Rationale and Design for the COCKTAIL Trial: A Single-center, Randomized, Double-blind, Sham-controlled Study Combining Shockwave Therapy and Platelet-rich Plasma for Erectile Dysfunction

1. Introduction

The development of erectile dysfunction (ED) therapeutics that focus on tissue regeneration and neovascularization is of great importance. Autologous platelet-rich plasma (PRP) and low-intensity shockwave therapy (SWT) are two promising restorative therapy approaches to treating the underlying causes of ED in men [1]. Preclinical research supports the angiogenic and regenerative properties of the therapies [2], suggesting that their combination could act in a synergistic manner. COCKTAIL is the first randomized controlled trial (RCT) to evaluate the safety and efficacy of this therapeutic combination. Success of our proposed work could fundamentally change the standards of care for ED and substantially improve the quality of life for tens of millions of men.

2. Study design

COCKTAIL is a phase 1 single-center clinical trial assessing the safety and efficacy of PRP and SWT administered in combination for men with mild to moderate ED (ClinicalTrials.gov; NCT05048667). Using a randomized, double-blind, placebo-controlled design, COCKTAIL examines whether a combination of two forms of restorative therapy is safe and efficacious for men with ED.

2.1. Study population

Sixty men aged between 30 and 80 yr with mild to moderate ED will be enrolled in the trial. ED severity is defined as an International Index of Erectile Function-Erectile Function (IIEF-EF) subdomain score of 12–25 at screening [3]. Use of phosphodiesterase 5 inhibitors (PDE5i) is permitted. The inclusion and exclusion criteria are summarized in Table 1. All individuals are required to provide informed consent before participating in the trial.

Table 1 –

Study eligibility criteria

Criteria	Rationale
Inclusion criteria
1. Male	The study disease only affects men
2. Aged 30–80 yr inclusive	Most men with ED will be within this age group
3. Be able to provide written informed consent	Requirement for research in human subjects
4. Diagnosis of mild to moderate (12–21) or mild (22–25) ED according to the IIEF-EF score	Preliminary data show better SWT efficacy in ED classed as mild or mild to moderate; ~65% of men with ED fit this definition
5. In a stable heterosexual relationship with a minimum of 2 sexual attempts per month for at least 1 mo before enrolment	The primary outcome is assessed using the IIEF score; the IIEF instrument is not validated in the MSM population
6. Agreement to comply with all study-related tests and procedures	Protocol compliance
Exclusion criteria
1. Previous penile surgery of any kind (except circumcision and condyloma removal), such as penile lengthening, penile cancer surgery, penile plication, grafting	Penile surgery can change the hemodynamic parameters of the penis and potentially affect transduction of shockwaves
2. History of priapism, penile fracture, Peyronie’s disease, or penile curvature that negatively influences sexual activity	These conditions suggest severe pathologic penile vasculature and corporal dysfunction
3. Abnormal morning serum testosterone, defined as <300 ng/dl (±5%)	Normal serum testosterone levels are necessary for adequate erectile function
4. Psychogenic ED as determined by the study investigator	Men with psychogenic ED may respond differently to men with ED of other etiologies
5. ICI for management of ED	ICI can lead to penile fibrosis, which could be a confounding factor for erectile function recovery
6. Generalized polyneuropathy, neurological conditions, or psychiatric disease (such as bipolar disorder or depression)	Could be a confounding factor for erectile function recovery.
7. Serious comorbid illness or condition that, in the opinion of the investigator, may compromise the safety or compliance of the subject or preclude successful completion of the study	Protocol compliance and minimization of attrition
8. History of consistent treatment failure with PDE5i for ED therapy	Could be a confounding factor for erectile function recovery.
9. Poorly controlled diabetes mellitus as indicated by hemoglobin A1c >9%	Poorly controlled diabetes is a risk factor for neurogenic and vascular ED and could be a confounding factor for erectile function recovery
10. Use of antiplatelet medication	Antiplatelet medication may affect platelet degranulation and release of cytokines

ED = erectile dysfunction; IIEF = International Index of Erectile Function questionnaire; ICI = intracavernous injection; MSM = men who have sex with men; PDE5i = phosphodiesterase type 5 inhibitor.

2.2. Intervention and comparator

Eligible participants are randomized to treatment or placebo (1:1 ratio). Therapy is administered over a 5-wk period (Fig. 1). Participants in the active treatment group undergo blood collection for autologous PRP preparation at baseline. Treatment in week 1 involves intracavernous injection of PRP and extracorporeal SWT. Participants return for three weekly SWT sessions in weeks 2–4, and then PRP and SWT are administered together in the final session in week 5. Participants in the control arm follow the same schedule but receive placebo (saline) injections and sham SWT in a manner similar to that for active therapy.

Fig. 1 –

Study timeline. After giving informed consent, subjects complete screening/baseline assessments and those who qualify are randomized 1:1 to receive active therapy or placebo/sham. Treatment visits occur weekly for 5 wk (Wk 1–Wk 5). Subjects are followed for up to 6 mo after therapy to assess primary and secondary study outcomes (safety and efficacy). IIEF = International Index of Erectile Function; PRP = platelet-rich plasma; SWT = shockwave therapy.

Autologous PRP is prepared from 120 ml of peripheral blood collected from each subject. Blood samples are processed using an autologous platelet separator with an optical sensor (Arthrex Angel; Arthrex, Naples, FL, USA). Approximately 2.5 ml of PRP is injected into the right and left corpus cavernosum (5 ml in total) in each session. To maintain the study blinding, participants in the control arm will have blood collected.

SWT is administered using a transducer (MoreNova; Direx Group, Canton, MA, USA) designed to deliver linear shockwaves to the left and right corpora cavernosa in the stretched flaccid state. The energy intensity is 0.09 mJ/mm² and the pulse frequency is 1 Hz. Participants randomized to sham SWT will follow the same treatment schedule with the device set to deliver 720 shocks with the same amount of energy, but a shield will be placed over the probe to prevent shockwaves from being transmitted to the penis.

The PRP and SWT sessions are performed in the outpatient setting and last approximately 60 and 20 min, respectively.

2.3. Primary and secondary outcomes

The primary outcome is the incidence of serious adverse events within 30 d of therapy (safety). All adverse events are recorded and classified according to the Common Terminology Criteria for Adverse Events [4].

Secondary outcomes include: (1) the change in IIEF-EF score from baseline to 3 and 6 mo after therapy; (2) the percentage of participants experiencing a minimum clinically important difference (MCID) in IIEF-EF from baseline to 3 and 6 mo after therapy (defined as an increase of 2 points for mild and 5 points for moderate ED on IIEF-EF [5]); and (3) the percentage of participants who decrease or discontinue their PDE5i use at 3 mo after therapy.

Long-term safety is an exploratory outcome for the study. On completion of the 6-mo trial, participants will be offered continuation of follow-up at 6-mo intervals for up to 2 yr to track adverse events.

2.4. Statistical considerations

We expect 15% of the placebo group and 50% of the intervention group to experience an MCID in erectile function. At 80% power and α = 0.05, 24 participants will be required in each arm to detect a difference of 35% between the arms. Assuming an attrition rate of approximately 20%, an additional six participant slots will be added to each group for a total sample size of 60 subjects.

To analyze between-group differences, Student’s t test or a Mann-Whitney U test will be used for continuous variables, and Fisher’s exact test for categorical variables.

3. Results and progress

The study protocol was reviewed and approved by the University of Miami institutional review board and is being monitored by a data and safety monitoring board. Results will be publicly available at ClinicalTrials.gov (NCT05048667) on completion of the trial.

4. Discussion

Restorative therapies are a particularly promising option for the treatment of ED because of their availability, proangiogenic properties, and perceived safety [6]. In the clinical setting, several studies have assessed the effects of SWT [7,8] and PRP [9,10] as monotherapy for men with ED. However, COCKTAIL is the first trial to evaluate the synergistic effects of these two restorative therapies in combination. If the trial shows a clear benefit of the combination, this could lead to a major shift in clinical approaches by treating the underlying causes of ED.

5. Conclusions

COCKTAIL will provide important insights into the potential therapeutic utility of PRP and SWT given in combination for patients with mild to moderate ED.