Randomization And Allocation
The randomization takes place when the participant has sent their signed informed consent form to the research team, agreeing to be a part of this clinical trial. 50 sheets of paper labeled “melatonin” and 50 sheets of paper labeled “control” will be preserved in a total of 100 sealed, identical envelopes, mixed in one box. When the written informed consent is received from a participant, we will randomly choose one of these envelopes and open it. The content will then determine the randomization of the patient i.e., melatonin or control. When the process of randomization is complete, the participant will be informed of the outcome. If they have been randomized to the melatonin group, they will receive a prescription for melatonin and an order will be placed for 15 containers of melatonin tablets (corresponding to 1 year of consumption) each year during the 5-year period. The participating research staff as well as the participants will therefore be aware of their randomization outcome, either to treatment with melatonin or to composing the control group.
Blinding
This trial is not blinded.
Intervention
Participants will be equally randomized into two groups: the melatonin group (treated with 20 mg melatonin each night for five years) or the control group (no intervention). When a patient is recruited and randomized to the melatonin group, blood samples will be ordered by a licensed physician regarding creatinine, electrolytes (Sodium, Potassium) and alanine transaminase (ALAT). This process will be repeated after 2 and 4 years.
Table 1. Study Design.
Time
|
Event in clinical routine
|
Other events for trial subjects
|
At diagnosis
|
Clinical examination of the eye. Radiological examination of the thorax and abdomen. Primary treatment*.
|
Provide information about the trial. Screen participant for inclusion and exclusion criteria.
Obtain written consent. Give medication instructions. Order blood tests to measure kidney function, electrolytes and liver function. Prescribe melatonin 20 mg every night for 5 years.
|
1 month
|
A
|
Ask about AE and SAE, and about prescription compliance.
|
6 months
|
B
|
Ask about AE and SAE, and about prescription compliance.
|
1 year
|
A+B
|
Ask about AE and SAE, and about prescription compliance.
|
1.5 years
|
B
|
Ask about AE and SAE, and about prescription compliance.
|
2 years
|
A+B
|
Ask about AE and SAE, and about prescription compliance. Ordering blood tests to measure kidney function, electrolytes and liver function.
|
2.5 years
|
B
|
Ask about AE and SAE, and about prescription compliance.
|
3 years
|
A+B
|
Ask about AE and SAE, and about prescription compliance.
|
3.5 years
|
B
|
Ask about AE and SAE, and about prescription compliance.
|
4 years
|
A+B
|
Ask about AE and SAE, and about prescription compliance. Order blood tests to measure kidney function, electrolytes and liver function.
|
4.5 year
|
B
|
Ask about AE and SAE, and about prescription compliance.
|
5 year
|
A+B
|
End of melatonin treatment. Evaluation of overall survival, metastasis-free survival, and proportion of subjects with metastases**. Ask about AE and SAE.
|
*= Primary treatment of uveal melanoma in the eye is either enucleation (surgical removal of the eye) or brachytherapy (local radiation therapy of the eye).
**=Evaluation of the proportion of subjects with metastases is performed through data collection via registries, chart documentation, and statistical work. It therefore does not require subjects’ active participation.
A= Follow-ups at St. Erik Eye Hospital or at the participants local eye clinic. Examination of the eye, for subjects treated with radiation, or of the prosthesis and/or orbita, for subjects treated with enucleation. Follow-up interval +/- 4 weeks during the first year and +/-8 weeks after the first year.
B = Radiological examination of the liver with ultrasound or computer tomography every six months for the first five years after diagnosis; can be performed at the participant’s local healthcare clinic. Follow-up interval +/- 4 weeks during the first year and +/-8 weeks after the first year.
Table 2. Flow chart
Time
|
Screening
- 30 days before 1 m visit
|
Month 1
+/-7 days
|
Month 6
+/- 4
weeks
|
Year
1
+/- 4
weeks
|
Year 1,5
+/- 8 weeks
|
Year
2
+/- 8 weeks
|
Year 2,5
+/- 8 weeks
|
Year
3
+/- 8 weeks
|
Year 3,5
+/- 8 weeks
|
Year 4
+/- 8 weeks
|
Year 4,5
+/- 8 weeks
|
Year
5
+/- 8 weeks
|
Inclusion/ Exclusion
|
x
|
|
|
|
|
|
|
|
|
|
|
|
Informed consent
|
x
|
|
|
|
|
|
|
|
|
|
|
|
Randomization melatonin/ Control group
|
x
|
|
|
|
|
|
|
|
|
|
|
|
Medical history, current medication
|
x
|
|
|
|
|
|
|
|
|
|
|
|
Medication instruction
|
x
|
|
|
|
|
|
|
|
|
|
|
|
Radiological examination – liver
|
|
|
x
|
x
|
x
|
x
|
x
|
x
|
x
|
x
|
x
|
x
|
Radiological examination – thorax and abdomen
|
x
|
|
|
|
|
|
|
|
|
|
|
|
Blood samples
|
x
|
|
|
|
|
x
|
|
|
|
x
|
|
|
AE & SAE, prescription compliance
|
|
x
|
x
|
x
|
x
|
x
|
x
|
x
|
x
|
x
|
x
|
x
|
End of study
|
|
|
|
|
|
|
|
|
|
|
|
x
|
Data collection
A case report form (CRF) will be established in paper form and used for data collection, where subjects will be identified through a trial-specific number only. The examiner is responsible for assuring that registered information is correct and complete, and that the reporting is performed according to the predetermined timeline. The principal investigator will sign the completed CRF and a copy will be archived where the trial takes place.
Follow-up
The subjects will take their medication (tablets) at home and confirm that they have received each package of melatonin sent to them. They will, one month following recruitment, be contacted via telephone and asked about their compliance to the treatment. The participants will then continue to be contacted via telephone every six months throughout the trial period and asked questions about compliance, adverse events (AE) and serious adverse events (SAE). After the termination of the trial, the subjects will continue their yearly control visits at St. Erik Eye Hospital, or at their local ophthalmology clinic, for the remainder of their lives, as all uveal melanoma patients do.
In the event of detection of metastases
If a suspected metastasis is detected in radiological examinations and then verified with a biopsy, the patient will be referred by their physician to an oncology clinic in their home region. This is a standard clinical routine and will not be impacted by this trial. The oncology clinic will make a decision regarding next steps to investigate, examine and treat the metastases. Patients with metastases typically receive systemic chemotherapy, immunotherapy with so-called checkpoint inhibitors, and/or regional perfusion treatment of the liver where high doses of chemotherapy are injected into the liver's circulatory system. These treatments are demanding for patients and can result in side effects such as fatigue, susceptibility to infection, dry mucous membranes, and pain. The average survival following metastasis detection is about one year. Metastasis detection does not alter the melatonin doses or treatment instructions in this trial. Melatonin given at a dose of 20 mg at 10 pm has shown particularly positive effects in advanced stages of cancer in earlier studies.10
It has also been reported that systemic chemotherapy is more easily tolerated in patients who are simultaneously treated with melatonin, particularly in regards to neurotoxicity, thrombocytopenia, weight loss, and asthenia.44 Furthermore, there are fewer cases of alopecia (hair loss) and infection in patients taking 20 mg of melatonin at 10 pm while undergoing radiotherapy.45 If participants in this trial take melatonin from the time that their metastases are detected, the metastases will be included in both the intention-to-treat as well as the per protocol analysis. Survival in the melatonin group following metastasis detection will therefore be counted in the patients still taking melatonin.
Withdrawal
Subjects may voluntarily withdraw from the trial at any time without impacting further standard treatment. The principal investigator reserves the final right to terminate the trial for a specific subject due to unacceptable side effects or poor compliance. If a subject terminates their participation in this trial, their trial-specific ID will not be re-used. They will not be able to re-join the trial. No further data will be collected, however, data that has already been collected will be used for the final analysis of the trial. Participants who withdraw within 6 months following randomization will be replaced by newly recruited and randomized patients with a ratio of 1:1 i.e., if two participants withdraw from the trial within 6 months, they will be replaced by two new participants. Patients who withdraw from the trial after 6 months following randomization will not be replaced.
Sample Size
Our power calculations will be based on the following:
-
A previously calculated metastasis incidence of 60% five years following diagnosis for individuals not taking melatonin (participants in the control group). This is a relevant calculation considering the high-risk population recruited based on our inclusion criteria.46–49
-
An earlier study which included study participants with surgically removed lymph node metastases of malignant melanoma which showed that 31% (5 of 16 participants) of those treated with 20 mg of evening melatonin developed distant metastases compared to 71% (10 of 14 participants) of those not treated with melatonin.8
Based on this previous research, the following assumptions are made:
-
The number of participants in the melatonin group which will have developed distant metastases after 5 years: 30%
-
The number of participants in the control group which will have developed distant metastases after 5 years: 60%.
-
Alpha: 0,05
-
Beta: 0,2
-
Power: 80%
-
Results: 42 participants must be included in each group, i.e., both the melatonin and the control group, in order to achieve statistical significance (Table 3). To obtain a safety margin in case some participants withdraw from the trial, we will strive after a group population of 50 participants per group.
Table 3
Melatonin, n= | 42 |
Control, n= | 42 |
Incidence, melatonin group | 30% |
Incidence, control group | 60% |
Alpha | 0,05 |
Beta | 0,2 |
Power | 0.8 |
Outcomes
The primary outcome is the number of patients which develop metastasis in the melatonin group vs. the control group. This will be evaluated as a relative risk (RR), measured as relative risk with a 95% confidence interval. The secondary outcomes include the following:
-
Number of patients developing metastasis in the melatonin group vs. the control group in 5 years, evaluated as Cox regression hazard ratio (HR), measured as hazard ratio with relevant covariants, with a 95% confidence interval.
-
The overall 5-year survival from randomization in the melatonin group vs. control group, evaluated with the Log-Rank test through Kaplan-Meier curve.
-
The overall 5-year survival from the detection of metastasis in the melatonin group vs. control group, evaluated with the Log-Rank test through Kaplan-Meier curve.
-
Number of patients which develop other types of cancer in the melatonin group vs. control group, evaluated as relative risk (RR), measured as relative risk with 95% confidence interval.
-
Number of patients developing other cancers in the melatonin group vs. control group, evaluated as Cox regression hazard ratio (HR), measured as hazard ration with relevant covariants, with 95% confidence interval.
-
Number of patients with AE and SAE in the melatonin group vs. control group, assessed by CTCAE and evaluated as relative risk (RR) with a 95% confidence interval.
Other outcome measures:
-
Interim analysis: number of patients developing metastasis within 3 years in the melatonin group vs. control group, evaluated as relative risk (RR), measured as relative risk with 95% confidence interval.
-
Interim analysis: overall survival in 3 years in the melatonin group vs. control group, evaluated with the Log-rank test.
Clinical effects
Our primary and secondary outcomes for the clinical effects of melatonin treatment will be performed through data collected from patient charts, where it is registered if the subject has developed metastasis, if they are deceased, and/or if they have received another cancer diagnosis in addition to uveal melanoma.
Clinical safety
Our outcomes for clinical safety will be the number of adverse events (AE), the number of serious adverse events (SAE), and the number of suspected unexpected serious adverse reactions (SUSAR) in the melatonin group and control group respectively. These will be measured through data collected from CRF forms and patients’ chart documentations. The subjects are encouraged to contact us is they experience side effects, or new or worsened symptoms. They will be asked about AE and SAE at three months and 1 year after starting melatonin treatment, and thereafter every six months until 5 years have passed since recruitment.
End Of Study Definition
The trial will be terminated when the last participant in this trial has had their five-year control (Last Subject Last Visit - LSLV). No further treatment or contact with the participants will be made after this point of time.
Statistical analysis
We will be analyzing our data according to “intention to treat” where all participants randomized to either the melatonin or control group are included in said group regardless even if some terminate their participation in the trial or are excluded from the trial later on. We will at the same time analyze our data “per protocol” where the participants who terminate their participation during the trial or are noncompliant to melatonin treatment are excluded from analysis.
To answer our primary and secondary objectives, we will use both the Chi-square test and the Log-rank test of cumulative survival with associated 95% confidence intervals and p-values. Relative risk will be calculated as the probability of metastasis in the melatonin group divided by the risk of metastasis in the control group.
-
P values less than 0.05 will be considered significant, and all tests will be double-tailed, or two-sided.
-
The Shapiro-Wilk test will be used to confirm if our continuous data is normally distributed.
-
A Student’s t-test will be used to compare the differences in normally distributed continuous data within the melatonin and control group, respectively. Data found not to be normally distributed data will be compared using the Mann Whitney U-test.
-
In order to compare the risk of death and metastasis between the melatonin and control group, we will use a Cox Regression, adjusted for covariates such as tumor size, T category, cell type, presence of extra scleral growth, presence of extracellular matrix patterns and BAP-1 expression.
Interim Analyses
Interim analysis will take place after two and three years during the trial.
Oversight and Monitoring
Monitoring
In order to assure that the trial is performed according to the protocol - that the data is collected, documented and reported according to ICH-GCP as well as regarding ethical and regulatory requirements - the trial will be monitored by an independent monitor before the start of the trial, during the course of the trial, and after the trial ends, through Karolinska Trial Alliance. This will take place according to the monitoring plan for the trial and aims to ensure the rights, safety and well-being of participants as well as to oversee that data in the CRF forms is filled in correctly.
Safety And Adverse Events
Registration of events
An AE is defined as any unfavorable event or worsening of an existing medical state in a subject that receives a trial medication, regardless of causation. An SAE is a serious event where a specific dose leads to death, is life threatening, requires health care, causes remaining or massive invalidation or disability, or causes an abnormality or malformation. A SUSAR is defined as a side effect or an incident that is serious, unexpected, and suspected to be caused by the treatment. Subjects will be encouraged to contact the principal investigator if any of these incidents occur. They will also be specifically asked about AE, SAE, and SUSAR after one month of treatment and at regular follow-ups throughout the course of the trial. All AE will be registered in the CRF and evaluated in regards to causation, intensity and if the incident is classified as an AE or an SAE. SAE will be reported in a specific form and submitted to the principal investigator within a day. SUSAR will be evaluated by a licensed physician and further reported to The Swedish Medical Products Agency and the physicians that have met the subject during check-ups. Lethal or life threatening SUSAR will be reported within a week and complemented with other relevant information within the 8 days following, while other types of SUSAR will be reported within 15 days.
Evaluation of events
The principal investigator will evaluate possible causation between AE/SAE and melatonin usage. If such an association is found, the subjects will be followed until declared healthy, until a “near healthy” status is declared, or until the principal investigator considers no further need for follow-up. All AE/SAE will be categorized as probably related, possibly related or not related. Probably related events are defined as clinical events, including abnormal laboratory analysis results occurring at a reasonable time following melatonin administration, if the event is unlikely to be related to an underlying disease or another medication, or if the symptoms are previously known side effects of melatonin. Possibly related events are defined as clinical events, including abnormal laboratory analysis results occurring after a reasonable time following melatonin treatment, where the event can be explained by the usage of melatonin, but there is not sufficient information to ensure the causation exists. Not related events are defined as clinical events including abnormal laboratory analysis results occurring at an unreasonable time as related to melatonin treatment, thereby suggesting the event likely not related to the intervention (melatonin) and can be explained by another medication or underlying disease.
Unfavorable medical events will be classified and graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. based on the following:
Grade 1: | Mild Asymptomatic or mild symptoms Only clinical or diagnostic observations; intervention not indicated |
Grade 2: | Moderate Minimal, local, or non-invasive interventions indicated; affects age-adjusted ADL |
Grade 3: | Severe Medically significant but not acutely life threatening; hospitalization or lengthened health care indicated; disabling; limits personal ADL |
Grade 4: | Life threatening Life threatening consequences, acute interventions indicated |
Grade 5: | Death related to side effects. |
In urgent situations, the principal investigator will immediately take urgent safety measurements required to protect the subjects, such as temporarily terminating the clinical trial medication or implementing additional monitoring measures. An overdose of medication associated with AE will be registered as a diagnosis or symptom in the CRF, and in the subject’s journal documentation if no associated symptoms are found. Women of fertile age will be excluded from this trial.
All study participants will be insured via LÖF (Landstingens regionernas ömsesidiga försäkringsbolag.
Dissemination plans
This study protocol follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines.50 In order to communicate the trial results to participants, healthcare professionals and the public we plan to publish our findings in peer-reviewed journals and present them at both domestic and international scientific conferences.