Administrative information
Title {1} | Efficacy of mistletoe extract as a complement to standard treatment in advanced pancreatic cancer: study protocol for a multicentre, parallel group, double-blind, randomised, placebo-controlled clinical trial (MISTRAL) |
Trial registration {2a and 2b} | EU Clinical Trial Register, EudraCT Number 2014-004552-64. Registered 19 January 2016 ClinicalTrials.gov, Identifier: NCT02948309. Registered 28 October 2016 |
Protocol version {3} | Date 15 July 2020, Version 3.3 |
Funding {4} | The trial is academic, with financial support provided by grants from the Oncological Department Endowment Fund at Karolinska University Hospital, The Cancer Research Funds of Radiumhemmet, Gyllenberg foundation, Ekhaga foundation, Dagmar Ferbs Memorial fund, Cancer Research Foundation in Northern Sweden and The Sjöberg Foundation. The funders did not have any role in trial design nor writing of the study protocol or this paper. No commercial interests are involved in the trial. Regional Cancer Centre Stockholm Gotland provided support with administration, research time for coordinating investigator, monitoring and analytic competence. Iscador AG, Switzerland manufacture and supply both mistletoe extract and placebo free of charge. |
Author details {5a} | KW: Dept. Nursing and Dept. Radiation Sciences, Umeå University, Umeå; Dept. Upper Abdominal Diseases, Karolinska University Hospital and Regional Cancer Centre Stockholm Gotland, Stockholm, Sweden JHN: Regional Cancer Centre Stockholm Gotland and Dept. Neurobiology, Caring Sciences, Society and Dept. Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden GSK: Centre for Complementary Medicine; Institute for Infection Prevention and Hospital Epidemiology, Medicine and Medical Centre, Faculty of Medicine, University Freiburg and Institute for Applied Epistemology and Medical Methodology at the University Witten/Herdecke, Freiburg, Germany NOE: Dept. Oncology and Dept. Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden BMB: Dept. Learning, Informatics, Management, and Ethics, Karolinska Institutet, Stockholm, Sweden BS: Dept. Nursing, Umeå University, Umeå; Dept. Clinical Intervention and Technology, Div. Surgery, Karolinska Institutet and Dept. Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden LS: Regional Cancer Centre Stockholm Gotland and Dept. Learning, Informatics, Management and Ethics, Karolinska Institutet, Stockholm, Sweden RH: Dept. Radiation Sciences, Umeå University, and Cancercentrum, Norrland University Hospital, Umeå, Sweden PF: Dept. Nursing, Umeå University, and Cancercentrum, Norrland University Hospital, Umeå, Sweden |
Name and contact information for the trial sponsor {5b} | Dept. Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden Contact and coordinating investigator Kathrin Wode, kathrin.wode@sll.se, phone: +46 8 123 142 61 |
Role of sponsor {5c} | The sponsor is non-commercial and represents the main study site, where most participants are expected to be recruited due to its size. The sponsor supports the study with trial unit facilities and study nurses. Karolinska University Hospital is responsible of personal data according to the General Data Protection Regulation (GDPR). |
Introduction
Background and rationale {6a}
Objectives {7}
Trial design {8}
Methods: participants, interventions and outcomes
Study setting {9}
Eligibility criteria {10}
Inclusion and exclusion criteria for participants
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Signed written informed consent
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Age ≥ 18 years
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Inoperable locally advanced or metastatic pancreatic cancer or relapse of pancreatic cancer
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Primary diagnosis: if histology is not clinically achievable, diagnosis is to be confirmed according to local practice sufficient for diagnosis and choice of therapy (such as CA19-9 and CT)
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Relapse: histology (not required) or diagnosis according to local practice such as clinical signs and/or imaging and/or CA19-9
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ECOG performance status 0–2
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Adequate negative pregnancy test and adequate contraception (where appropriate)
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Life expectancy less than 4 weeks
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Pregnancy or breastfeeding
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Neuroendocrine tumours of the pancreas
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Current use of interferon, granulocyte-colony stimulating factor and thymus preparations
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Symptomatic brain oedema due to brain metastases
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Known hypersensitivity to mistletoe-containing products
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Current use of ME preparations in any form
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Chronic granulomatous disease or active autoimmune disease or autoimmune disease with immunosuppressive treatment
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Medical, psychiatric, cognitive or other conditions that may compromise the patient’s ability to understand the patient information, give informed consent, comply with the study protocol or complete the study (e.g. needle phobia)
Study site requirements
Who will take informed consent? {26a}
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Interventions
Explanation for the choice of comparators {6b}
Intervention description {11a}
Product | Quantity of drug substance per 1 mg ampoule; extract 1:5 | Corresponding amount of fresh mistletoe |
---|---|---|
Iscador® Qu 0.01 mg | 0.05 mg | 0.01 mg |
Iscador® Qu 0.1 mg | 0.5 mg | 0.1 mg |
Iscador® Qu 1 mg | 5 mg | 1 mg |
Iscador® Qu 10 mg | 50 mg | 10 mg |
Iscador® Qu 20 mg | 100 mg | 20 mg |
Criteria for discontinuing or modifying allocated interventions {11b}
Maintenance of dose
Reduction of dose
Temporal interruption of trial intervention
Termination of trial intervention
Strategies to improve adherence to interventions {11c}
Drug account
Education study sites, palliative home care teams
Relevant concomitant care permitted or prohibited during the trial {11d}
Provisions for post-trial care {30}
Outcomes {12}
Participant timeline {13}
Sample size {14}
Recruitment {15}
Assignment of interventions: allocation
Sequence generation {16a}
Concealment mechanism {16b}
Implementation {16c}
Assignment of interventions: blinding
Who will be blinded {17a}
Procedure for unblinding if needed {17b}
Data collection and management
Plans for assessment and collection of outcomes {18a}
Primary outcome
Secondary outcomes
Documentation and training plans
Plans to promote participant retention and complete follow-up {18b}
Data management {19}
Confidentiality {27}
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
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H0: no difference between ME and placebo
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H1: difference between ME and placebo
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H0: no difference between ME and placebo
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H1: difference between ME and placebo
Analysis data sets
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Full Analysis Set (FAS)—All randomised patients who received at least one dose of ME or placebo will be included in the statistical analyses of primary and secondary endpoints. FAS is equivalent to an ITT analysis set, as all participants will take their first injection with the study drug at baseline visit. To be included in the analysis of the secondary endpoints, a baseline value and at least one post baseline assessment is required. Patients will be included in the treatment groups according to randomisation. Patients lost to follow-up or withdrawing consent from the trial will be censored for the primary analysis and will not be replaced.
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Per Protocol (PP) analysis set—A per protocol analysis will be performed for OS as a sensitivity analysis. This analysis will exclude any patient who has at least one significant protocol deviation believed to have a potential impact on the efficacy outcome (OS), e.g. patients who received the wrong treatment, not enough treatment, or patients receiving prohibited therapy. Decisions regarding major protocol deviation will be made before unblinding the trial.
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Safety Analysis Set (SAS)—All randomised patients who received at least one dose of ME or placebo will be included in the statistical analyses of primary and secondary endpoints. Patients will be included in the treatment groups according to treatment actually given. SAS represents a PP analysis set including all participants that have started treatment.