Howells et al. (2011): Phase I randomised double-blind pilot study of micronized resveratrol (SRT501) in patients with hepatic metastases - safety, pharmacokinetics and pharmacodynamics

Reference ↗
Title	Phase I randomised double-blind pilot study of micronized resveratrol (SRT501) in patients with hepatic metastases - safety, pharmacokinetics and pharmacodynamics
Topic	Resveratrol
Author	Howells, LM, Berry, DP, Elliott, PJ, Jacobson, EW, Hoffmann, E, Hegarty, B, Brown, K, Steward, WP, Gescher, AJ
Year	2011
Journal	Cancer Prevention Research
DOI	http://10.1158/1940-6207.CAPR-11-0148

Brief summary

This study compared two groups of patients, all of whom had colorectal carcinoma (stage IV) with liver metastases and a life expectancy of more than 3 months. The patients received a resveratrol solution with micronized resveratrol (5.0 g) or a matching placebo once a day for approximately 14 days prior to surgical removal of the liver metastases. The purpose of the study was to assess the safety, pharmacokinetics and pharmacodynamics of the formulation (micronized resveratrol). The side effects were recorded in a daily diary according to fixed criteria. The two groups were comparable before treatment. Various side effects occurred, especially diarrhea, but the side effects were predominantly mild (grade 1). One patient discontinued the study due to diarrhea. One patient died after surgery due to peritonitis and liver failure, which, according to the study director, was not caused by resveratrol. The authors conclude that a 14-day intake of resveratrol (5.0 g) is well tolerated in colorectal cancer patients.

In dieser Studie wurden zwei Gruppen von Patienten miteinander verglichen, welche alle ein kolorektales Karzinom (Stadium IV) mit Lebermetastasen und eine Lebenserwartung von mehr als 3 Monaten hatten. Die Patienten haben ungefähr 14 Tage vor der operativen Entfernung der Lebermetastasen täglich eine Resveratrol-Lösung (5,0 g) oder ein passendes Placebo bekommen. Ziel der Studie war es, die Sicherheit, Pharmakokinetik und Pharmakodynamik der Formulierung (mikronisiertes Resveratrol) zu bewerten.Die Nebenwirkungen wurden mittels täglicher Tagebuchführung nach festen Kriterien erhoben. Die beiden Gruppen waren vor der Behandlung vergleichbar. Es traten verschiedene Nebenwirkungen v.a. Durchfall auf, allerdings waren die Nebenwirkungen überwiegend mild ausgeprägt (Grad 1). Ein Patient brach die Studie wegen Durchfall ab. Ein Patient starb nach der OP an einer Bauchfellentzündung und Leberversagen, was aber laut des Studienleiters nicht durch Resveratrol verursacht war. Die Autoren schließen, dass eine 14 tägige Einnahme von Resveratrol (5,0 g) bei Darmkrebspatienten gut verträglich ist.

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	2

Study characteristics

Inclusion criteria	Subjects (18 years or older) presenting with confirmed stage IV colorectal cancer and hepatic metastases, who had not received therapeutic intervention for their cancer within 6 weeks of study commencement and had a life expectancy of >3 months, were recruited into the study. All patients were due to undergo resection of liver metastases. Participants had to be physically capable of complying with the protocol and had a normal ECG and no history of HIV or hepatitis B/C.
Exclusion criteria	Patient were asked to refrain from large quantities of resveratrol-containing foods and drinks such as peanuts, grapes, mulberries and alcohol within 48 h of scheduled PK collection days, and the day of surgical resection.
N randomized	9
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.	?
Specifications on analyses	All nine subjects were analysed. This is a Phase I study about safety, pharmapharmacokinetics, pharmacodynamics and not an efficacy study. PK: Statistical analyses for pharmacokinetic data included linear regression with 1/concentration weighting and descriptive statistics. PD: Means were compared via one way, one sided ANOVA followed by Tukey’s post hoc test.
Countries of data collection	United Kingdom
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	Patients ingested the formulation pre-operatively daily for a minimum of 10 and a maximum of 21 days, dependent upon surgical scheduling. Plasma samples for PK assessment were obtained on days 1 and 2, and on the day of surgical resection. Plasma for PD assessment was obtained pre-dose, immediately prior to, and during surgery. Diseased and normal adjacent hepatic tissue was resected 6-7 h after the last dose.

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.	Palliative
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Colorectal 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	Advanced Stage
Specifications on cancer stages	Stage IV colorectal cancer and hepatic metastases
Comorbidities	NI
Current cancer therapies	Surgery
Specifications on cancer therapies	Resection of liver metastases
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	SRT501 (resveratrol): Male (5), female (1) Placebo: Male (1), female (2)
Age groups	Adults (18+)
Age groups specification	SRT501 (resveratrol): 68.5(10.8) years Placebo: 64.3(6.35) 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	6
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	0
Drop-out reasons	NA
Intervention	Resveratrol
Dosage and regime	Oral (suspension) of microparticular resveratrol (SRT501): 1 x 5,0 g daily for approximately 14 days (minimum of 10 and a maximum of 21 days before surgery)
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.	14
Side effects / Interactions	AEs possibly or probably attributable to agent intake: They were primarily of a gastrointestinal nature, including nausea and diarrhoea, and mild in grade (grade 1 NCI CTC v3.0). Other AEs included chills, lethargy, rash, skin irritation and vascular flushing, which resolved without sequelae.

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	3
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	0
Drop-out reasons	NA
Intervention	Placebo
Dosage and regime	Oral (suspension) of placebo 1 x daily for approximately 14 days (minimum of 10 and a maximum of 21 days before surgery)
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.	14
Side effects / Interactions	One case of lethargy in the placebo group, which was ongoing at follow-up. One case with diarrhoea.

Outcomes

PK (Pharmacokinetics)

Outcome type As specificed by the authors	Others
Outcome specification	Resveratrol pharmacokinetics in blood (1) and concentration in liver tissue (2): (1) Patients’ plasma was analysed by HPLC-MS/MS for resveratrol. (2) Resveratrol was quantified in tumor and normal adjacent hepatic tissues.
Type of measurement	Blood Test, Histological examination
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".	NA
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".	Overall: (1) Blood: Resveratrol concentrations were below the lower limits of quantitation (LLOQ) for all samples from subjects receiving placebo, and measurable in patients who received SRT501. Cmax levels were reached 2.8 h post-dose, and the mean maximum plasma concentration was 1942 ng/mL (8.51 nmol/mL). The mean plasma elimination half-life was just over 1h. (2) Tissue: Levels of resveratrol were below the LLOQ in all subjects on placebo and one of the six patients on SRT501. Mean resveratrol levels in the remaining five patients receiving SRT501 were 1098±1393 ng/g (4.81 nmol/g, range 52-2834 ng/g) and 420±341 ng/g (1.84 nmol/g, range 46-914 ng/g) in tumor and normal tissue, respectively.

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	?

PD (Pharmacodynamics)

Outcome type As specificed by the authors	Others
Outcome specification	Potential effects of SRT501 on processes relevant to cell survival and apoptosis were measured in plasma and tissue.
Type of measurement	Blood Test, Histological examination
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".	NA
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".	Overall: There was no difference between patients who received placebo or SRT501 in terms of plasma/serum levels of prostaglandin E2 (PGE-2) and vascular endothelial growth factor (VEGF). The analysed tissue samples show no significant differences between placebo and SRT501. Apoptosis, as reflected by immunohistochemistry for cleaved caspase 3 in tumor tissue, was significantly increased by 39% (to 1.44% total apoptotic cells, p=0.038) in patients on SRT501 compared to those taking placebo.

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	Study was designed and sponsored by Sirtris
Conflicts of Interest	According to authors no conflict of interest.

Further points for assessing the study

As this is a Phase I study, this section is not applicable. This assessment was designed for efficacy studies.

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	Yes

Alternative Explanation

Other explanations for an effect besides the investigated intervention
- Possibility of attention effects	NA
- Possibility of placebo effects	NA
- 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	NA
Measurement of compliance	NA
Consistent reporting in numbers (figures, flowchart, abstract, results)	?
Comprehensive and coherent reporting	?
Cross-over
- Sufficient washout period	NA
- Tested for carry-over effects	NA
- Tested for sequence effects	NA

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	NA
Side effects systematically recorded	NA
Side effects considered in result interpretation	NA
Ethics votum	Study was funded by Sirtris."Study was funded by Sirtris." is not in the list (Yes, No, NI, ?) of allowed values for the "Ethics / CoI / Funding" property.