Evidence Table C7. Intra-urethral Suppositories

Author
Funding
N; study design; eligibilityParticipants characteristicsDiagnosis detailsInterventionOutcomes
Ekman, P (2000) 203


Funding source:
Astra Lakemedel AB
N screened = NR
N randomized = 166

IG1, n = 83
IG2, n = 83
CG, n = NA

Intention to Treat (ITT) analysis: yes

Inclusion: men 18 y or older, with ED

Exclusion: hypersensitivity to alprostadil (MUSE), abnormal penile anatomy, acute or chronic urethritis or indwelling catheter, penile implant, untreated hypogonadism, testosterone substitution for < 3 mo, known risk of priapism, concomitant tx with appetite suppressants or anticoagulants, partner planning to become or already pregnant. Also concomitant dx (poorly controlled diabetes, hypertension, unstable angina, heart failure, severe vascular dx, severe neurological or psychiatric dx)
Age, mean (sd):
60 (10) y

Race: 100% Caucasian

Co-morbidities: NR

Previous ED treatment: NR

Smoking status: NR

Body weight, mean (sd): 86 (12) kg
Concomitant medications: NR

Duration of ED: 41 (31) mo

Underlying disease, (%): > 1 cause:
Vascular 47 vs. 43 neurogenic 18 vs. 17
Diabetes 21 vs. 21 hormonal 0 vs. 4
Psychogenic 12 vs. 7
Unknown 27 vs. 27
Other 22 vs. 17

Psychogenic ED: NA

Physiologic ED: NA

Mixed ED: NA

Other: capable of partial erection mean (%)= 78 (76 vs. 81)
IG1: PgE1 alprostadil (MUSE) (optional pubic band)
IG2: PgE1 alprostadil (MUSE), (optional pubic band)

IG1:
Dose: starting dose of 250 μg (clinic), titrated up to 250,500,1000 μg or down to 125 μg after 4 wks at 4 wk intervals (home application)
Duration: 12 wks
Frequency: at least 4 applications/ 4 wk
Compliance: NR

IG2:
Dose: as IG1, starting dose of 500 μg (titration regiment as IG1)
Duration: 12 wks
Frequency: as IG1

Run In period: NR
Wash out period: NR

F/u duration: NR
Primary outcomes (EF):
Quality of erection reported for both IG1 & IG2 combined:
Grade 4/5 at least once, n (%): 122 (73); these pts all reported coitus
Grade below 4, n (%): 44 (27)
IIEF (Q1–5 & 15), mean change in score (%):
Q1= 1.8 (100); Q2= Q3=1.7 (100); Q4=1.9 (146); Q5=1.9 (136); Q15=1.2 (136) all sign. p <0.001
Final dose (% of total n=142): 125 μg - 1%; 250 μg - 6%; 500 μg - 18%; 1000 μg - 75%
Sexual intercourse at least once: 113 (68%)

Other outcomes assessed: NA

Withdrawals/drop-outs/loss to f/u: 24 (included 1 due to depression, and 3 unknown

WDAE: 9 (5%) penile pain, hypotension)
TAE: NR
AE, n (%): Pain 50 (30%) with 4 (2%) rated severe; Hypotension, dizziness: (no detail reported)
SAE: 0

Ascertainment of outcomes assessed: Pts filled personal diary; IIEF; Erection Assessment Scale (EAS)
Lazzeri (1994) 204


Funding source: NR
N screened = NR
N randomized = 20 (parallel design)

IG1, n = 5
IG2, n = 5
IG3, n = 5
CG, n = 5

ITT analysis used for primary outcome: NR

Inclusion: ED

Exclusion: NR
Age, mean (SE): 55.4 (5) y

Co-morbidities: NR

Previous ED treatment: NR

Smoking status: NR

Body weight: NR
Concomitant medications: NR

Duration of ED: NR

Underlying disease: NR

Psychogenic ED: 20

Physiologic ED: 0

Mixed ED: 0
IG1: capsaicin IU
IG2: papaverine IC
IG3: papaverine IC + capsaicin IU
CG: placebo IU

IG1:
Dose: capsaicin
10–5 M
Duration: NR (injection length= 2 min)
Frequency: 1 dose

IG2:
Dose: 8 mg
Duration: as IG1
Frequency: 1 dose

IG3:
Dose: 8 mg + capsaicin 10–5 M
Duration: as IG1
Frequency: 1 dose

CG:
Dose: saline
Duration: as IG1
Frequency: 1 dose

Compliance all grps: NR

Run In period: NR
Wash out period: NA

F/u duration: NR
Primary outcome results:
No response was reported for all variables with placebo, results for IG1 vs. IG2 vs. IG3:

Penile diameter, Mean (sd) maximal ▴:
2.9 (0.93) vs. 3.7 (1.1) vs. 3.8 (0.96)

Rigidity, mean maximal (%):
43 (12) vs. 63 (10) vs. 74 (16)

Mean latency (seconds)
219 (44) vs. 198 (10) vs. 107 (29)

Mean duration (seconds)
322 (58) vs. 248 (39) vs. 390 (48)

Other outcomes assessed: NR

Withdrawals/drop-outs/loss to f/u: 0

WDAE: 0
TAE: NR
SAE: NR

Ascertainment of outcomes assessed: RigiScan™ Rigidity Assessment System
Padma-Nathan (1997) 205
Companions 206 208


Funding source: Vivus Inc.
N screened = NR
N randomized, phase I- clinic test = 1511 (at clinic test with alprostadil)
N randomized - Phase II-home tx= 996 (responders to alprostadil test)

IG, n = 485
CG, n = 511

ITT analysis used for primary outcome: no

Inclusion: men with chronic ED without spontaneous erection sufficient for intercourse within past 3 mo; response = 4 or 5 to initial dose response test (125 –1000 μg alprostadil)

Exclusion: hx of urethral stricture or obstruction, indwelling urethral catheter, penile implant or prior penile surgery, sickle cell dx, paraplegia or quadriplegia, congestive heart failure, unstable angina, or recent acute MI; poorly controlled DM (complete list could be found in original study)
Age, mean (range):
62 (38–84) vs. 61 (30–83) y

Co-morbidities: NR

Previous ED treatment: 52% vs. 57%

Smoking status: NR

Body weight: NR
Concomitant medications: NR

Duration of ED:
51 (3–528) mo

Underlying disease:
Vascular disease: 29% v. 28%
Diabetes: 19 vs. 19
Surgery or trauma: 32% vs. 31%
Other: 21% vs. 21%

Psychogenic ED: NA

Physiologic ED: 100% primary organic ED

Mixed ED: NA

Other: capable of partial erection (% of men): 63.3% vs. 60.9%
IG: alprostadil home tx
CG: placebo home tx

IG1:
Dose:
125 μg (n=116, 12%),
250 μg (n=171, 17%),
500 μg (n=302, 30%),
1000 μg (n=407, 41%)
Duration: 3 mo
Frequency: NR
Compliance: NR

CG:
Dose: same as IG
Duration: 3 mo
Frequency: NR
Compliance: NR

Run In period: NR
Wash out period: NR

F/u duration: 3 mo
Other: 88% of IG rated the transurethral application of alprostadil as neutral
Primary outcome results:
IG (n=411) vs. CG (n=500), % of successful tx

Intercourse: 50 vs. 10
Intercourse/orgasm: 56 vs. 15
Intercourse/orgasm/10-min erection sufficient for intercourse: 57 vs. 15

Other outcomes assessed: 88% of IG rated the transurethral MUSE neutral, comfortable or very comfortable

Withdrawals/drop-outs/loss to f/u: n=123 (12)

WDAE, n (%): 15 (2)
TAE, n (%):
Penile pain: 159 (33) vs. 17 (3); also in 11% of administrations of alprostadil
Minor urethral trauma: 25 (5) vs. 5 (1)
Urinary tract infection: 1 (0.2) vs. 3 (0.6)
Priapism-prolonged erection: 0 vs. 0
Penile fibrosis: 0 vs. 0
Dizziness: 9 (2) vs. 1 (0.2)
Hypotension (dose response observed):0 v. 1 (0.2)
SAE: NR

Ascertainment of outcomes assessed: EAS (1= no response to 5= full rigidity); comfort by self assessment
Peterson (1998) 209


Funding source: VIVUS Inc.
N screened = NR
N randomized = 234 (CCT- crossover design)

IG1/IG2/IG3/ CG, n = 234

ITT analysis used for primary outcome: NR

Inclusion: men with ED 3 mo before enrolment, in stable relationship, who tolerated, and had a measurable response to 500 μg alprostadil in clinic

Exclusion: Waking or early-morning erections sufficient for vaginal penetration within past 3 mo; hx of urethral stricture or obstruction; penile implant; indwelling urethral catheter or penile surgery; sickle cell dx; paraplegia or quadriplegia; uncontrolled congestive heart failure; unstable angina or acute MI within in 3 mo; poorly controlled DM; use of investigational tx other than IC injections within 2 mo of study entry; hx of epilepsy; active vasculitis; life expectancy < 6 mo; morbid obesity
Age, mean SD): 60 (10), range 26.8–81.5 y

Co-morbidities: NR

Previous ED treatment, n (%): None 94 (40), counselling 22 (10), hormonal tx 44 (18.8), IC 78 (33), band therapy 10 (4), vacuum pump 43 (18), other 6 (3)

Smoking status NR

Body weight: NR

Other: Acute onset 67 (29), gradual onset 167 (71)
Concomitant medications: Testosterone replacement therapy and concomitant medications for unrelated conditions continued at stable dose throughout study

Duration of ED: 4, range 0.25–30

Underlying disease: Vascular 92 (39), diabetes 42 (18), surgery/trauma 58 (25), other 42 (18)

Psychogenic ED: NR

Physiologic ED: NR

Mixed ED: NR
IG1: MUSE
IG2: prazosin hydrochloride
IG3: MUSE+prazosin (ratios 1:1, 1:2 and 1:4)
CG: placebo

IG1:
Dose: 125, 250, 500 or 1000 μg
Duration: 2–4 wks
Frequency: 2 doses
IG2:
Dose: 250, 500, 1000 or 2000 μg
Duration: 2–4 wks
Frequency: 2 doses

IG3:
Dose: 1 of 9 combinations
Duration: 2–4 wks
Frequency: 2 doses

CG:
Dose: placebo
Duration: 2–4 wks
Frequency: 1 dose
Compliance all: NR

Run In period: NA
Wash out period: at least 2 wks
F/u duration: 7, -60 min after dosing
Primary outcome (EF):
Grade 3 or higher, (%): 52 vs. 13 vs. 59 vs. 3
Grade 4 or 5, (%): 31 vs. 3 vs. 36 vs. 0.4
Median visual analogue scale (1–100), range: 37–50 vs. 8–22 vs. 42–60 vs. 4

Other outcomes assessed: pts comfort with

Withdrawals/drop-outs/loss to f/u: 17

WDAE: 2
TAE: NR
AEs, % (range) of total doses:
penile pain or discomfort: 17–24 vs.1–6 vs. 17–32 vs. 2
testicular pain: 2–4 vs. 0–1 vs. 2–7 vs. 0.4
urethral pain: 1–9 vs. 0–2 vs. 2–14 vs. 2
dizziness 0–6 vs.0–1 vs. 0–12 vs. 0; hypotension: 1–4 (dose response for MUSE)vs. 0–2 vs. 0–14% vs. 0
prolonged erections, 4–6 hr, n (%): 2 (1)
minor urethral bleeding, n (%): 12 (5)
SAE: 0

Ascertainment of outcomes assessed: erection grading system (0–5)
Shabsigh (2000) 210


Funding source:
Schwarz Pharmaceuticals AL
N screened = NR
N randomized = 111 (two phase cross over study, Phase I: office dose titration; phase II: at home treatment)

IG1/IG2, n = 111
CG, n = NA

ITT analysis used for primary outcome: yes (Phase I, n= 95; Phase II, n= 68)

Inclusion: ED at least 6 mo, stable heterosexual relationship

Exclusion: pts with past IC or IU tx, chemotherapy, other meds that might produce bleeding or bruising after drug administration, monoamine oxidase inhibitors up to 2 wk before enrolment, \concomitant medication for ED or oral alpha-adrenergic receptor blocking agents, had ED due to urologic abnormality, penile fibrosis or untreated endocrine disorder (hypogonadism) or systolic BP < 100 mm Hg
Age, mean (sd):
59.2 (10.6) y, range 30–79 y

Co-morbidities: NR

Previous ED treatment: NR

Smoking status: NR

Body weight: NR

Other: Blood pressure, mean (sd):
Systolic: 139(15) mm Hg
Diastolic: 83 (8) mm Hg
Heart rate: 73 (10) beats per minute
Concomitant medications: NR

Duration of ED, mean (sd): 5 (4) y
Underlying disease: NR

Psychogenic ED: NR

Physiologic ED: NR

Mixed ED: NR
IG1: IC injection of alprostadil (EDEX)
IG2: IU injection of alprostadil (MUSE) with option of ACTIS

IG1:
Dose: mean optimal dose = 27.3 μg (up to 40 μg, also most frequently used dose)
Duration: phase I=1–14 d; phase II=21 d
Frequency: phase II=max of 9 IU/ 21 d administrations in 21 d
Compliance: NR

IG2:
Dose: optimal dose = 921 μg (up to 1000 μg, 33% of all administrations)
Duration: as IG1
Frequency: as IG1
Compliance: NR

Run In period: 1 to 14 d
Wash out period: NR

F/u duration: 3 wk off treatment
Primary outcome results:
IG1 vs. IG2
Grade ≥ 3, n (%):
By physician: 59 (62) vs. 19 (20)
Patient assessment: 63 (66) vs. 25 (26)
Positive buckling tests (1 kg), n (%): 58 (61) vs. 20 (21)
Erection sufficient for intercourse, (%): 82 vs. 47
Satisfaction rating mean: 6 vs. 3
IIEF score, baseline all vs. IG1 vs. IG2, mean (sd):
EF Q1–5, 15: 9 (6) vs. 25 (7) vs. 17 (9)
Intercourse satisfaction Q6–8: 5 (4) vs. 11 (3) vs. 8 (4)

Other outcomes assessed: NA

Withdrawals/drop-outs/loss to f/u, n: 43 (phase I, 16; phase II, 27)

WDAE: NR
TAE: pts with at least 1 AE [phase I]; [phase II], (%): [31 vs. 56], [53 vs. 58]
Application site reaction: [4 vs. 16], [2 vs. 10]
Other penile pain: [20 vs. 30], [34 vs. 25]
Prolonged erection: [2 vs. 0], [3 vs. 0]
SAE: 0

Ascertainment of outcomes assessed: IIEF (Q1–5, 15; and Q9, 10; and Q6–8; and Q13, 14), Buckling test; grading system 0–3
Shokeir (1999) 211


Funding source: NR
N screened = NR
N randomized = 60 (parallel design)

IG1, n = 30
IG2, n = 30
CG = NA

ITT analysis used for primary outcome: NR

Inclusion: men 18 y or older, with ED of primarily organic aetiology, inability to achieve erection sufficient for intercourse at least 1 time during 3 mo before study period

Exclusion: previous use of IC injections

Data reported as IG1 vs. IG
Age, mean (sd):
55 (18) vs. 56 (17) y

Co-morbidities: NR

Previous ED treatment, n (%): 16 (53) vs. 17 (57); vacuum pumps, band therapy, hormones

Smoking status: NR

Body weight: NR
Concomitant medications: NR

Duration of ED, mean (sd): 36 (8) vs. 38 (10)

Underlying disease, n (%):
Vascular disease: 9 (30) vs. 6 (20); diabetes: 15 (50) vs. 18 (60); surgery/ trauma: 3 (10) vs. 3 (10); other causes 3 (10) vs. 3 (10)

Psychogenic ED: NR

Physiologic ED: NR

Mixed ED: NR
IG1: IC PgE1(injection)
IG2: IU MUSE

IG1:
Dose: 20 μg
Duration: 3 mo
Frequency: at least 1/wk
Compliance: 33%

IG2:
Dose: 1 mg
Duration: 3 mo
Frequency: at least 1/wk
Compliance: 83%

Run In period: NR
Wash out period: NR

F/u duration: 3 mo
Primary outcome results:
IG1 vs. IG2
Erection score of 4 and 5 in clinic, n (%): 27 (90) vs. 18 (60)

Sexual intercourse (at least once) at home: 26 (87) vs. 16 (53)

Other outcomes assessed: Ease of treatment

Withdrawals/drop-outs/loss to f/u: n = 25, IG1 n=20 vs. IG2 n=5

WDAE, n: 9 (due to pain) vs. 0
IG1:
IG2: 0
TAE, n (%):
All AE, Urogenital pain 14 (47) vs. 2 (7); dizziness 0 vs. 2; urethral bleeding 0 vs. 1
SAE: 0

Ascertainment of outcomes assessed: Personal diaries, Erection Assessment Scale 0–5
Williams (1998) 212


Funding source: Grant from VIVUS Inc. Manufacturer of MUSE (Alprostadil (PGE1) in transurethral route)
N screened = 249
N randomized = 159 (64% of screened pts who achieved erection adequate for intercourse on test dose)

IG, n = 78
CG, n = 81

ITT analysis used for primary outcome: ITT efficacy 44%

Inclusion: men 18 y or older with primary organic ED 3 mo or longer in duration, inability to achieve erection for intercourse on all attempts for 3 mo before study, stable, heterosexual, monogamous relationship, willing to have intercourse 4/mo + use contraception

Exclusion: NR

Data reported for IG vs. CG
Age, mean (range):
57.3 (25–78) y vs. 57.3 (26–77) y

Co-morbidities: NR

Previous ED treatment, (%):
51 vs. 54 (constrictive bands, IC, vacuum, counseling)

Smoking status:
NR

Body weight: NR
Concomitant medications: NR

Duration of ED, mean (range):
59.6 (3–644) vs. 63.3 (4–417) mo

Underlying disease: NR

Psychogenic ED: NR

Physiologic ED:
Vascular disease: 33% vs. 41%
Diabetes 18% vs. 15%
Surgery/trauma: 24% vs. 21%
Other organic (includes; alcohol or tobacco use; neurological diseases; medication adverse reaction): 24% vs. 24%

Mixed ED: NR
IG1: Alprostadil (PgE1) transuretrhal pellet as per protocol
CG: Placebo

IG1:
Dose: Escalating dose of 125, 250, 500 or 1000 μg
Duration: 3 mo
Frequency: at least 1/mo
Compliance: 53 (68%)

CG:
Dose: Placebo
Duration: 3 mo
Frequency: as IG 1/mo
Compliance: 64 (79%)

Run In period: 3 mo
Wash out period: NA

F/u duration:
3 mo

Other: Final patient selected dose distribution (μg), n (%):
1000 μg =103 (65%)
500 μg= 27 (17%)
250 μg =21 (13%)
125 μg =5 (5%)
Primary outcome results:
EAS, score ≥ 4: in all pts, 159 (64%)
Intercourse ≥ once during 3 mo, n (%): 46(69) vs. 8/73 (11%), p<0.001
Intercourse/ total injections: 390/ 763 (51) vs. 46/611 (7.5) CG

Other outcomes assessed: NA

Withdrawals/drop-outs/loss to f/u, n (%): 42 (26%) [n=25 vs. n=17]

WDAE: 4
TAE: self reported AEs, n (%):
Urogenital pain/ burning: 5 (6) vs. 0
Penile pain: 4 (5) vs. 1 (1)
Testicular pain: 2 (3) vs. 0
Urethral bleeding/spotting: 1 (1) vs. 1 (1)
Urinary tract infection: 0 vs. 0
Prolonged erection < 5 hr: 1 (1) two events vs. 0
Priapism (≥ 6 hr)= firbrosis= hypotension: 0 vs. 0
Dizziness: 2 (3) vs. 0
SAE: 0

Ascertainment of outcomes assessed: Erectile Assessment Scale (1=no response to 5=rigid erection) Comfort with therapy, intercourse rate, and AE by diary/self report

List of abbreviations: %=percent, ▴=increased, ▾=decreased, AE=adverse event, SAE=serious adverse event, BMI=body mass index, CC=controlled clinical trials, CG=comparator/control group, ctrls=controls, DM=diabetes mellitus, E1 IC=intracavernosal injection, ECG=electrocardiograms, ED=erectile dysfunction, EDV=end-diastolic velocity, f/u=follow-up, FMD=flow mediated dilation, GAQ=global assessment question, GEQ=global efficacy question, grp=group/s, HbA1C=haemoglobin, hr=hour(s), hx=history, IG=intervention group, IIEF= international index of erectile function (EF=erectile function, OF=orgasmic function, OS=overall satisfaction, SD=sexual desire), ITT=intent-to-treat (Y = yes, N = no, NR = not reported), IU=intraurethral, kg=kilograms, lbs=pounds, LUTS=lower urinary tract symptoms, M=male, max=maximum, mo=month(s), NA=not applicable, PADAM=partial androgen deficiency of the aging male, PgE1=Prostagladin, PRL=prolactin, PSA=prostate-specific antigen, RAU=rigidity activity unit, RCT=randomized control trial, SBP=systolic blood pressure, sign.=significant; TAE=total adverse events, TAU=tumescence activity unit, vs.=versus, WDAE=withdrawals resulting from adverse events, wk=week(s), yr=year(s).

From: Appendix C. Evidence Tables

Cover of Diagnosis and Treatment of Erectile Dysfunction
Diagnosis and Treatment of Erectile Dysfunction.
Evidence Reports/Technology Assessments, No. 171.
Tsertsvadze A, Yazdi F, Fink HA, et al.

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