This study protocol was prepared in accordance with the CONSORT (Consolidated Standards of Reporting Trials) Extension to Pilot and Feasibility Trials guidelines (43).
Study setting
This study is multicentered involving 6 sites consisting of healthcare centers, community clinics and academic hospitals in the United States of America.
Participants
Participation will be discussed to patients that meet the inclusion criteria. The patients will be given the opportunity to read an informed consent form (ICF) and get answers to all questions before considering participation at the enrollment/baseline visit. Trial participants will be men from ages 40 to 80 years old with moderate ED for at least 1 year and less than 10 years.
The other inclusion criteria are:
- A body mass index (BMI) of <35kg/m2
- ED for at least 1 year but less than 10 years and be unresponsive to PDE5i (phosphodiesterase type 5 inhibitors)
- Have a minimum International Index Erectile Function (IIEF-EF) domain score of 11-16 classifying them as moderate ED
- An IIEF-ED score of 11 or greater and 25 or less if taking PDE5i or in ICI (injection therapy)
- Be willing and capable of giving written informed consent to participate in the clinical study and comply with study-related requirements, procedures and visits
The exclusion criteria are:
- History of radical prostatectomy or extensive pelvic surgery
- Recovering from cancer or radiation therapy of the pelvic region within 12 months prior of enrollment
- Taking blood thinners
- History of Diabetes Mellitus, untreated hypogonadism or thyroid disease
- Penis deformity on physical exam
- Recent participation in another clinical trial or treatment with any investigational product within 30 days prior to inclusion in the study
- Serious neurological, psychological or psychiatric disorder which may affect erectile function
- Medical conditions determined by site principal investigator as interfering with the study
- Injury or disability claim under current litigation or pending or approved workers’ compensation claim.
Participants may voluntarily withdraw from the study at any time. Withdrawal from the study will not affect the patient’s access to other treatments nor will the patient be subjected to any sanctions.
Participation in the study may be terminated if continued participation in the study is not in the subject’s best interest, according to the Principal Investigator’s opinion or if the subject withdrawals participation. Determination of therapy cessation and need of explanation will be done by the Principal Investigator based on standard medical practice. Any patient who suffers an adverse event whether or not related to treatment may withdraw voluntarily.
Study design
The study is a randomized, prospective, single-blinded, feasibility study. The short-term efficacy of DualStim therapy with intracavernosal WJ injection will be assessed in patients with ED. The treatment arm will have subjects receive DualStim therapy – fESWT and rESWT with ICI of Umbilical cord derived WJ (1ml GeneXSTEM, BioIntegrate LLC, New York, NY, USA; dilute to q.s. 5ml with sterile normal saline). The control arm will have subjects receiving DualStim therapy with 5 ml ICI of sterile normal saline. Patients will be followed for 6 months after last treatment visit with optional follow-up visits up to 18 months (Fig.1 and Fig.2). Figure 1 shows the study flow diagram based on the CONSORT Extension to Pilot and Feasibility Trials guidelines (43).
Randomization
Patients will be assigned to treatment groups using sealed opaque enveloped coded with an alphanumeric identifier to ensure consecutive allocation of envelopes. Block randomization across sites will be used to ensure even distribution to each group with a 1:1 allocation.
Ethics
This study will be conducted in accordance with Good Clinical Practice (GCP) guidelines and recommendations guiding physicians in biomedical research involving humans. This study has been granted ethical approval by GARM International Foundation IRB (IRB unique identifier: GXS-ED; Study number: GARM04132020-1). Written, informed consent will be obtained from all participants. All participants will be given sufficient time to reach a decision to sign the consent form prior to the study. The protocol has been registered on ClinicalTrials.gov (ID: NCT04424394).
Assessment points
Assessments for the study period will occur at week 0 (baseline visit) with collection of data using the Case Report Forms (CRFs) that include IIEF-EF domain score, Sexual Encounter Profile Questionnaire (SEP), Global Assessment Questionnaire (GAQ) and Erection Hardness Score (EHS) forms. There will be 6 procedure visits with Dual Stim Therapy and injection of WJ or Saline. The second assessment will be at week 4 (1-month follow-up) with collection of data using the same CRFs. The next assessments will be at week 12 (3-month follow-up) and week 24 (6-month follow-up) with data collection using the CRFs. There will be two optional follow up visits at weeks 48 (12-month follow-up) and 72 (18-month follow-up) with data collection with the same CRFs.
Interventions
After completion of the week 0 baseline visit, and determination of patient’s eligibility to be enrolled in the study, patient will be scheduled for 6 procedure visits. The procedure visits will involve all interventions over a period of 7 weeks. During the first procedure visit, patient will be randomized and enrolled into either the treatment arm or the control arm. Once randomized the subject will receive DualStim therapy using both rESWT and fESWT without an ICI on week 1 and 2. On the third procedure visit (week 3) both the treatment arm and the control arm will receive DualStim Therapy. The treatment arm will receive 2.5 ml ICIs of GeneXSTEM (Wharton’s Jelly) in each corpus cavernosum. The control arm will receive 2.5 ml ICIs of sterile saline in the same manner. No visit or procedure will be scheduled for week 4. Patients from both the treatment and control arms will both receive DualStim therapy on procedure visits 5 and 6 (week 5 and 6). On visit 7 (week 7) before any intervention the subject will be required to fill the necessary CRFs. After the CRFs are completed both arms will receive DualStim therapy with the treatment arm receiving 2.5 ml ICIs of WJ in each corpus cavernosum. The control arm will again receive 2.5 ml ICIs of sterile saline in each corpus cavernosum (Fig. 3).
Outcome measures
Primary outcome measurements
The IIEF-EF questionnaire score is a multidimensional scale that addresses the relevant domains of male sexual function (44). It demonstrates the sensitivity and specificity for detecting treatment related changes in ED (44). Evaluating the immediate and short-term efficacy of DualStim Therapy with WJ post intervention is one of the main primary outcomes of this study. The IIEF-EF score will be used to gauge the treatment related changes in this study in relation to the subject’s baseline. The score will be recorded at baseline and compared to follow-ups 1,3 and 6 months post treatment. The second primary outcome measurement is determining the safety of intracavernosal umbilical cord derived WJ injection. The patients will be monitored for adverse events (AEs) and safety outcomes. Any AEs will be recorded in the corresponding CRFs and the principal investigators (PI) will determine if it is a serious adverse event (SAEs) or an AE.
Secondary outcome measurements
Sexual Encounter Profile Questionnaire (SEP) is widely used to quantify the number of intercourse attempts and sexual events and is favored due to its decreased susceptibility to recall bias (46). SEP has been used in over 100 publications and has been recommended by the International Consolation of Sexual Dysfunction for clinical trials in ED (45). The SEP, as well as the Global Assessment Questionnaire (GAQ) and the Erection Hardness Score (EHS) will be used to evaluate the improvement in sexual activity from baseline leading to optimal penetration at follow-ups 1,3 and 6 months post treatment. Lastly the IIEF-EF score will be used to evaluate the immediate and short-term efficacy of DualStim Therapy with WJ compared to DualStim Therapy with saline are each time-point throughout the study.
Adverse Events (AEs)
The following is a list of potential adverse events expected:
- Related to DualStim Therapy:
- Bruising (unlikely)
- Excoriation of skin surface (highly unlikely)
- Worsening of condition (highly unlikely)
- Related to Wharton’s Jelly injection:
- Injection Site Pain (possible)
- Inflammation (possible)
- Swelling (possible)
- Infection (unlikely)
- Allergic reaction (highly unlikely)
- Death (highly unlikely)
Serious Adverse Events (SAEs)
The following is a list of potential severe adverse events expected:
- Leads to death
- Leads to a serious deterioration of the health of the patient that results in:
- Life-threatening illness or injury
- Permanent impairment of a body structure or body function
- Inpatient hospitalization or prolongation of existent hospitalization
- Medical or surgical intervention to prevent permanent impairment to body structure or body function
All SAEs will be reported to the sponsor within 24 hours after the PT first learns of the event and to the Institutional Review Board (IRB) within 5 days after.
Sample Size
For this feasibility study, we propose an estimated group size of 30 patients per group, a total of 60 patients overall. Considering dropout rate and possible loss to follow up the goal is to have complete information on 25 patients per arm to achieve >80% power. An interim analysis will be performed, and group size will be adjusted, if necessary
Statistical analysis
All statistical analysis will be performed by an independent statistician. Descriptive statistics will be computed for all study variables. Continuous variables will be described with central tendency measures (mean, median) and dispersion (range, standard deviation). Categorical variables will be summarized as frequencies and percentages. Chi-Square or Fisher’s Exact test will be used to compare categorical variables. The Student’s t-test/ANOVA or nonparametric equivalent, depending on distribution, will be used to compare continuous variables. Paired data will be assessed with paired t-test or Wilcoxon Rank sum test. Logistic regression will be used to assess predictors of improvement. Odds ratios with 95% confidence intervals will be reported. A mixed model repeated measures analysis with appropriate post hoc tests will be used to analyze score over time. P-values less than 0.05 will be considered statistically significant.
Data collection and handling
The PI will maintain all source documents and data will be transcribed on to paper study CRFs. The original data will be secured by the PI and be made available to the sponsor and study monitors. The PI will also be required to maintain records for a period of five years. All CRFs pages will be subject to initial inspection for omitted data, data inconsistencies, illegible data and deviations b stud monitors. All hard copies of CRFs and media will be stored in a secure location.
The PI will be responsible for submitting data and reports as follows:
- AEs: In an ongoing basis. This will be reported in the proper section of the CRFs.
- SAEs: Report within 24 hours of knowledge of event to Sponsor and report to IRB within five days as per their regulations.
- Deviations, exceptions, violations of protocol: Report to Sponsor within 5 days and report to IRB per their regulations.
- Protocol Progress report: Provide a copy to Sponsor and IRB as per regulations.
- Study Closure report: Provide a copy to Sponsor and IRB as per regulations.
Quality control and assurance
All documents and data will be produced and maintained in such a way to assure control of documents and data to protect the patient’s privacy as far as reasonably practicable. The sponsor, study monitors, and representatives of regulatory authorities are permitted to access study documents as needed. All attempts will be made to preserve patients’ privacy and confidentiality.