to changes in penile blood ﬂow caused by plaque

formation or psychological due to patient concern

with the malformation.

5,6

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-

apies.

2,7–9

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.

10–12

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.

13–16

This

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-

nase.

17,18

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.

MATERIALS AND METHODS

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.

Treatment

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

identical.

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

titers.

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

PHASE 2B STUDY OF COLLAGENASE CLOSTRIDIUM HISTOLYTICUM

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