Methods

Double‐blind, placebo‐controlled parallel group trial followed by an open‐label extension for 8 weeks. Conducted prospectively from June 2008 to November 2012.

Participants

13 participants recruited from regional haematology and urology clinics randomised to sildenafil or placebo. Inclusion criteria were occurrences of at least two self‐reported priapism episodes per week and ability to provide written informed consent.

Exclusion criteria were estimated GFR < 50 mL/min, clinical cirrhosis, pulmonary hypertension based on echocardiography, alcohol use exceeding 2 standard drinks daily, formal contraindications for using phosphodiesterase type 5 inhibitor therapy.

Participant age: sildenafil (n = 6) mean (SD) age: 21.7 (5.3) years; placebo (n = 7) mean (SD) age: 23.0 (8.7) years.

Disease status: SCD (confirmed SS or SC haemoglobinopathy) and recurrent ischaemic priapism.

Hypertension no (%) placebo 1 (14.3%), sildenafil 2 (33.3%).

Stroke no (%) placebo 3 (42.9%), sildenafil 1 (16.7%).

Avascular necrosis no (%) placebo 1 (14.3%), sildenafil 0 (0).

Acute chest syndrome no (%) placebo 1 (14.3%), sildenafil 2 (33.3%).

Asthma no (%) placebo 2 (28.6%), sildenafil 2 (33.3%).

Smoker no (%) placebo 1 (14.3%), sildenafil 2 (33.3%).

Alcohol use no (%) placebo 3 (42.9%), sildenafil 3 (50%).

Interventions

Intervention: sildenafil 50 mg.

Placebo: sugar pill.

Either placebo or sildenafil was taken daily for 8 weeks. Participants were instructed to take the medication in the morning a few hours after awakening and without sexual stimulation.

An 8‐week open‐label phase followed.

Outcomes

Primary efficacy outcome was 50% reduction in frequency in priapism episodes bi‐weekly from baseline at the end of the 8‐week double‐blind phase.

Secondary outcomes included subjective improvements in episode frequency/duration and decrease in the number of of bi‐weekly episodes of priapism using a scoring system:

0 = no episodes;

1 = 1 to 2 episodes;

2 = 3 to 4 episodes;

3 = 5 to 8 episodes;

4 = 9 to 16 episodes;

5 = > 16 episodes.

Adverse effects were also recorded for the whole trial period including the open label phase.

Outcomes were measured via twice‐weekly nurse co‐ordinator phone calls to record progress, medication changes and adverse events.

In‐clinic evaluations were carried out at baseline, week four and week eight which included repeat administration of trial instruments.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Participats were randomised in a 1:1 allocation. Method of randomisation not described.

Allocation concealment (selection bias)

Unclear risk

Allocation concealment not described.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind trial where the participant, caregiver and investigator were blinded.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Double‐blind trial where the participant, caregiver and investigator were blinded.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants were included in the analysis. Both ITT and per protocol analyses were carried out.

No data were shown for decreased median weekly change in priapism episode score, just that there were no significant differences between groups.

Adverse effects were not listed in the methods section but were reported in the results. Adverse events were reported for the whole trial period including the open label phase (confirmed by author team).

Selective reporting (reporting bias)

Unclear risk

The publication states that there were no significant differences between groups for decreased median weekly change in priapism episode score but no data were shown. The same paper reported adverse effects in the published paper but did not include this as an outcome in either the methods section or in the trial registration document.

Other bias

Low risk

None identified.

Methods

Double‐blind, placebo controlled parallel group trial with four arms. The first phase of the trial was an observational phase lasting a minimum of three weeks and a maximum of 13 weeks to give a baseline before participants were randomised to intervention or placebo. The intervention phase ran for 26 weeks.

Participants

131 participants were enrolled onto the trial.

86 participants completed the observational phase of the trial.

78 participants were randomised to 1 of the 4 treatment arms.

Inclusion criteria: males aged 12 or over with confirmed sickle cell anaemia or sickle cell beta‐thalassaemia on haemoglobin electrophoresis and stuttering priapism.

Participants had to be in active attendance at a designated care centre (1 visit in last 6 months).

Participant characteristics were only reported for the complete group of 86 not specifically for the 46 randomised participants.

Age (participants who completed phase A n = 86): mean age was 23.6 (range 14.5 ‐ 46.1).

Median weekly number of attacks in phase A ‐ 1.5 (range 0 – 7).

Median weekly duration of attacks in phase A – 2.0h (range 0 – 42 h).

Number (%) of weekly attacks > 4h duration in phase A – 22 (26%).

Average attack pain score (mean (range)) in phase A – 3.4 (0 – 8.8).

Participants were excluded if there was a history of an attack lasting longer than 4 hours or who needed acute hospital. admission and intervention or history of cerebrovascular accident or hypertension.

Interventions

Group 1: participants received 15 mg ephedrine per day.

Group 2: participants received 30 mg ephedrine per day.

Group 3: participants received 50 mg etilefrine per day.

Group 4: participants received a placebo.

All treatments were taken once a day at bedtime for 6 months.

Outcomes

Weekly total number of attacks expressed as a ratio of phase B to phase A.

Mean difference in pain score from phase A to phase B.

Number of participants who had an attack lasting more than four hours.

Adverse events (palpitations, tachycardia, lack of sleep, hand shaking, anxiety, dry mouth) experienced during the trial period.

Participants were reviewed on a 6‐weekly basis when diaries were monitored and BP was taken.

Notes

None of the participants were on a chronic hypertransfusion program. One participant had been on hydroxyurea for 18 months prior to the trial.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of randomisation not stated.

Allocation concealment (selection bias)

Unclear risk

No description of allocation concealment.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Blinding of the trial drug was carried out by Bilcare Ltd clinical trial supplies although the authors do not state who was blinded and what methods were used. It is a double‐blind trial.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding of the trial drug was carried out by Bilcare Ltd clinical trial supplies although the authors do not state who was blinded and what methods were used. It is a double‐blind trial.

Incomplete outcome data (attrition bias)
All outcomes

High risk

86 participants completed the observational phase and of these, 59% entered the intervention phase.

78 participants were randomised to the intervention phase but data was only available for 46. The remainder were lost to follow‐up.

46 participants entered the intervention phase and 25 participants (54%) completed 26 weeks.

Selective reporting (reporting bias)

Low risk

No protocol available therefore outcomes reported in the results section against the methods section of the paper; no discrepancies found.

Other bias

Low risk

None identified.

Methods

Double‐blind, placebo‐controlled cross‐over trial, with two 14‐day treatment periods. Allocation concealment and method of randomisation was unclear.

Participants

11 males with stuttering priapism and homozygous sickle cell (SS) disease were randomised. 9 completed the trial, 1 participant defaulted after baseline and 1 participant had a painful crisis which aborted the priapism before any tablets were taken. Participants came from the sickle cell clinic of the University Hospital of the West Indies, Kingston, Jamaica.

Interventions

Stilboestrol 5 mg daily versus placebo.

Outcomes

Reduction in frequency of stuttering priapism. Return of priapism.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described.

Allocation concealment (selection bias)

Unclear risk

Not described.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Described as double blind.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not described if outcome assessors were blinded.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

1 participant defaulted, and in two participants the attacks of stuttering priapism ceased spontaneously during the baseline observation period. There was a fourth participant who initially did not take the placebo because a painful crisis aborted the stuttering priapism prior to taking the assigned tablet. In this participant (identified as patient 9) attacks of priapism recurred 2 weeks later and data on a second baseline period were collected.

The paper did not discuss an ITT analysis.

Selective reporting (reporting bias)

Low risk

No protocol available therefore outcomes reported in the results section against the methods section of the paper; no discrepancies found.

Other bias

Low risk

None identified.