to changes in penile blood flow caused by plaque
formation or psychological due to patient concern
with the malformation.
Historically various medical therapies have been
used to treat PD, including oral medication (vitamin
E, potassium aminobenzoate, tamoxifen, colchicine,
carnitine and pentoxifylline), injectable agents (col-
lagenase, interferon and verapamil), electromotive
therapy or iontophoresis and radiation therapy.
Limited clinical data show the efficacy of these ther-
Surgery is the standard of care for mod-
erate to severe cases of PD unresponsive to medical
therapy. However, surgery is only recommended for
patients with sexual dysfunction in the stable phase
of disease since complications include penile short-
ening, sensory change, recurrent penile curvature
and ED.
We present the results of a recent phase 2b study
to evaluate PD treatment with CCh (Xiaflex® or
Xiapex®). CCh is a purified mix of 2 collagenases
(AUX-I and II) that showed safety and efficacy in
patients with PD in early clinical studies.
early clinical program consisted of 5 studies of 299
subjects with PD over a wide dose range with
slightly different study end points, evaluation meth-
ods and study procedures that investigators used to
build to the design of the current phase 2b study.
CCh at a dose of 0.58 mg (10,000 U) per injection is
approved by the United States Food and Drug Admin-
istration, and the European Medicines Agency for Du-
puytren contracture, a collagen disorder of the hand.
To facilitate enzymatic cord disruption in these cases
CCh is injected directly into a palpable cord, followed
by a finger extension procedure intended to further
disrupt the cord that was weakened by the collage-
In the current phase 2b study we examined
the ability of CCh treatment to improve penile curva-
ture as well as its effect on a PD specific PD-PRO. We
also assessed the safety of penile injections of CCh.
Study Design
A phase 2b, randomized, double-blind, placebo controlled
study of CCh was done in subjects with PD from 12 Amer-
ican sites. Institutional review board approval was ob-
tained from all sites (central quorum and/or institutional).
Appendix 1 lists study inclusion and exclusion criteria. Ef-
ficacy and safety assessments for all subjects were recorded
during 36 weeks. All subjects were recruited by the investi-
gators and received a nominal fee to participate in the study.
Subjects were stratified by degree of penile curvature (30
to 60 or greater than 60 degrees) and randomized into 4
groups using the Interactive Web Response Services ran-
domization computer system, including CCh or placebo
(3:1) with or without penile plaque modeling (1:1). All
investigators were assigned in blinded fashion to active vs
placebo treatment using the Interactive Web Response
Services program and given drug kits that were visually
Each cycle consisted of 2 injections of CCh (0.58 mg or
10,000 U) or placebo with an interval of 24 to 72 hours
between the injections. This regimen was repeated after 6
weeks for up to 3 treatment cycles. A 26 or 27 gauge needle
was used to inject CCh or placebo directly into the primary
plaque at the point of maximal curvature. After the needle
was positioned properly in the plaque the study medica-
tion was injected as the needle was withdrawn to deposit
the drug along the needle track.
Between 24 and 72 hours after the second injection of
each treatment cycle, subjects randomized to modeling
underwent gradual, gentle stretching of the flaccid penis
in the opposite direction of the curvature. The physician
held the stretched position for 30 seconds, before allowing
the penis to return to the nonmodeled state for 30 seconds.
This procedure was repeated 3 times.
Efficacy and Safety Assessments
Penile length and plaque measurements were made on a
stretched, flaccid penis using a cm ruler or calipers. To
accurately measure penile curvature subjects were in-
jected with prostaglandin E1 to induce erection and the
angle was determined using a goniometer protractor. Ad-
ditional PD specific symptoms were assessed by the phy-
sician and documented as mild, moderate or severe.
The PD-PRO and IIEF were used to assess the impact
of PD on patient quality of life and erectile function. PD-
PRO questions were grouped into domains, including in-
tercourse discomfort and constraint, penile pain and PD
symptom bother. For the IIEF questionnaire patients re-
ported the domains of erectile and orgasmic function, sex-
ual desire, and intercourse and overall satisfaction.
Primary efficacy end points were the change and the
percent change from baseline to week 36 in penile curva-
ture and the change in total score for each PD-PRO do-
main. Safety analysis was based on the AE incidence, and
the change from baseline in laboratory values and vital
signs. AEs were considered treatment emergent when ob-
served at any time after the first dose of CCh. They were
considered treatment related when defined by the in-
vestigator as possibly or probably related to CCh treat-
ment. Immunogenicity was assessed with CCh antibody
Statistical Analysis
Power calculations were based on the percent reduction in
penile curvature and on the degree of interaction assumed
between the drug effect and the modeling effect. A sample
size of 120 subjects was determined to be sufficient to
measure the effect of the drug (CCh vs placebo) with a
power of at least 90%. The ITT population was defined as
all randomized subjects who received at least 1 injection of
study drug. The mITT population was defined as all ITT
subjects in whom at least 1 penile curvature measurement
was made after the first injection of study drug. Only 2
patients were excluded from the CCh without modeling
group according to these criteria.
The PD-PRO population was defined as all mITT sub-
jects who completed a PD-PRO response at baseline and