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Prolonged Remission Induced by FENofibrate in children with newly diagnosed type 1 diabetes (PRIFEN): protocol of a randomised controlled trial
  1. Lidia Groele1,
  2. Katarzyna Dżygało2,
  3. Agnieszka Kowalska2,
  4. Agnieszka Szypowska1,2
  1. 1Department of Paediatrics, Medical University of Warsaw, Warsaw, Poland
  2. 2J.P. Brudziński Children's Clinical Hospital, University Clinical Centre of Warsaw Medical University, Warsaw, Poland
  1. Correspondence to Professor Agnieszka Szypowska; agnieszka.szypowska{at}wum.edu.pl

Abstract

Introduction Sphingolipids regulate proinsulin folding, insulin secretion and control beta cells apoptosis. Recent evidence has demonstrated that, among other factors, reduced amounts of sulfatide may be relevant in the development of type 1 diabetes (T1D). Thus, fenofibrate, which activates sulfatide biosynthesis, may prolong remission in subjects with T1D. The aim of the study is to evaluate clinical efficacy of fenofibrate on the maintenance of residual beta-cell function in children with newly diagnosed T1D.

Methods and analysis A total of 102 children aged 10–17 years with newly diagnosed T1D will be enrolled in a double-blind, two-centre randomised, non-commercial, placebo-controlled trial. Subjects who will meet all inclusion criteria will be randomly assigned to receive fenofibrate at a dose of 160 mg or an identically appearing placebo, orally, once daily, for 12 months. The primary endpoint will be the area under the curve of the C-peptide level during 2-hour responses to a mixed-meal tolerance test (MMTT). Secondary endpoints include fasting and maximum C-peptide concentration in the MMTT, parameters of diabetes control and glucose fluctuations, daily insulin requirement, inflammation markers, genetic analysis, safety and tolerance of the fenofibrate

Ethics and dissemination The study protocol was approved by the Bioethics Committee. The results of this study will be submitted to a peer-reviewed diabetic journal. Abstracts will be submitted to international and national conferences.

Trial registration number EnduraCT 2020-003916-28.

  • DIABETES & ENDOCRINOLOGY
  • Paediatric endocrinology
  • Child protection
  • PREVENTIVE MEDICINE
  • Chronic Disease
  • Clinical Trial
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STRENGTHS AND LIMITATIONS OF THIS STUDY

  • The Prolonged Remission Induced by FENofibrate clinical trial is a prospective, randomised, double-blind, placebo-controlled study—a design considered the ‘gold standard’ in interventional research.

  • This is the first study evaluating the effect of fenofibrate on beta cell function in teenagers with newly diagnosed type 1 diabetes (T1D).

  • It remains unclear which dose of fenofibrate is potentially the most useful for the management of T1D.

  • The intervention of taking a daily pill carries the risk of missing a dose, and therefore, the risk of non-compliance.

Introduction

Type 1 diabetes (T1D) involves the autoimmune destruction of the insulin-secreting pancreatic islets of Langerhans, leading to insulin deficiency.1–3 The prevalence of T1D varies considerably geographically,3 but in many regions, it is rising.4 The pathophysiology is multifactorial. In addition to genetic background, several environmental factors have been claimed to influence T1D epidemiology, including the mode of birth, early infant diet, viral infections and antibiotic use.5–7 Recent evidence has demonstrated that reduced amounts of sulfatide in pancreatic islets also may be relevant.8

Sulfatide is produced in a relatively large amount in pancreatic beta-cell. It is known to have an important role in insulin secretion: stimulating calcium ion-dependent insulin exocytosis and promoting proinsulin folding. Moreover, sulfatide mediates the monomerisation of insulin and induces glucose-dependent stimulation of insulin. Sulfatide also prevents apoptosis in insulin-secreting cells by preventing the effects of interleukin-1 beta (lL-1β), interferon beta 1b (lFN-1β) and tumour necrosis factor-alpha (TNF-α), induced nitric oxide synthase.

Compared with healthy controls, subjects with newly diagnosed T1D demonstrated reduced amounts of sulfatide in pancreatic islets, which were associated with reduced expression of enzymes involved in sphingolipid metabolism. There were identified genes polymorphism involved in sphingolipid metabolism that contribute to the genetic predisposition to T1D and correlated with the degree of cellular islet autoimmunity in a cohort of individuals with T1D.8

Fenofibrate is used to treat primary hypercholesterolaemia, mixed dyslipidaemia and severe hypertriglyceridaemia in adult patients and in children with very high triglyceride levels to prevent pancreatitis. Moreover, some studies indicate that fenofibrate is an independent protective factor for the development of diabetic retinopathy and neuropathy.9–11

Data on the effects of fenofibrate in subjects with T1D are very limited. However, preliminary reports are promising. Fenofibrate altered islet sphingolipid metabolism in T1D. Increasing sulfatide levels and decreasing insulitis prevents diabetes in non-obese diabetic (NOD) mice suggesting that upregulation of sulfatide biosynthesis may represent a promising therapeutic route in T1D. In animals, studies using the NOD mice model showed that using fenofibrate protected diabetes in NOD mice with insulitis and even reversed the disease in half of the otherwise diabetic animals. Treatment initiated after the onset of diabetes reversed diabetes in 46% (6/13) NOD mice after 3 weeks of treatment.12

In human, young women with newly diagnosed T1D, following fenofibrate treatment became insulin independent for at least 21 months. Unstimulated C-peptide has increased by 51% and IA-2 autoantibody level has decreased by 65%.13 Further studies to confirm this association are needed.

Trial objectives and hypothesis

The aim of the study is to examine the effects of fenofibrate on pancreatic beta-cell function in children with newly diagnosed T1D. We hypothesise that children and adolescents who receive fenofibrate at the recognition of T1D will have more preserved beta-cell function than children who receive a placebo over a 12-month period.

Potential benefits of the trial

Confirmation of our hypothesis would be a new indication for fenofibrate treatment in order to prolong partial remission in people with newly diagnosed T1D. Preservation of residual pancreatic beta cell function in children with newly diagnosed T1D gives a chance for better diabetes control, reduction of chronic diabetes complications and possibly temporary insulin withdrawal.

Methods

Trial design

This study is designed as a randomised, double-blind, placebo-controlled trial with 1:1 allocation ratio. The trial was registered at EnduraCT 2020-003916-28 prior to the inclusion of the first patient. ClinicalTrials.gov Identifier: NCT05909800. Date and protocol version identifier: V.3.0, Date: 25 April 2023.

Patient and public involvement

No patient involved.

Settings and participants

Recruitment will be through the paediatric diabetes clinics at two participating centres in Warsaw, Poland (Department of Paediatrics, the Medical University of Warsaw and Department of Endocrinology and Diabetology, Children’s Memorial Health Institute). Both are tertiary care hospitals that provide annually diabetes care to more than 250 children with newly recognised T1D. The personnel is adequately trained and competent in conducting clinical trials. The first patient was enrolled in September 2022 and the study should be completed in 2024.

Eligibility criteria

Eligible children must fulfil all the following inclusion criteria:

  • T1D as defined by Polish Diabetes Association and ISPAD (the International Society for Pediatric and Adolescent Diabetes) criteria,14 15 diagnosed within 8 weeks before randomisation.

  • Presence of at least one positive autoantibody (autoantibodies to glutamic acid decarboxylase (GADA), the tyrosine phosphatase-related insulinoma-associated 2 molecule (anti-IA-2), insulin autoantibody (anti-IAA), the zinc transporter (ZnT8)).

  • Age 10–17 years.

  • Written informed consent signed by parents or legal caregivers and children.

  • Male or non-pregnant and non-lactating female who is abstinent or agrees to use effective contraceptive methods.

  • A female with a negative result on a pregnancy test at the time of screening and randomisation visit.

Exclusion criteria:

  • Age under 10 or over 17.

  • Lack of consent.

  • Treatment with any oral or injected antidiabetic medications other than insulin.

  • The participant’s or family history of allergic or hypersensitivity reactions to fenofibrate or any of the excipients.

  • Severe hypersensitivity reaction to any drug.

  • Current or history of clinically significant hepatic or renal impairment, gastrointestinal disease, gall bladder disease, acute or chronic pancreatitis, except acute pancreatitis due to severe hypertriglyceridaemia.

  • Phototoxic reaction to fenofibrate or chemically related substances, for example, ketoprofen.

  • Hypersensitivity to fenofibrate.

  • Positive for a pregnancy test or current breast feeding.

  • Low blood albumin defined as clinically significant by the investigator.

  • Predisposing factors for myopathy and/or rhabdomyolysis, including personal and familial history of hereditary muscular disorders.

  • Unexplained persistent elevated creatine phosphokinase levels considered clinically significant by the investigator.

  • The presence of other circumstances, any medical condition or treatment that the investigator considers problematic or that may invalidate the interpretation of test results or expose the subject to unnecessary risk during the study.

  • Inability or unwillingness to comply with study procedures.

  • Participation in interventional or other drug research studies that could affect the objectives of this study or participation in a clinical study within 3 months before the screening visit.

Interventions

The intervention will be the administration of fenofibrate dose of 160 mg (Grofibrat S, manufacturer Geoden Richter Polska Sp. z o. o.) EudraVigilance:SUB07576MIG. A placebo comparator was chosen as the gold standard for testing the efficacy of a new treatment.16 17 The placebo will contain Microcrystalline cellulose 102 594 mg (99%) and Magnesium stearate 6 mg (1%). Its taste and appearance will be identical to those of the active product. The study products will be manufactured in tablets and supplied by Cefea Sp. z o.o. The manufacturer will have no role in the conception, protocol development, design, or conduct of the study, or in the analysis or interpretation of the data.

Discontinuation of study treatment

Use of concomitant medications that in the investigator’s opinion may confound assessments of efficacy and/or safety is not permitted during the study.

A subject must permanently discontinue study treatment for any of the following reasons:

  • The subject becomes pregnant.

  • The subject experiences a medical emergency that necessitates permanent discontinuation of study treatment or unblinding of the subject’s treatment assignment.

  • Adverse event (AE) of special interest:

    • Transaminase levels increase to more than three times the upper limit of the normal range or 100 IU.

    • Pancreatitis.

    • Creatine phosphokinase levels exceeding five times the normal range and/or clinically significant muscle toxicity.

    • Creatinine level increase 50% above the upper limit of normal.

Study procedure

Patients and parents/caregivers will receive oral and written information regarding the study during their regular diabetes outpatient clinic visits within 8 weeks after T1D recognition. Written informed consent, signed by the legal caregivers and the patients, will be obtained by a physician involved in the study. An example of the patient consent form is provided as online supplemental file 1.

Participants will be randomly assigned to two groups, receiving either fenofibrate at a dose of 160 mg or placebo, orally, once daily, for 12 months. Study visits at month 3 (V1), month 6 (V2), month 9 (V3) and month 12 (V4) and a telephone visit 6-week after the end of treatment. In case of AE (including laboratory abnormal values) during the follow-up visit subjects could be ask to come to the site for additional procedures. The study procedures are described in table 1.

Table 1

A schedule of study procedures

At study entry and all study visits, all children will undergo a physical examination, including evaluation of anthropometric measurements (weight, height and body mass index (BMI)), which will be plotted on WHO growth curves18). Children will be treated with intensive insulin therapy (continuous subcutaneous insulin infusion or multiple daily injections) using insulin analogues. The total daily insulin dose and basal insulin will be downloaded from insulin pumps or will be collected from patients’ diaries. The FreeStyle Libre glucose monitoring system will be inserted at each visit, to assess glucose variability. In addition, episodes of severe hypoglycaemia and ketoacidosis will be noted.

In our study, we chose to use the mixed-meal tolerance test (MMTT), as it is widely regarded as the gold standard for measuring endogenous insulin production among patients with T1D to assess residual beta cell function.19 Participants will ingest 6 mL/kg of Boost meal solution (maximum 360 mL), within 10 min. Blood samples for the measurement of C-peptide and glucose will be collected 10 min prior to the meal (−10 min), at the time of ingestion (0 min), and at 15, 30, 60, 90 and 120 min. The 2-hour MMTT will be performed three times: at allocation and in months 6 and 12.

Compliance will be assessed by collecting empty packages and the remainder of the product that was not used as well as by direct interview with the patient and/or caregiver. Participants receiving <75% of the recommended doses will be considered non-compliant.

At any time point, children and/or caregivers will have the right to withdraw from the study without giving the reason for discontinuation. There will be no effect of this discontinuation on subsequent physician and/or institutional medical care.

Endpoints

Primary

  • Area under the curve of the C-peptide level (AUC CP) during 2-hour responses to the MMTT at visit 4 (month 12).

Secondary

  • C-peptide concentration (fasting, peak, AUC).

  • Diabetes-associated autoantibodies.

  • Insulin requirement (U/kg body mass).

  • Diabetes compensation (glycated haemoglobin, HbA1c, and based on FreeStyleLibre reports: mean glucose, SD, time in range -TIR, coefficient of variation, CV%).

  • Interleukins: IL-1, IL-2, IL-10, TNF-α, IFN-γ.

  • Whole Exome Sequencing (WES), high-resolution HLA-DRB1 and HLA-DQB1 sequencing.

  • Anthropometric parameters (weight, height, BMI z-score).

  • Side effects (eg, abdominal pain, diarrhoea).

  • Occurrence of other autoimmune diseases.

  • Acute complications of T1D such as severe hypoglycaemia or ketoacidosis.

Participant timeline

The schedule for enrolment, interventions, assessment and visits for the participants is described in table 1.

Sample size

The sample size was calculated based on recommendations on sample size calculation to be used in studies on the effects of new agents on the 2-hour AUC of the C-peptide in MMTT in newly diagnosed patients with T1D by Lachin and McGee.20 A normalising transformation ln(x+1) for C-peptide AUC is planned to be used. Assuming increase by 50% of AUC of C-peptide in the test group compared with placebo (with expected mean of the C-petide AUC after 12 months of 0.248 pmol/mL/120 min) and SD of 0.179 pmol/mL/120 min, 88 subjects are needed to achieve power of 85%. If about 13% drop-out is assumed, the total group size is 102 patients. Given randomisation ratio 1:1, there is 51 patients in each group.

Randomisation

Prior to the start of the study, a randomisation list and list of drug code will be generated by a statistician from the Contract Research Organisation (CRO). Drug coded will be transmitted to the assigned clinical packaging organisation for labelling. Subjects who have been found to comply with all inclusion criteria and have none of the exclusion criteria will be randomised centrally (by computer) into consecutive blocks in a 1:1 ratio for the active treatment group and placebo group.

Blinding

All study staff and participants will be blinded to the subject treatment assignments until the completion of the study. Blinding codes should only be broken in emergency situations for reasons of subject safety. When the blind for a subject has been broken, the reason must be fully documented in the source document and electronic case report form (CRF). Whenever possible, the investigator should contact sponsor or its designee (CRO) before breaking the blind. Data from the subject for whom the blind was broken will be included in the analysis.

Allocation concealment

The study products are packaged and assigned the random numbers generated by the computer. The staff will dispense the numbered study products.

Data collection and management

All study participants will be assigned a study identification number. CRFs will be completed on paper forms . Data will then be entered and stored in a password-protected electronic database. The original paper copies of CRFs and all study data will be stored in a locker within the study site, accessible to the involved researchers only. The reason for discontinuation of study treatment must be recorded in the CRFs. Subjects who prematurely discontinue treatment should be encouraged to continue with regular visits on-site or by phone. If possible, on-site early treatment termination visit should be completed at the time of treatment discontinuation.

Monitoring

An authorised sponsor representative—CRO provides trial management and monitoring services, which consists of controlling compliance with the protocol and review the study progress and all AEs. Sponsor reserves the option to terminate the study at any time.

Statistical analysis

Analysis of covariance (ANCOVA) model of effect of assigned treatment on C-peptide AUC at visit 4 (month 12) will be prepared. This model will be adjusted for age, gender and baseline value C-peptide mean AUC. ANCOVA will be performed of normalised AUC for C-peptide using log(1+XC−Pep) transformation. The normality and equal variance assumptions underlying the ANCOVA model will be assessed graphically. Residuals from the primary model will be plotted against the predicted values and a QQ-plot of the residuals versus the expected quantiles of the standard normal distribution will be presented. If either the equal variance or the normality assumption appears to be grossly violated, other methods including an ANCOVA on ranks model or an appropriate transformation of the primary endpoint might be considered. Additional sensitivity analysis of primary endpoint will be conducted using mixed model for repeated measure (MMRM) method with an additional fixed factor for visit. Data from visit 2 will be included in this model. This model will account for the interaction between a treatment and a visit. Subject will be treated as a random effect, with an unstructured covariance structure to account for the correlation among repeated measurements. If the model does not converge, another covariance structure will be explored. The model formula that will be used for this analysis:

AUC change–baseline AUC+age+gender+treatment×visit+us(visit|subject ID).

MMRM will be performed of normalised AUC for C-peptide using log(1+XC−Peptide) transformation, as well

In the analysis of secondary endpoints (C-peptide, insulin dose, HbA1c), a prespecified ANCOVA model will be used. Additional models will employ linear mixed effect models with additional fixed factor for visit and a random effect—a subject ID. This model will include interaction between treatment and visit. Inflammation markers, anti-insulin antibodies, genetic analysis and time spent in normoglycaemia will be summarised descriptively.

All analyses will be performed on the intention-to-treat basis and per-protocol analysis. The significance level will be set at 0.05 and all statistical tests will be two tailed. The statistical analysis will be performed using the R statistical software package (V.4.0 or later).

Harms

Data on AEs will be collected. All serious AEs (SAEs) will be reported within 24 hours to sponsor or CRO. Sponsor or designee (CRO) will send copies of expedited reports for SAEs that are unexpected and at least possibly related to the study treatment to all concerned regulatory authorities and active investigators. The coordinating investigator will be responsible for sending reports to the ethics committee.

Auditing

Sponsor/CRO personnel or their designee may perform an audit at any time during or after completion of the clinical study. The investigator will permit authorised representatives of CRO and the respective national or local health authorities to inspect facilities and records relevant to this study.

Ethics and dissemination

The study was approved by the ethics committee of the Medical University of Warsaw. Any modifications to the protocol that may affect the conduct of the study will be presented to the ethics committee. Sponsor and investigators will have access to the final trial dataset. The full protocol will be available freely due to open-access publication. The findings of this randomised controlled trial (RCT) will be submitted to a peer-reviewed journal. Abstracts will be submitted to relevant national and international conferences. The standards from the guidelines of the Standard Protocol Items for Randomised Trials will be followed for this RCT. The sponsor has covered this clinical study by means of insurance of the clinical study according to national requirements.

Subject confidentiality

Information obtained during the study is confidential and may be inspected by the clinical investigator, the investigator’s staff, and sponsor and its representatives to check, process, evaluate and use in accordance with applicable law protecting subject privacy.

Patient and public involvement

Patients and members of the public will be involved in developing patient information leaflets or posters and will be undertaking interviews with research participants.

Ethics statements

Patient consent for publication

Acknowledgments

The authors would like to thank prof. K. Buschard for support of scientific and technical information regarding the project and the BioStat® company for CRO service.

References

Footnotes

  • Contributors AS conceptualised the study. LG developed the first draft of the manuscript. KD and AK performed critical revision of the manuscript for important intellectual content. All authors contributed to the development of the study protocol and approved the final draft of the manuscript.

  • Funding The study is funded by The Medical Research Agency grant nr 2019/ABM/01/00054 provided by the Medical Research Agency 1A Moniuszki Street, 00-014 Warsaw, Poland, phone: +48 (0) 222707069.

  • Disclaimer The funders will have no role in the conception, protocol development, design, or conduct of the study, or the analysis or interpretation of the data.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.