Administrative information
Title {1} | Randomized, double-blind, multicenter placebo-controlled study assessing neurotoxicity in patients with metastatic gastrointestinal adenocarcinoma taking phycocyanin or placebo during oxaliplatin-based chemotherapy |
Trial registration {2a and 2b} | Registration number NCT05025826 |
Protocol version {3} | The updated protocol is version 2 of May 23, 2022. |
Funding {4} | PROPERTY was supported by AlgoSource, Saint-Nazaire, France |
Author detail {5a} | Christele Le Gouill-Jaijarat and Claire Peluchon are part of the Gastroenterology Department of CHU Nantes; Claire Peluchon is also part of the Clinical Investigation Centre CIC1413 (INSERM and CHU Nantes), while Alexandra Poinas is solely a member of the CIC. Maxime Leroy, Caroline Perrault, Christelle Volteau, Anne-Sophie Martineau, Simon Korner and Anne Chiffoleau are from the Sponsor Department of CHU Nantes. Olivier Lépine and Aymeric Loloum are part of the AlgoSource laboratory. Jaafar Bennouna Asmahane Benmaziane, Paul Girot, Caroline Petorin, Clément Perret, Catherine Ligeza-Poisson, and Didier Mayeur are principal investigators, who are members of the Gastroenterology Department of Foch Hospital, Vendée Departmental Hospital, Estaing Hospital, Saint-Grégoire Private Hospital, Saint-Nazaire Hospital, and Georges and François Leclerc Center respectively. Laurent Flet works in the Pharmacy Department and Yann Péréon in the Department of Clinical Neurophysiology, both at CHU Nantes. |
Name and contact information for the trial Sponsor {5b} | The Sponsor Department of CHU Nantes responds to any requests sent to this e-mail address: BP-direction-de-la-recherche@chu-nantes.fr. |
Role of the Sponsor {5c} | All the submissions/declarations were made by the Sponsor Department at CHU Nantes, which manages the quality of the data collected. The data collected during the study will be processed electronically in accordance with the requirements of the CNIL (the French Data Protection Authority) and with the European and French regulations on safety matters. The sponsor should address any requests for substantial modifications of the protocol to the French regulatory authorities and/or the relevant Ethics Review Board for approval or notification, in compliance with French Law 204-806 of August 9, 2004 and its implementing decrees. It should be noted that the funding body is not connected with the data collected or with the protocol and any amendments thereto. |
Introduction
Background and rationale {6a}
Objectives {7}
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➢ Percentage of patients who stopped oxaliplatin due to neurological toxicity
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➢ Percentage of patients with an oxaliplatin dose decrease
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➢ Neurological toxicities according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0
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➢ Overall toxicity (including hematological toxicity, gastrointestinal toxicity, etc.)
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➢ Patient’s quality of life according to the EORTC-QLQ-C30 questionnaire
Trial design {8}
Methods: participants, interventions, and outcomes
Study setting {9}
Eligibility criteria {10}
Inclusion criteria | Exclusion criteria |
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• Male or female with the age > or = to 18 years old. • Negative pregnancy test for women with child-bearing potential if applicable (without hysterectomy for example) • Information given to the patient who must have signed informed consent • Patient with Histologically or cytologically proven gastrointestinal adenocarcinoma including oesogastric, colorectal, and pancreatic cancers and planned to be treated with oxaliplatin • Patient with metastasic disease not previously treated • Previous radiotherapy is authorized if discontinued ≥15 days prior to randomization • Sites of disease evaluated within 42 days prior C1 day 1 of chemotherapy with thoracic-abdominal-pelvic CT scan (or abdominal-pelvic MRI and chest X-ray) • Patient with ECOG Performance status 0 or 1 • Patients with a Life expectancy ≥12 weeks • Laboratory results: ° Hematologic function: ▪ Polynuclear neutrophils ≥ 1.5.109/L ▪ Platelets ≥100.109/L ▪ Haemoglobin ≥9 g/dL ° Hepatic function: ▪ Transaminases ≤2.5 times upper limit of normal (ULN) (≤5 ULN in case of hepatic metastases), ▪ Alkaline phosphatases ≤2.5 × ULN (≤5 ULN in case of hepatic metastases), ▪ Total bilirubin ≤1.5 × ULN ° Renal function: ▪ Creatinemia clearance >50 ml/min (Cockcroft and Gault) • Patient with Public Health insurance coverage | • Patients with phenylketonuria • Patients with known meningeal or brain metastases • Patient previously treated for their metastatic cancer • Patient previously treated with oxaliplatin • Patient with specific contraindication or known hypersensitivity to spirulina • Patient with specific contraindication or known hypersensitivity to oxaliplatin. • Known allergy or hypersensitivity to antibodies or any preservatives if patient is treated with a monoclonal antibody combined to chemotherapy (bevacizumab or cetuximab or panitumumab or nivolumab), • Patient with clinically significant coronaries affection or myocardial infarction within 6 months prior to randomization. • Patient with peripheral neuropathy >1 (CTCAE scale version 5.0). • Patients with known dihydropyrimidine dehydrogenase (DPD) deficiency. • Patient with acute intestinal obstruction or sub-obstruction, history of inflammatory intestinal disease or extended resection of the small intestine or presence of a colic prosthesis. • Patient with unhealed wound, active oesogastric or duodenal ulcer, or bone fracture • Patient with an history of abdominal fistulas, trachea-esophageal fistulas or any other grade 4, gastro-intestinal perforations or non-gastrointestinal fistulas or intra-abdominal abscesses during the 6 months before randomization. • For patient treated with bevacizumab: patient with uncontrolled arterial hypertension (systolic pressure >150 mmHg and/or diastolic pressure >100 mmHg) with and without antihypertensive medication. Patients with high hypertension are eligible if antihypertensive medication lowers their arterial pressure to the level specified by the inclusion criterion. • Patient with an history of hypertensive crisis or hypertensive encephalopathy • Patient with other concomitant malignancy or history of cancer (except in situ carcinoma of the cervix, or non-melanoma skin cancer, treated with curative intent treatment) except if considered in complete remission for at least 2 years before randomization • Existence of any other pathology, metabolic problem, anomaly during the clinical examination or biological anomaly which may reasonable suspect an underlying pathology which would contra-indicate the use of the study medication or any other risk of complication related to the treatment. • Any treatment including an experimental drug, or participation in another clinical trial within 28 days before randomization. • Pregnant women, or women who could possibly be pregnant (or who expect to fall pregnant within 6 months of the end of treatment), or who are breast feeding are not eligible. • Men and women of child-bearing potential who do not accept to use a highly effective contraceptive (as per currently acceptable institutional standards) or abstinence during the study and for the 6 months after the last administration of the study treatments. • Persons deprived of liberty or under guardianship. • Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule |
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}
Assessments | Inclusion visit D-30 to D-4 | Cycle 1 | Cycle 1 to 12 | Cycle 13 to 18 | End of study visit / 28 days after last day of PHYCOCARE® /PLACEBO | |
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D-3 to D-1 | D1 to D3 | D4 to D14 | D1 to D14 | |||
Informed consent | X | |||||
Medical History | X | |||||
Clinical examination (Performance status (ECOG), vital signs, symptoms) | X | X (D1) | every 28 days | X | ||
ONLS questionnaire | X | at M4 (C9D1) | X | |||
QLQ-C30 questionnaire | X | at M4 (C9D1) | X | |||
EDX | X | at M4 (C9D1) | X | |||
Randomisation | X | |||||
Scanner | at D-42 | |||||
PHYCOCARE® or placebo treatment | X | X | X (days without chemotherapy) | |||
Oxaliplatin-based chemotherapy | X | |||||
Chemotherapy maintenance regimen | If applicable | |||||
Adverse events (AE) | AE assessed at each patient visit | X | ||||
Treatment adherence (patient diary) | Compliance assessed at each patient visit | X |
Scale | NCI-CTC grading for neuropathy |
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Grade 1 | Asymptomatic, loss of deep tendon, reflexes, or paresthesia (including tingling), but not interfering with function |
Grade 2 | Sensory alteration or paresthesia (including tingling) interfering with function, but not ADL |
Grade 3 | Sensory alteration or paresthesia interfering with ADL |
Grade 4 | Disabling |
Criteria for discontinuing or modifying allocated interventions {11b}
Strategies to improve adherence to interventions {11c}
Relevant concomitant care permitted or prohibited during the trial {11d}
Provisions for post-trial care {30}
Outcomes {12}
Oxaliplatine dosage adjustment according to neurotoxicity | ||||
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Neurotoxicities | Grade | Toxicity duration | ||
1 to 7 days | > 7 days | Persistent between cyclesa | ||
Paresthesias/dysesthesiasb that do not interfere with fine motor skills | 1 | No dose reduction | ||
Paresthesias/dysesthesiasb that interfere with fine motor skills but do not affect activities of daily living (ADLs) | 2 | No dose reduction | 75% of the dose | |
Paresthesias/dysesthesiasb with pain or decreased fine motor skills that affect activities of daily living (ADLs) | 3 | 1st time: 75% of the dose 2nd time: 50% of the dose | Discontinue treatment | |
Persistent or incapacitating or lifethreatening paresthesia/dysesthesia | 4 | Discontinue treatment | ||
Acute toxicity: laryngeal-pharyngeal dysesthesiab (during or within 2 h after infusion) | NA | Extend the oxaliplatin infusion to 6 h on the next treatment. | NA |
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⇨ Time frame for definitive discontinuation or decrease in oxaliplatin treatment. The dose or discontinuation of oxaliplatin will be noted at each chemotherapy visit, in accordance with the process established in Table 3
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⇨ Dose intensity of oxaliplatin noted at each chemotherapy visit (see Table 3)
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⇨ Neurological adverse events at the following hospital visits: baseline, M4, and M9/termination visit
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⇨ Nerve electrodiagnostic examination (EDX) and neurology questionnaire: Overall Neuropathy Limitation Scale (ONLS) French translation according to Graham et Hugues [14] at baseline, M4 and M9/termination visit
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⇨ Adverse Events collected at each chemotherapy visit or in patient diary
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⇨ Quality of life questionnaire: QLQ C30 at baseline, M4 and M9/termination visit
Participant timeline {13}
Sample size {14}
Recruitment {15}
Assignment of interventions: allocation
Sequence generation {16a}
Concealment mechanisms {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}
Plan 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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Comparison of time before cessation or reduction of chemotherapy treatment will be estimated using the Kaplan-Meier method and tested with the log-rank test;
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Comparison of patients with a decrease in treatment due to neurological toxicity will take place via mixed linear regression on both treatment arms;
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Progression of grades 3 and 4 neurological adverse events at baseline, M4, and M9 (or at the last visit if earlier) will be tested using mixed linear regression with a random center effect;
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EDX data will be compared using Fisher’s exact test and the Wilcoxon-Mann-Whitney test;
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The chi-square test or Fisher’s exact test will be used to compare Adverse Events in both arms;
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Progression of grades 3 and 4 neurological QLQ C30 at baseline, M4, and M9 (or at the last visit if earlier) will be tested via mixed linear regression with a random center effect; and
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Median progression-free survival will be estimated and plotted using the Kaplan-Meier method and the response rate will be estimated as a percentage with a 95% confidence interval.
Interim analyses {21b}
Methods for additional analyses (e.g., subgroup analyses) {20b}
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Plans to give access to the full protocol, participant-level data and statistical code {31c}
Oversight and monitoring
Composition of the coordinating center and the trial steering committee {5d}
Composition of Data Monitoring Committee, its role and reporting structure {21a}
Adverse event reporting and harms {22}
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▪ PHYCOCARE®Spirulina has been the subject of preclinical and clinical studies. Preclinical data have not shown toxicity of spirulina at high doses (for administered doses up to 30g/kg/day or ad libitum in mice). In the numerous clinical studies carried out at doses of up to 19g/day of dry spirulina, only a few gastrointestinal (moderate vomiting and diarrhea episode) and headache-type adverse effects linked to the consumption of spirulina have been reported.Products containing spirulina may be contaminated with cyanotoxins, with bacteria or by metallic trace elements (Report of the French Agency for Food, Environmental and Occupational Health Safety (ANSES) available from: https://www.anses.fr/fr/system/files/NUT2014SA0096.pdf); no clinical impact (infection/signs of poisoning) is expected, however.
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▪ The placebo:
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° Hypersensitivity reaction to colorant (dry blue) or Cinnamomum camphora cineol may be expected
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° Toxicity: camphor laurel is mildly toxic to humans, and mild symptoms may occur if large quantities are eaten. All parts of the plant are poisonous and can cause nausea, vomiting, and respiratory distress. Allergic skin reactions can also occur
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° Headache (moderate and intermittent),
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° Constipation or loose stools
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° Elevated transaminases
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The protocol:
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° Disagreement or anxiety about randomization to the placebo arm
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° EDX: mild discomfort related to electrical stimulation and muscle needle examination
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° Asthenia, boredom, due to difficulty or inability to complete the questionnaires,
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The disease:
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° Anxiety/depression (including sleep disorders, suicide attempts)
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° Progression of the disease
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° Metastasis and related symptoms
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Chemotherapy and associated treatments. The main adverse reactions due to chemotherapy are:
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° Hematological toxicity
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° Gastrointestinal toxicity (nausea, vomiting, diarrhea, stomatitis)
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° Cutaneous-mucosal toxicity
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° Neurological toxicity
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° Fatigue
Chemotherapy also requires standard prophylaxis for drug toxicity and the risk of thrombosis, and pain killers. -