient
could not be measured for the hard tissue and relative
attachment level endpoints at baseline because the distance from the edge of the stent to the base of the lesion
was greater than the calibrated length of the periodontal
probe. There were a minimum of 14 valuable subjects
and 28 sites for all endpoints.
The demographics of the re-entry and relative attachment level parameters of the study teeth at baseline are
depicted in Tables 5 and 6. All data were entered into a
statistical analysis program from the case report forms.
Quality control was performed by independent verification of the entered data. Initial analysis revealed that the
data did not exhibit a normal distribution. Consequently,
data were analyzed for statistical differences by the nonparametric two-sided Wilcoxon signed rank test. Statistical analysis yielded no statistically significant differences
between the two control groups for any parameter (data
not shown). Consequently, comparisons were made between the test and combined surgery alone and surgery
plus placebo gel (control) groups.

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J Periodontol
December 1997

PDGF AND IGF-I THERAPY FOR PERIODONTAL DISEASE

Table 4.

Efficacy

Hard tissue endpoints. The principal efficacy endpoints were the hard tissue assessments measured during
re-entry surgery at 6 months in LD-PDGF/IGF-I subjects
and 9 months for HD-PDGF/IGF-I subjects. No significant differences between LD-PDGF/IGF-I-treated subjects and standard care or standard care plus vehicle could
be noted (Fig. 2A). The LD-PDGF/IGF-I subjects were
surgically re-entered prior to the high dose-treated subjects. The investigators noted that re-entry of the surgical
sites at 6 months may have been early and that the procedure was disturbing the newly regenerated tissue. Thus,
a decision was made to re-enter the remaining HD-PDGF/
IGF-I-treated patients at 9 months. At surgical re-entry at

Measurements

Clinical (re-entry) Hard Tissue Measurements


Defect depth
Defect bone height
Percent defect fill
Open horizontal furcation probing depth
Crestal bone height

Clinical Soft Tissue Assessments


Clinical attachment level
Horizontal furcation probing depth

Baseline Periodontal Lesion Distribution for Patients Treated with LD-PDGF/IGF-I

Table 5.

Angular (n

(Mean
Lesion
Hard tissue

Soft tissue

Mean vertical osseous de


feet depth (mm)
Mean horizontal osseous
defect depth (mm)
Relative attachment level

Furcation (n

8)
S.E.M.)*
=

(Mean

Control

LD-PDGF/
IGF-I

4.69 1.12

4.63 0.84

6.38

(mm)

0.31

8)
S.E.M.)
=

Control

LD-PDGF/
IGF-I

5.50 0.76

5.86 1.01

6.25 0.53

5.13 0.35

6.77 0.49

Closed horizontal furcation

probing depth (mm)


*Standard

error measurement.

Osseous Defect Fill

Linear Bone Height

60

3.6

50

3.0

40

2.4

(mm)

30

1.8

(%)

10

0.6

Angular

Furcation

Combined

Angular

Furcation

Combined

2. Periodontal bone response in patients treated with LD-PDGF/IGF-I by surgical re-entry at 6


months. Panel A shows linear bone height mean values (mm apposition S.E.M.) for pooled control (open
bars) or LD-PDGF/IGF-I-treated subjects (closed bars). There were no significant differences between treated and control groups. Panel shows the percentage of the original osseous defect filled with new bone
following treatment with either control therapy or LD-PDGF/IGF-I. No significant differences were found
between treatment and control defects (n=16).

Figure

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Number 12

HOWELL, FIORELLINI, PAQUETTE, OFFENBACHER, GIANNOBILE, LYNCH


Osseous Defect Fill

Linear Bone Height

60

3.6

50

3.0
I

(mm)

1191

30

1.8

(%)

1.2

0.6

Angular

Furcation

Combined

Angular

Furcation

Combined

3. Periodontal bone regeneration in patients treated with HD-PDGF/IGF-I by surgical re-entry at


9 months. Panel A shows linear bone height mean values (mm apposition S.E.M.) for pooled control
(open bars) or HD-PDGF/IGF-I (closed bars). Statistically significant differences in furcation lesions compared to paired controls as well as in combined furcation and angular lesions versus pooled control groups
(P < 0.05). Panel shows the percentage of the original osseous defect filled with new bone following
treatment with either control therapy or HD-PDGF/IGF-I. Statistically significant differences were found in
the percentage of the original osseous defect filled with new alveolar bone (P < 0.05);
16.

Figure

9 months in the HD-PDGF/IGF-I-treated subjects, the


mean new bone height (i.e., the change in bone height
from baseline to month 9) was 0.75 mm (0.28; S.E.M.)
in the control group and 2.08 mm (0.40; S.E.M.) in the
HD-PDGF/IGF-I group (P < 0.05; Fig. 3A).
Because the absolute height of new bone does not necessarily reflect the degree to which the original osseous
lesion was healed, the percentage of osseous defect fill
was also calculated. There was again no significant differences found in defect fill in the LD-PDGF/IGF-I subjects (Fig. 2B). However, in HD-PDGF/IGF-I subjects,
control defects resulted in 18.5 7% (mean S.E.M.)
bone fill, while defects in patients treated with HD-PDGF/
IGF-I resulted in 42.3 9% bone fill. Similar to new
bone height measures, furcation lesions responded most

favorably (Fig. 3B).


Soft tissue assessments. Relative attachment level
(from occlusal Stents) measurements were obtained at 3,
6, and 9 months (HD-PDGF/IGF-I subjects) using calibrated UNC manual probes. Data on the reduction of horizontal furcation probing depths are shown in Tables 7

and 8. Gains in attachment level were found for both test


and control groups following periodontal surgery. However, for both LD-PDGF/IGF-I and HD-PDGF/IGF-Itreated subjects, no statistically significant differences
were found between treatment and controls at any time
point. Trends of effect were found for both horizontal
furcation probing depth and relative attachment level in
the HD-PDGF/IGF-I-treated subjects.

DISCUSSION
This Phase I/II clinical trial was the first human study to
evaluate the effects of purified recombinant proteins on

periodontal regeneration. Its principal objective was to establish the safety of the growth factors; the secondary
objective was to begin to accrue data on the biological
effects of the drug with respect to efficacy. Further, it was
hoped that some information might be obtained in regard
to: 1) dosing; 2) identification of a subpopulation of periodontal lesions which represented the highest responders;
and 3) identification of the most appropriate endpoints.
The aforementioned objectives were accomplished.
Most importantly, there were no safety issues which resulted from the use of the drug. Additionally, data demonstrating the biological activity of the product were obtained in the HD-PDGF/IGF-I group at surgical re-entry.
Significantly greater bone formation occurred in osseous

defects treated with HD-PDGF/IGF-I than in sites receiving full-thickness flap reflection and thorough debridement. These results appeared consistent with the findings
in preclinical dog and non-human primate studies. When
this growth factor combination was used to treat natural
periodontal osseous defects in beagle dogs, substantial
amounts of new bone and cementum were seen within 2
weeks following a single application.4 Normal maturation
of the bone continued for 3 to 6 months following treatment. A functionally oriented periodontal ligament was
present connecting the new bone to the tooth root surface.
Further, ligature-induced periodontal osseous defects in

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PDGF AND IGF-I THERAPY FOR PERIODONTAL DISEASE

treated in this

study with HD-PDGF/IGF-I responded


and
robustly
consistently to the drug. The small
in
this
sample size
study, however, does not allow for
conclusive evidence for this effect in all patients.
Future expanded studies utilizing the information
gained from this trial evaluating the continued safety and
efficacy of PDGF/IGF-I therapy to patients with periodontal disease are warranted. Higher doses may reveal
improved efficacy and give insight into the scope of this
unique therapy to the field of periodontology. This first
study in man not only produced encouraging safety and
biological activity data, but also provided information essential to the refinement of future protocols.
The use of PDGF alone or in combination with IGF-I
may also have many other applications as a stimulus for
bone wound healing. Several preclinical animal studies
have demonstrated potent increases in Osteogenesis in
bone defect models and in the treatment of osteoporosis.317 More recently, systemically administered PDGF
has been demonstrated to increase bone density (by Dexa

treated with 150 g/ml each of rhPDGF and


demonstrated
42.5% defect fill, while placebo
rhIGF-I
gel-treated sites showed only 14.5% bone fill measured
by histomorphometry.612 The values reported here for
HD-PDGF/IGF-I (Fig. 3) represent the high degree of
consistency between the human and non-human primate
model in response to PDGF/IGF-I-mediated periodontal

monkeys

most

regenerative therapy.

The selection of osseous defects for future studies may

rely on the distribution of the response of defect morphology to treatment. This study shows, as other regenerative trials have demonstrated, that interproximal defects respond more favorably to conventional methods
than furcations.13-15 Osseous fill was found to be variably
increased in angular lesions with or without treatment,
while new bone fill was consistently low or non-existent
in furcation lesions treated by control therapy. Extensive
furcation lesions may represent "critical size" defects
which fail to respond to conventional periodontal debridement and flap surgery.16 By contrast, furcation lesions

Baseline Periodontal Lesion Distribution for Patients Treated with HD-PDGF/IGF-I

Table 6.

Angular (n

(Mean

Soft tissue

Mean vertical osseous de


feet depth (mm)
Mean horizontal osseous
defect depth (mm)
Relative attachment level

HD-PDGF/
IGF-I

4.18 0.36

4.25 0.38

6.41 0.47

(mm)

Furcation

11)
S.E.M.)*

Control

Lesion
Hard tissue

(Mean

(n 5)
S.E.M.)
=

Control

HD-PDGF/
IGF-I

5.40 0.93

5.20 0.58

6.17 2.17

5.67 0.

6.63 0.50

Closed horizontal furcation

probing depth (mm)


*Standard

error measurement.

Table 7.

Soft Tissue

Responses

to HD-PDGF/IGF-I

Therapy

in Patients at

3, 6, and 9 Months

Horizontal

Probing Depth

Time

(months)

Reduction

Group
Control
PDGF/IGF-I
Control
PDGF/IGF-I
Control
PDGF/IGF-I

Numbers
Table 8.

are means

standard

Soft Tissue

error

(mm)

0.50 0.29
2.33
0.33
0.50
0.76
3.00
0.00
1.30
1.40
2.00
1.14

Value
NS

NS
NS

Relative Attachment
Level Gain (mm)

0.50
1.40
1.03
1.77
1.98
1.52

0.52
0.64
0.56
0.62
0.49
0.62

Value
NS
NS
NS

measurement.

Responses to LD-PDGF/IGF-I Therapy

in Patients at 3 and 6 Months

Horizontal
Time

(months)

Probing Depth

Reduction (mm)

Group
Control
PDGF/IGF-I
Control
PDGF/IGF-I

Numbers

are means

standard

2.33
1.67
2.38
0.69

0.62
0.72
0.71
1.21

error measurement.

Value
NS
NS

Relative Attachment
Level Increase (mm)

1.07 0.47
1.40 0.64
1.22 0.56
1.77 0.62

Value
NS
NS

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HOWELL, FIORELLINI, PAQUETTE, OFFENBACHER, GIANNOBILE, LYNCH

and histomorphometry) and strength in ovarectomized animals.18 Expanded human clinical trials appear
warranted to assess the effects of growth factor-mediated
therapy on the repair of orthotopic tissues.

scanning

1193

like

growth factors on periodontal wound healing. J Periodontol


1991;62:458-467.
6. Giannobile WV, Hernandez RA, Finkelman RD, et al. Comparative
effects of platelet-derived growth factor, insulin-like growth factor,

individually and in combination on periodontal regeneration in Mafascicularis. J Periodont Res 1996;31:301-312.


Rutherford RB, Niekrash CE, Kennedy JE, Charette MF. Plateletderived and insulin-like growth factors stimulate regeneration of
periodontal attachment in monkeys. J Periodont Res 1992;27:285caca

Conclusion
The results from this Phase I/II human clinical trial show
that: 1) the product is safe when applied topically to periodontal osseous lesions during periodontal surgery; and
2) a single application of the HD-PDGF/IGF-I is effective, resulting in a significant improvement in bone
growth and fill of periodontal defects compared to the
current standard practice (with or without placebo gel).
Moreover, the results of this trial make possible additional
refinements to future protocols.

7.

290.
8. Park JB, Matsuura M, Han KY, et al. Periodontal regeneration in
Class III furcation defects of beagle dogs using guided tissue regenerative therapy with platelet-derived growth factor. J Periodontol

1995;66:462-477.

9. Le H, Silness J. Periodontal disease in pregnancy I. Prevalence and


severity. Acta dontl Scand 1963;21:533-551.
10. Silness J, Le H. Periodontal disease in pregnancy II. Correlation
between oral hygiene and periodontal condition. Acta dontl Scand

1964;22:121-135.
11.

Acknowledgments
This investigation was approved by

the Harvard Medical


School Human Studies Committee and the University of
North Carolina-Chapel Hill School of Dentistry. This
study was funded in part by NIDR grants K16 DE00275
and 5T32 DE07010 and by a grant from the Institute of
Molecular Biology, Inc. This paper is dedicated to the
memory of Professor Harry N. Antoniades (1923-1995).

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Send reprint requests to: Dr. T. Howard Howell, Department of Periodontology, Harvard School of Dental Medicine, 188 Longwood Avenue,

Boston, MA 02115-5888. Fax: 617/432-4262.


for publication April 25, 1997.

Accepted