Trial design
This was a single centre randomized placebo controlled trial.
Participants
The study was conducted in the Department of Hepatology and Liver Transplantation, Institute of Liver and Biliary Sciences (ILBS), New Delhi from 30 June 2018 to 28 December 2019. The study was conducted on patients attending outpatient department or day care (for endoscopy or hepatic hemodynamic studies) of Department of Hepatology. The study was approved by the ILBS Institutional Review Board (Number: IEC/2018/60/MA04).
Patients who fulfilled the following inclusion criteria were eligible to participate in the study: male patients, age from 21 years to 60 years; Child´s Grade A or B cirrhosis (CTP score up to 9) of any etiology; a minimum 3-month history of ED; a stable monogamous relationship with a female partner and anticipate having same adult female sexual partner during the study; and Karnofsky performance status of ≥ 70%.
After the screening visit, eligible candidates qualified for randomization by making at least four attempts at sexual intercourse during a 4-week treatment free run-in phase to determine baseline erectile function. They should also agree to make at least 1 sexual intercourse attempt per day with the female partner during days 1–4 following randomization (with a minimum of three attempts required during that period). Also agree to make at least 3 intercourse attempts during days 5–14 following randomization.
Following beta-blocker therapy was allowed: carvedilol (up to the max. dose of 25 mg) and propranolol (up to the max. dose of 160 mg). Patients were included if they were not on beta-blocker or on a stable dose of beta-blocker for at least last 6 weeks (beta-blocker dose was not modified during the duration of the study). Patients with history of endoscopically diagnosed large esophageal varices without previous bleeding were included if they were on a stable dose of prophylactic beta blocker for at least last 6 weeks (beta-blocker dose was not modified during the duration of the study) or on endoscopic band ligation sessions (should have small esophageal varices at the time on enrollment in the study, and the last endoscopic band ligation session at least > 1 week ago). Patients with history of variceal bleeding were included if they bled > 4 weeks ago and were on secondary prophylaxis with endoscopic band ligation (should have small esophageal varices at the time on enrollment in the study, and the last endoscopic band ligation session at least > 1 week ago) and beta-blockers were continued if they were using them (beta-blocker dose was not modified during the duration of the study).
Exclusion criteria were the following:
1. Patients with overt hepatic encephalopathy; CTP score ≥ 10; history of variceal bleeding within last 4 weeks [ patients were included if they bled > 4 weeks ago and were on secondary prophylaxis with endoscopic band ligation( should have small esophageal varices at the time on enrollment in the study, and the last endoscopic band ligation session at least > 1 week ago) and beta-blockers were continued if they were using them (beta-blocker dose was not modified during the duration of the study). ; and hepatocellular carcinoma; acute decompensated state of cirrhosis like gastrointestinal bleed/increased jaundice, active infection; post TIPS patients; acute febrile illness; and no consent.
2. Patients with HbA1c > 13.0% at the screening visit (visit 1, week − 4); a recent history of diabetic ketoacidosis (≥ 2 episodes), or ≥ 3 episodes of hypoglycemia requiring assistance. However, men with micro vascular complications, including retinopathy, were eligible.
3. Patients with history of angina during intercourse, unstable angina, or any other evidence of recently diagnosed coronary artery disease; poorly controlled blood pressure (systolic > 170 or < 90mm Hg or diastolic > 100 or < 50 mmHg) or orthostatic hypotension; arrhythmia, uuncontrolled congestive heart failure; renal or respiratory failure; uncontrolled thyroid disorders and hemoglobin < 7.0.
4. Men who failed to achieve an erection after radical prostatectomy or pelvic surgery; those who had penile implants, clinically noteworthy penile deformities, or a history of psychiatric disorders, stroke or spinal-cord trauma within 6 months of study onset; those who were receiving nitrates, antiandrogens, antidepressant, anticonvulsants, other hypnotics or cancer chemotherapy; and patients with active alcohol/substance intake or intake within 1 month of enrollment.
5. Patients with history of hypersensitivity to the trial drugs or to drugs with a similar chemical structure.
6. Patients with Karnofsky performance status of below 70%.
Interventions: After the screening visit, eligible candidates qualified for randomization by making at least four attempts at sexual intercourse during a 4-week treatment free run-in phase to determine baseline erectile function. Participants were randomly allocated to one of two 12-week treatment arms: tadalafil 10 mg (n = 70) or placebo (n = 70)
Men were instructed to take one dose of their treatment at any time before anticipated sexual activity on days with anticipated sexual activity and daily at night after meals on days with no anticipated sexual activity.
Baseline and follow-up assessments:
Baseline assessment: Both the group of patients underwent the following investigations at baseline: History and physical examination, complete hemogram, renal function tests, serum electrolytes, liver function tests including INR, 12-lead electrocardiogram (ECG), urinalysis, etiological workup for cirrhosis as needed, ultrasound abdomen with Doppler splenoportal axis and hepatic veins, blood sugar fasting, HbA1c, alfa feto protein (AFP), serum thyroid stimulating hormone (TSH), serum sex hormone binding globulin (SHBG), serum testosterone (free and total), serum prolactin, serum luteinizing hormone (LH), serum follicle stimulating hormone (FSH), serum c-reactive protein (CRP), and chest X-ray.
Questionnaires assessment with Karnofsky Performance Score (KPS), International Index of Erectile Function (IIEF) questionnaire, Sexual Encounter Profile (SEP) diaries, quantitative Androgen Deficiency in the Aging Male (ADAM) questionnaire, Patient Health Questionnaire (PHQ-9), Generalized Anxiety Disorder 7 (GAD-7) questionnaire, and SF-36 questionnaire was also done at baseline. Nutritional assessment [by body mass index (BMI), bioelectrical impedance (BIA) and whole body Dual-energy X-ray absorptiometry (DXA)] and hepatic venous pressure gradient (HVPG) (only for patients posted for HVPG measurements, no HVPG was done specifically for this protocol) was also done at baseline.
Assessments at 4 and 8 weeks
History and physical examination, complete hemogram, renal function tests, serum electrolytes, liver function tests including prothrombin time and INR, Sugar (f), HbA1c.
Assessments at 12 weeks
History, physical examination, complete hemogram, renal function tests, serum electrolytes, liver function tests including INR, 12-lead ECG, urinalysis, blood sugar fasting, HbA1c, serum TSH, SHBG, serum testosterone (free and total), serum prolactin, serum LH, serum FSH, and serum CRP. Questionnaires assessment with KPS, IIEF questionnaire, SEP diaries, quantitative ADAM questionnaire, PHQ-9 questionnaire, GAD-7 questionnaire, SF-36 questionnaire; nutritional assessment and HVPG measurement was also done at week 12.
The effects of tadalafil on erectile function were evaluated using the IIEF questionnaire, SEP diaries and Global Assessment Question (GAQ).
The patients completed the IIEF at the conclusion of the run-in period (baseline) and after 12 weeks of double blind therapy. They completed the SEP diary after each sexual encounter and reviewed the diary with the physician at each visit. The patients completed the GAQ at the final visit (study end or early discontinuation).
Patients were monitored for side effects of drugs and complications at each visit.
Outcomes
Primary outcome measure was proportion of patients achieving more than a five-point gain from baseline to end point (at end of 12 weeks) in the erectile function domain of the IIEF.
Other secondary outcome measures studied included:
1. Changes from baseline to end point in scores on the following domains of IIEF: erectile function domain, orgasmic function domain, sexual desire domain, intercourse satisfaction domain, and overall satisfaction domain.
2. Change from baseline to end point in the proportion of patients achieving a final IIEF erectile function domain score of at least 26 (normal erectile function according to Cappelleri et al [29].
3. Changes from baseline to end point in proportions of “yes” responses to 2 yes/no questions in the SEP diary: “Were you able to insert your penis into your partner’s vagina?” (SEP-Q2) and “Did your erection last long enough for you to have successful intercourse?” (SEP-Q3 i.e. absolute proportion of successful intercourse completion among all sexual attempts)
4. Absolute proportion of affirmative responses to the GAQ 1 (“Did the
treatment improve your erections?”) and GAQ 2 (If yes to GAQ1,“Did the treatment improve your ability to engage in sexual activity?”).
5. Changes from baseline to end point in q ADAMS, PHQ-9, GAD-7, and SF-36 scores.
6. Effect on HVPG [in the subgroup of patients who underwent HVPG measurements at baseline (and had HVPG > 10 mm Hg)] at end of 12 weeks, and
7. Side effects of the treatment.
Randomization: Random allocation sequence was done by computer generated random numbers code with an equal number of the alternative treatments. Patients were randomized to either of the two groups in 1:1 ratio.
Allocation concealment
Randomization was done with sequentially numbered, sealed envelopes using the previously determined code to either tadalafil or placebo. Sealed opaque thick papered envelops were used to conceal the sequence until interventions were assigned.
Implementation
The computer generated random allocation sequence was generated by SK from the information technology department of the Institute; AB from the clinical research department of the Institute assigned participants to interventions (opened the sealed envelopes and assigned the subjects in either group as per randomization list); RKJ, MK and AB from Department of hepatology and liver transplantation enrolled participants in the study.
Blinding
Treatment and placebo pills were of similar size, shape and color. The participants, care providers, and those assessing outcomes were blinded. The code was not broken until the end of the study
Definitions and Study Assessments
Diabetes
A clinical diagnosis of diabetes was predicated on either current therapy with insulin, metformin, or sulfonylureas or a history within the previous year of two occasions of diagnostic-level hyperglycemia, including 1) fasting plasma, serum, or blood glucose > 7 mmol/l (126 mg/dl); 2) randomly obtained plasma, serum, or blood glucose ≥ 11.1 mmol/l (200 mg/dl) associated with symptoms of polyuria, polydipsia, or unexplained weight loss; or 3) plasma, serum, or blood glucose ≥ 11.1 mmol/l (200 mg/dl) 2 h after administration of 75 g oral glucose. Any patient with an onset of diabetes before the age of 30 years who had received continuous insulin treatment since diagnosis was considered to have type 1 diabetes.
Karnofsky Performance Score (KPS)
The Karnofsky Performance Score (KPS) ranking ranges from 100 to 0, where 100 is "perfect" health and 0 is death [30].
International Index of Erectile Function (IIEF), Sexual Encounter Profile (SEP) and Global Assessment Question (GAQ): The effects of tadalafil on erectile function were evaluated using the IIEF questionnaire, SEP diaries and GAQ. IIEF is a 15-item questionnaire that assesses five domains of male sexual function using 5- to 6-point Likert scales, with 0 or 1 signifying a low frequency or ability and 5 signifying a high frequency or ability [31]. These domains include erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction. The erectile function domain consists of six questions concerning erection frequency, erection firmness, frequency of partner penetration, frequency of maintaining erection after penetration, ability to maintain erection to completion of intercourse, and confidence in achieving and maintaining erection. The erectile function domain possible scores range from 1 to 30. Severity of ED was defined using the IIEF-EF domain score: 5 or lower (no attempts at intercourse); 6 to 10 (severe ED); 11 to 16 (moderate ED); 17 to 25 (mild ED); and 26 to 30 (“normal” erectile function i.e. absence of ED). IIEF has been validated in the Indian population also [32].
Patients also used Sexual Encounter Profile (SEP) diaries, which are immediate recall instruments which allow the patients to document each sexual attempt during the course of the study. The percentage of ‘yes’ responses to the following SEP questions were assessed in this analysis: SEP2 “Were you able to insert your penis into your partner’s vagina?” and SEP3 “Did your erection last long enough for you to have successful intercourse?”.
In addition, at study end point or early discontinuation, each patient was asked two global assessment questions (GAQ 1 and 2). These questions were presented to patients at the last visit of the study and asked “whether treatment improved their erections” (GAQ1) (yes/no); and, if so, “whether treatment improved their ability to engage in sexual activity” (GAQ2) (yes/no).
Quantitative ADAM questionnaire
The qADAM questionnaire consists of the 10 questions on a Likert scale of 1–5, in which 5 represents the absence of a given symptom and 1 represents maximal symptoms. All questions are weighted equally. The summation of these responses yields a total qADAM score between 10 and 50, with 10 being most symptomatic and 50 being least symptomatic [33].
Generalized Anxiety Disorder 7 (GAD-7) questionnaire
GAD 7 is a self-reported questionnaire for screening and severity measuring of generalized anxiety disorder (GAD). The GAD-7 score is calculated by assigning scores of 0, 1, 2, and 3, to the response categories of 'not at all', 'several days', 'more than half the days', and 'nearly every day', respectively, and adding together the scores for seven questions. GAD-7 score of ≥ 10 indicated probable diagnosis of GAD [34].
Patient Health Questionnaire (PHQ-9)
The PHQ-9 is the depression module, which scores each of the nine DSM-IV criteria as "0" (not at all) to "3" (nearly every day). PHQ-9 score ≥ 10 was taken as indication of major depression [35].
Short Form (36) Health Survey
Assessment of health related quality of life (HRQOL) was done using the Short Form (36) Health Survey. SF-36(v2) is designed to measure the full range of health status and wellbeing by means of 36 multiple-choice questions. It measures 4 scales in the area of physical health (physical functioning, role-physical, bodily pain, general health) and 4 in the area of mental-health (vitality, social functioning, role- emotional and mental health). Two comprehensive indexes of HRQOL were also computed, physical component summary and mental component summary. The lower scores indicate more disability [36].
Nutritional assessment
Height was measured to the nearest centimeter using a wall mounted standing measure. Current weight was recorded to the nearest 0.1 kg. Dry body weight was estimated using published suggested adjustment for the degree of fluid retention and a dry BMI estimated [37].Body composition analysis was done by bioelectrical impedance (BIA) for fat, muscle and hydration assessment [38, 39]; and whole body Dual-energy X-ray absorptiometry (DXA) was done for measurement of human body composition [40]. BIA appendicular skeletal muscle index (ASMI) and DEXA ASMI calculations were done using standard formulae [38, 39, 40].
Statistical methods
Data was processed using the software packages SPSS version 20.0. Data were expressed as mean ± S.D in case of normally distributed continuous variables and median (range) for continuous variables not normally distributed. Categorical variables were expressed as number (percentage).For comparison of categorical variables; chi-square and Fisher’s exact tests were used. For comparisons of continuous variables, t-test for normally distributed continuous variables and Mann-Whitney test for continuous variables not normally distributed were used. Wilcoxon rank sum test for paired continuous data and McNemar test for paired categorical variables were used.
All analyses were conducted on an intention-to-treat basis. The analysis of efficacy included all
patients who had a baseline measurement and at least one post-baseline measurement. The analysis of safety included all randomized patients.
For each SEP question, baseline and post-baseline scores were percentage of yes responses relative to number of sexual encounters during the run-in period and the treatment period, respectively. Proportions of yes responses to SEP diary questions were treated as continuous variables. P value of less than 0.05 was said to statistically significant.
Sample size
There were no previous RCTs of tadalafil for erectile dysfunction in cirrhotics. Placebo response rate for increase more than five points in erectile function domain score was taken as 15%, as one trial on tadalafil in diabetics reported placebo response rates of 13% at 12 weeks [41]. Response rates in tadalafil group were assumed to be 40% as one study on tadalafil in diabetics reported increase of more than five points in erectile function domain score of 44% after 12 weeks of tadalafil 10 mg daily[41]. And one study in cirrhotics reported that 44% of patients had resolution of ED at 4 weeks of tadalafil 10 mg treatment [2].
Assuming that increase more than five points in erectile function domain score would be 40 % with tadalafil and 15% with placebo, with alpha 5% and power 80% we needed to enroll 114 cases. Assuming defaulter rate to be 20 % it was decided to enroll total 140 cases (70 cases in each group). No interim analysis was planned.