Cavallini et al. (2005): Acetyl-L-carnitine plus propionyl-L-carnitine improve efficacy of sildenafil in treatment of erectile dysfunction after bilateral nerve-sparing radical retropubic prostatectomy

Reference ↗
Title	Acetyl-L-carnitine plus propionyl-L-carnitine improve efficacy of sildenafil in treatment of erectile dysfunction after bilateral nerve-sparing radical retropubic prostatectomy
Topic	Carnitine
Author	Cavallini, G, Modenini, F, Vitali, G, Koverech, A
Year	2005
Journal	Urology
DOI	https://doi.org/10.1016/j.urology.2005.05.014

Brief summary

This study investigated the effect of carnitine as an adjuvant to the usual medication (sildenafil) in erectile dysfunction following prostatectomy. Ninety-six patients participated in the study, of which 29 were in the control arm and received a placebo, 35 received a placebo and sildenafil as needed (intervention control group) and 32 received two carnitine preparations (ALC, PLC) and sildenafil as needed (intervention group). After 4 months of use, there were significant improvements in the intervention group compared to the intervention control group and the control arm, and satisfaction with sexual activity and the ability to achieve an erection was highest in the intervention group. Despite promising results, a high number of side effects occurred in both intervention groups, which, according to the authors, were caused by the sildenafil. The analysis is clear and logical, but the reporting often omitted statistically relevant values that would have shown (no) difference.

In dieser Studie wurde der Einfluss von Carnitin als Verstärkung der üblichen Medikation (Sildenafil) bei erektilen Dysfunktionen in Folge einer Prostatektomie untersucht. Es nahmen 96 Patienten an der Studie teil, davon waren 29 in der Kontrollgruppe und erhielten ein Placebo, 35 erhielten ein Placebo und Sildenafil bei Bedarf (Interventions-Kontrollgruppe) und 32 erhielten zwei Carnitinpräparate (ALC, PLC) und Sildenafil bei Bedarf (Interventionsgruppe). Nach 4-monatiger Einnahme zeigten sich deutliche Verbesserungen in der Interventionsgruppe im Vergleich zur Interventions-Kontrollgruppe und der Kontrollgruppe, auch die Zufriedenheit mit der sexuellen Aktivität und der Fähigkeit für eine Erektion war am höchsten in der Interventionsgruppe. Trotz vielversprechender Ergebnisse trat eine hohe Anzahl an Nebenwirkungen in den beiden Interventionsgruppen auf, welche laut Autoren allerdings durch das Sildenafil verursacht wurden. Die Analyse ist übersichtlich und logisch, jedoch wurde bei der Berichterstattung häufig auf statistisch relevante Werte verzichtet, welche (k)einen Unterschied belegt hätten.

Study Design

Prospective / Retrospective Prospective: forward-looking, examples include clinical trials, cohort studies, and long-term observational studies;</br>Retrospective: backward-looking, relying on existing data, examples include case-control studies and retrospective cohort studies	Prospective
Monocentric / Multicentric Monocentric: conducted in one center/ hospital; </br>Multicentric: conducted in multiple centers/ hospitals	Multicentric
Blinding No: Open, all parties are aware of group assignments;</br>Single: one party is unaware of group assignments (generally participants);</br>Double: two parties are unaware of group assignments (generally the participants and the researchers); </br>Triple: concealing group assignment from additional parties	Double
Is randomized	Yes
Cross-over Participants alternate between different treatment groups or conditions over a specified period, allowing each participant to serve as their own control	No
Number of arms	3

Study characteristics

Inclusion criteria	Completely functional erections before surgery (corroborated by the partner and documented in the patient file), bilateral nerve-sparing radical retropubic prostatectomy (indicated on the surgical report) performed for pathologically proven organ-confined disease at least 6 months before screening, no adjuvant or neoadjuvant therapy for prostate cancer, no other treatment for ED before or after surgery, an undetectable postoperative prostate-specific antigen level, and involvement in a stable heterosexual relationship for at least 6 months before surgery
Exclusion criteria	Peyronie’s disease, hormonal abnormalities, any drug consumption that could interact with sildenafil or carnitines as indicated on the technical form, recent (less than 6 months) myocardial or cerebral ischemia or major surgery, alcohol or tobacco abuse, alterations in aspartate and alanine transaminase levels, compensated or uncompensated diabetes, and uncompensated hypertension or hypotension
N randomized	110
Analysis PP: Per Protocol analysis, i.e. only participants included who adhered to the study protocol.</br>ITT: Intention-to-treat analysis, i.e. all randomized participants included regardless of any drop-outs or changes in assignment.</br>mITT: modified Intention-to-treat analysis can refer to analyses in which participants with missing outcome data are excluded or it can refer to analyses in which only participants who received at least one treatment dose are included. In this case, participants dropped out of the study prematurely for reasons unrelated to the treatment.	PP Analysis
Specifications on analyses	NA
Countries of data collection	NI
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: prior to therapy T1: 4 month of therapy

Characteristics of participants

Setting Refers to cancer therapy setting.</br>- Curative therapy: aims to completely eradicate a disease and achieve a full recovery; </br>- Neo-adjuvant therapy: form of curative therapy, given before the primary treatment for cancer (usually surgery); </br>- Adjuvant therapy: form of curative therapy, given after the primary treatment for cancer (usually surgery); </br>- Palliative therapy: focuses on providing relief from symptoms and improving the quality of life for patients, without necessarily targeting the underlying disease; </br>- Active surveillance: involves close monitoring of disease progression without any intervention (typically used for prostate cancer);</br>- No therapy setting: Patients who completed therapy/are currently not in cancer treatment, cancer survivors.	No therapy setting
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Prostate Cancer
Cancer stages Early Stage: generally refers to cancer that is localized to the area where it started, mostly stages I and II;</br>Advanced Stage: cancer that has spread beyond its original site, mostly stages III and IV, with stage IV indicating distant metastasis	NA
Specifications on cancer stages	NA
Comorbidities	Past smokers n (%): Carnitin + Sildenafil 16 (55.1), Sildenafil + Placebo 18 (56.2), Placebo 18 (56.1); Compensated hypertension n (%): Carnitin + Sildenafil 18 (62.7), Sildenafil + Placebo 19 (53.1), Placebo 19 (54.2); Hypercholesterolemia n (%): Carnitin + Sildenafil 16 (55.1), Sildenafil + Placebo 17 (53.1), Placebo 17 (48.6); Obesity n (%): Carnitin + Sildenafil 3 (10.3), Sildenafil + Placebo, 3 (9.3), Placebo 4 (6.7)
Current cancer therapies	No therapy
Specifications on cancer therapies	Post-Surgery: bilateral nerve-sparing radical retropubic prostatectomy
Previous cancer therapies	Surgery
Gender	Male
Gender specifications	100% male
Age groups	Adults (18+)
Age groups specification	Mean (SD) Arm Carnitin+ Sildenafil: 63 (3.9) years, Arm Sildenafil: 61 (4.4) years, Arm Placebo: 61.4 (4.4) years

Arms

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	37
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	5
Drop-out reasons	Protocol violations
Intervention	Propionyl-L-Carnitin (PLC) + Acetyl-L-Carnitin (ALC) + Sildenafil if required
Dosage and regime	Propionyl-L-Carnitin (PLC) 2g daily + Acetyl-L-Carnitin (ALC) 2g daily + 100mg Sildenafil if required Duration: 4 month
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	122
Side effects / Interactions	Headache (25%), flushing (21.8%), drowsiness (9.4%), nausea (6.2%), rhinitis (6.2%), euphoria (6.2%), according to authors caused by sildenafil (no difference in side effects between both sildenafil arms)

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Placebo, Active control
Number of participants (arm) N randomized	40
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	5
Drop-out reasons	Protocol violations n=4, Insufficient therapeutic effect n=1
Intervention	Sildenafil + Placebo
Dosage and regime	Sildenafil 100mg if required + Placebo Duration: 4 month
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	122
Side effects / Interactions	Headache (28.1%), flushing (22.8%), drowsiness (8.5%), rhinitis (8.5%), nausea (5.7%), according to authors caused by sildenafil (no difference in side effects between sildenafil arms)

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Placebo
Number of participants (arm) N randomized	33
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	4
Drop-out reasons	Protocol violation n=2, Insufficient therapeutic effect n=2
Intervention	Placebo
Dosage and regime	Duration: 4 month
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	122
Side effects / Interactions	Abdominal pain (3.4%)

Outcomes

Erectile dysfunction

Outcome type As specificed by the authors	Primary
Outcome specification	NA
Type of measurement	IIEF (International Index of Erectile Function)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	4 month after therapy start: Carnitin + Sildenafil Arm significantly better than Sildenafil + Placebo Arm, and Sildenafil + Placebo Arm better than Placebo Arm in domains: Erectile Function (Mean(SD) = 27.3 (4.6) > 21.7 (6.8) > 11.7 (3.7)), Satisfaction with Sexual Activity (8.9 (4.7) > 4.8 (2.5) > 3.1 (0.6)), Orgasm (8.8 (2.6) > 5.9 (2.9) > 3.0 (0.6)), and General Sexual Well-Being (8.6 (2.0) > 5.4 (2.7) > 2.8 (0.7); p = not given)
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Erectile dysfunction

Outcome type As specificed by the authors	Primary
Outcome specification	Satisfaction with sexual function with semi-structured interview
Type of measurement	Interview
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	4 month after therapy start: Higher satisfaction in the Carnitin-Sildenafil Arm (87.5%) compared to the Sildenafil + Placebo Arm (51.3%; p < 0.05) and in the Sildenafil + Placebo Arm compared to the Placebo Arm (6.8%; p < 0.01)
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Arterial inflow

Outcome type As specificed by the authors	Secondary
Outcome specification	Peak systolic velocity and end-diastolic velocity of cavernosal arteries
Type of measurement	Echo-color Doppler
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	4 month after therapy start: No significant differences between or significant changes within the arms
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Erectile dysfunction

Outcome type As specificed by the authors	Secondary
Outcome specification	Positive ICI test - positive result was considered the ability to achieve a 30 to 40-minute full erection 10 to 15 minutes after ICI of 10 g PGE
Type of measurement	ICI Test (Intracavernosal Injection Test)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	4 month after therapy start: Significant increase in positive tests in the Carnitin + Sildenafil Arm compared to Baseline (36.4% vs. 63.6%; p < 0.01)
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Toxicity

Outcome type As specificed by the authors	Secondary
Outcome specification	NA
Type of measurement	Observation
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Carnitin + Sildenafil Arm and Sildenafil + Placebo Arm had significantly more side effects than the Placebo Arm (χ² = 18.786; p < 0.01), but no difference between the intervention arms
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Funding and Conflicts of Interest

Funding	NI
Conflicts of Interest	NI

Further points for assessing the study

Sample

Power analysis performed	?
- Sample size corresponds to power analysis	?
- Reasons for insufficient sample size based on power analysis	?
If no power analysis performed: at least moderate sample size (n >= 30 per arm)	?
Ethnicity mentioned	?

Alternative Explanation

Other explanations for an effect besides the investigated intervention	?
- Possibility of attention effects	?
- Possibility of placebo effects	?
- Other reasons	?

Statistics

Correct use of parametric and non-parametric tests Testing for normal distribution only necessary if parametric tests are used, NI: use of parametric tests without report of normal distribution testing	?
Correction for multiple testing	?
Measurement of compliance	?
Consistent reporting in numbers (figures, flowchart, abstract, results)	?
Comprehensive and coherent reporting	?
Cross-over	?
- Sufficient washout period	?
- Tested for carry-over effects	?
- Tested for sequence effects	?

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	?
Side effects systematically recorded	?
Side effects considered in result interpretation	?
Ethics votum	?

Additional Notes

PRO:

• Ethical approval obtained.
• Double-blind and control confirmed.
• Monitoring of correct medication/placebo intake.
• Detailed presentation of attrition and drop-outs.
• Randomized block analysis (matching).
• Active and passive control groups.

CONTRA:

• Unclear why group sizes were unequal at randomization.
• Inconsistent reporting of the number in the placebo group (with/without attrition – abstract vs. main text).
• No effect sizes reported.
• No significance values reported, especially for IIEF.
• No intention-to-treat analysis.
• No group comparison for ICI.
• No information on who conducted the interviews or how/where variables were collected.
• Unclear recruitment method.
• No reliability data for measurement instruments provided.
• Assessment of ICI success partially subjective.
• High number of drop-outs due to protocol violations, raising feasibility concerns.
• Table lacks description of data (means, SD?).
• No details on how much sildenafil was actually taken (as needed?).
• Analysis assumes groups took it as prescribed.