The HOME study is a prospective, randomized, controlled, double-blind, international, multicenter phase IV clinical trial with two parallel groups to be conducted in European Hospitals that treat HPN patients. It aims to investigate safety and tolerability of an n-3 PUFA enriched MCT/LCT ILE in stable adult CIF patients on long-term HPN and to show its non-inferiority compared to an MCT/LCT ILE with regard to liver function. A total of 160 (80 per group) eligible patients will be randomly assigned to receive the n-3 PUFA enriched MCT/LCT ILE or the MCT/LCT ILE within their PN regimen.
The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) checklist for this study can be found in Additional file 2.
The settings of the study are the surgical or gastroenterological outpatient clinics of the participating hospitals, where patients are cared for and monitored, however the PN regimen including Investigational Product (IP) is administered to patients at their homes. The processes of HPN supply can differ widely between countries and even between hospitals within the same country, but it is intended to follow the local standard procedures in this multicenter study as far as possible. The recruitment period was initially set to 18 months.
Trial population and eligibility criteria
Patients will be screened from the existing patient pool of the participating hospitals and must meet the following inclusion criteria to be considered eligible for the trial: Informed consent has to be available, male or female patients ≥ 18 years of age with CIF receiving HPN including lipids in whom the parenteral macronutrients have not been changed by more than 10 % for at least six months, and patients must receive ≥ 3.0 g lipids/kg BW per week.
It was decided to present the dose of lipids is presented as g/kg BW/week as the accepted policy in the designing of the HPN regimen is to reduce PN infusion days to a necessary minimum per week, maintaining the obligatory provision at the same time.
A patient who meets any of the following criteria will be excluded from participation: (1) persistent high total bilirubin values in medical history of the last six months (> 40 µmol/l), (2) interruption of PN for longer than four continuous weeks in the preceding six months, (3) history of cancer and anti-cancer treatment within the last two years, (4) hypersensitivity to egg, fish, peanut or soybean protein or to any of the active substances or excipients, (5) treatment with teduglutide in the past or currently, (6) contraindications to IPs (if available from medical records), which are severe hyperlipidemia including severe hypertriglyceridemia (≥ 1000 mg/dl or 11.4 mmol/l), severe coagulopathy, intrahepatic cholestasis, severe hepatic insufficiency, severe renal insufficiency in the absence of renal replacement therapy, acute thromboembolic events, fat embolism, aggravating hemorrhagic diatheses and metabolic acidosis, (7) general contraindications to PN (if available from medical records) including unstable circulatory status with vital threat (states of collapse and shock), acute phase of cardiac infarction or stroke, unstable metabolic conditions (e.g. decompensated diabetes mellitus, severe sepsis, coma of unknown origin), inadequate cellular oxygen supply, disturbances of the electrolyte and fluid balance (e.g. hypokalemia and hypotonic dehydration), acute pulmonary edema, decompensated cardiac insufficiency, (8) positive test for Human Immune-deficiency Virus, Hepatitis B or C (from medical history), (9) known or suspected drug or alcohol abuse, (10) patients who are unwilling or mentally and/or physically unable to adhere to study procedures, (11) participation in another interventional clinical trial in parallel or within three months prior to the start of this clinical trial, (12) any medical condition that in the opinion of the investigator might put the subject at risk or interfere with patient participation, (13) women of childbearing potential testing positive on standard pregnancy test (urine dipstick), (14) lactating women, (15) women of childbearing potential who do not agree to apply adequate contraception, and (16) persons of legal age who are the subject of a legal protection measure or who are unable to express their consent.
Investigational products (IPs)
The test IP Lipidem / Lipoplus® 200 mg/ml (B. Braun Melsungen AG, subsequently referred to as Lipidem® 200 mg/ml) is a milky-white oil-in-water emulsion for infusion. One liter of emulsion contains 100.0 g MCT, 80.0 g LCT and 20.0 g n-3 PUFA and provides the following amounts of EFAs: 38.4 – 46.4 g Linoleic acid (n-6 PUFA), 4.0 – 8.8 g alpha-Linolenic acid (n-3 PUFA), and 8.6 – 17.2 g EPA and DHA in sum. Additional excipients are all-rac-α-Tocopherol, egg lecithin, glycerol, ascorbyl palmitate, 2.6 mmol/l sodium as sodium hydroxide and sodium oleat, and water for injection. The energy content of 1000 ml Lipidem® 200 mg/ml is 7990 kJ ≈ 1910 kcal, the theoretical osmolality is approximately 410 mOsm/kg and pH range is 6.5 – 8.5 (NaOH or HCl < 0.5 mmol/l for adjustment to pH 7.4).
The reference IP Lipofundin® MCT/LCT / Medialipide® 20% (100 mg/ml + 100 mg/ml) (B. Braun Melsungen AG, subsequently referred to as Lipofundin® MCT/LCT 20%) is a milky-white oil-in-water emulsion for infusion. One liter contains: 100 g MCT and 100 g LCT and provides the following amounts of EFAs: 48.0 – 58.0 g Linoleic acid (n-6 PUFA) and 5.0 – 11.0 g alpha-Linolenic acid (n-3 PUFA) (n-3 PUFA). Additional ingredients are all-rac-α-tocopherol, egg lecithin, glycerol, sodium oleat and water for injection. The energy content of 1000 ml Lipofundin® MCT/LCT 20% is 8095 kJ ≈ 1935 kcal, the theoretical osmolarity is approximately 380 mOsm/l and pH range is 6.5 – 8.5 (NaOH or HCl < 0.5 mmol/l for adjustment to pH 7.4).
The administration of the IP is performed intravenously. The IP will be delivered as the lipid part of the PN. Besides the lipid PN contains glucose, amino acids, electrolytes, trace elements and vitamins and will be administered according to the individual patient’s normal prescription. The weekly dose of IP will be at least 3.0 g lipid/kg BW (corresponding to 15 ml emulsion/kg BW).
Randomization, Blinding and Unblinding
Eligible patients will receive a patient number indicating country, study site and randomization number. The randomization to either treatment will be in a 1:1 ratio with stratification for study center. A list of treatment assignments has been generated prior to the initiation of the study using consecutive blocks with the order of assignments chosen at random by an independent biometrician. The study is double-blind.
The processes of HPN supply differ between the study sites. The PN is prepared either in stocks as all-in-one admixtures in the hospital pharmacy or a compounding unit (CU) of a pharmacy service company or it is provided in multi-chamber bags to which the IP is added or it is mixed from the single nutrients on a daily base. In this multicenter clinical trial it is intended to follow the hospitals’ local standard procedures of PN supply as far as possible. This requires blinded IP in those sites where the patient will admix the PN including the lipid by him/herself. The production of the blinded IP is at the sponsor site and the sponsor’s Qualified Person for IP is responsible for blinding the samples prior to shipment to the sites. In study sites where either the hospital pharmacy or a CU is involved in preparing the all-in-one PN admixtures including the IP as the lipid part, unblinded IP will be delivered to the pharmacy/CU. The PN including the lipid will be prepared and provided to the participating patient as in routine practice. Treatment allocation is realized by randomization envelopes, which are issued by the independent statistician and provided to an unblinded pharmacist (or a delegate). Of note, the blinding of the investigators or other staff outside the pharmacy/CU will be maintained throughout the complete process. Finally, the PN bag label of the pharmacy/CU will not reflect which lipid is used, but only the amount of lipid. Thus, it is guaranteed also that the patient is kept blinded.
Based on the randomization list sets of emergency envelopes have been prepared for each participating site and the sponsor in case unblinding becomes necessary. Except for emergency reasons, the study will only be unblinded after closure of the database and determination of the analysis populations in a blinded data review meeting.
Interventions and procedures
The schedule of enrolment, interventions and assessments is shown in Figure 1 (SPIRIT figure).
Screening and randomization
Patients will be enrolled for the trial from the existing patient pool of the participating clinic and information about the trial can be provided in advance by phone and with information materials. After obtaining informed consent, the patient will be checked for eligibility. If all inclusion criteria are met and all exclusion criteria are excluded the patient will be randomized.
The baseline assessment is performed after randomization on the day of screening. Collected and generated data will be recorded in electronic Case Report Forms (eCRFs). Patient characteristics (demographic data, anamnesis and physical examination) and vital signs will be documented. Routine blood samples are taken and results for hepatic function, blood count and coagulation as well as biochemical parameters will be documented for the trial. For central laboratory analysis of primary variable and fatty acid (FA) pattern in red blood cells (RBCs) and plasma, additional blood samples are drawn and processed. Blood samples are taken no sooner than 3 hours after completion of the last PN infusion. Patients will be asked to complete a quality of life (QoL) questionnaire (EQ-5D-5L™, EuroQol Group, [Herdman et al., 2011]). Concomitant medication and adverse events (AEs) will be monitored and recorded continuously from study start (randomization) throughout the duration of patient’s study participation.
Patients are provided with a diary for documentation of IP administration on a daily base until visit 1. The patient has to enter date, start and end time of infusion of each PN-bag containing the IP as well as the weight of the bag before and after infusion. Furthermore, the intake of oily-fish meals is recorded.
The PN regimen including IP will be prescribed and prepared as needed. The infusion of IP will start within one week after baseline visit. If applicable, changes in prescription will be documented throughout the course of the study.
The study visit 1 will be conducted 4 weeks after start of IP infusions. The visit should be preferably the same day of week and time of day as the baseline visit. If this is not possible, it should be the same interval between PN infusion and visit day as it was for baseline (e.g. if baseline visit was after a day free of PN, visit 1 should be after a day free of PN as well).
Depending on patient’s travel distance and organizational circumstances, the study visit can be scheduled around the intended visit date within a tolerance timeframe of -3 days up to +2 weeks.
All assessment of safety, efficacy and other variables will be performed except blood draw for FA pattern and the QoL questionnaire. The first part of the patient diary will be collected and checked for accurateness and completeness. The data will be entered into the eCRF and the second part of the patient diary will be handed out for the treatment period until visit 2.
Visit 2 (final visit)
Visit 2 will be conducted 4 weeks after visit 1 and is the final visit. As for visit 1 it should also be preferably the same day of week and time of day as the baseline visit (and/or visit 1). If this is not possible, it should be the same interval between PN infusion and visit day as it was for visit 1. The tolerance timeframe for visit 2 is -3 days up to +2 weeks around the intended visit date. All assessment of safety, efficacy and other variables will be repeated at visit 2. The second part of the patient diary will be collected. After visit 2 the study ends for the patient and no IP must be administered. The PN treatment will continue according to the decision of the physician with a regularly used ILE.
Study and treatment duration
The study starts with randomization and ends with the final visit (visit 2). The IP administration will start within one week after randomization and the duration of treatment with IP is projected to be a period of 8 weeks on average.
The primary objective of the study is to prove safety and tolerability of HPN with an n-3 PUFA enriched ILE in adult patients with CIF in need of long-term HPN. It aims to show non-inferiority of the test IP in comparison to the reference IP with regard to liver function.
The primary endpoint of the study is the change of liver function parameters defined as the sum of the N(0,1)-transformed differences in bilirubin, ALT and AST from baseline to visit 2
with BILI = change of total bilirubin, D1 = mean change of BILI, SD1 = standard deviation of change of BILI; ALT = change of SGPT, D2 = mean change of ALT, SD2 = standard deviation of change of ALT; AST = change of SGOT, D3 = mean change of AST, SD3 = standard deviation of change of AST.
The secondary objectives are the further evaluation of safety and efficacy. Secondary safety variables include parameters of hepatic function, blood count and coagulation, blood biochemistry, triene:tetraene ratio calculated from plasma FA pattern and AEs. Body mass index (BMI) and FA pattern in plasma and RBCs are secondary efficacy variables. Other secondary variables are demographic data, anamnesis and physical examination, vital signs, calculated BW change, QoL according to EuroQol Group EQ-5D™, concomitant medication, energy requirements, PN prescription per week and treatment compliance. Detailed secondary safety, efficacy and other variables are listed in Additional file 1.
Concomitant medication, therapies
The following concomitant medications are allowed:
- Nutritional components (glucose, amino acids, vitamins, trace elements and electrolytes) according to patient’s needs and investigator’s prescription either in a 2-chamber bag or in a compounded all-in-one PN-bag to which the IP will be added
- Due to manufacturing/transportation steps there is a time interval between the baseline visit and the first administration of IP (maximum of 1 week). During this time-frame the administration of the usually prescribed lipid emulsion is allowed until the IP is provided to the patient.
- Administration of concomitant medication as clinically required, but always considering IP’s special warnings and precautions for use
The following concomitant medications are not allowed:
- With the exception of the situation as described above (maximum interval of 1 week after baseline visit), the administration of lipid emulsions other than IP
- Any dietary supplements containing n-3 PUFA including but not limited to fish-oil capsules, enteral/oral nutritional supplements containing fish-oil etc.
Safety evaluation and reporting of adverse events
Throughout the course of the clinical trial from the moment of randomization until the last study visit particular attention will be paid to all AEs including serious AEs (SAEs). The investigator must record all AEs in detail whether serious or not. SAEs have to be reported to the sponsor within 24 h after the first knowledge that they have occurred.
SAEs with suspicion of causal relationship to the study treatment (serious adverse reaction, SAR) that are unexpected according to the available summaries of product characteristics of Lipidem® 200 mg/ml and Lipofundin® MCT/LCT 20% have to be considered as Suspected Unexpected Serious Adverse Reactions (SUSARs). SUSARs are subject to expedited reporting. The sponsor will notify the competent authorities, ethics committees and all investigators concerned about SUSARs, in line with pertinent legal requirements.
The entire clinical study might be discontinued upon unexpected high frequency of (S)AEs / (S)ARs or the occurrence of SUSARs. Individual patients might be withdrawn by the investigator in case of (S)AEs leading to non-acceptance of study continuation.
Sample size calculation
The sample size calculation is based on the primary endpoint of the study, which is the change of liver function parameters defined as the sum of the N(0,1)-transformed differences from baseline in bilirubin, ALT and AST after eight weeks of treatment. It is the aim to demonstrate non-inferiority of the test IP as compared to the reference IP with respect to 'deterioration in liver function'. Because of the normality and equal variance, the one-sided two-sample t-test will be applied. The standard deviation of the specified endpoint was derived from previous study data providing a standard deviation of σ = 2.3029, so the non-inferiority margin for this study is taken as σ/2 i.e. δ= 1.151. For the sample size calculation the power was taken as 1-β = 0.8 and the significance set at α = 0.025, resulting in a sample size of 128 patients for two groups (64 per group). Assuming a drop-out rate of 20 %, a total of 160 patients should be randomized in the ratio of 1:1 for assessment of the primary endpoint.
The All-Patients-Screened population will comprise all patients that gave written informed consent to participate in the study. The Intention-To-Treat Set will comprise all randomized patients enrolled in the study. The All-Patients-Treated Set will comprise all patients of the ITT set who received at least one dose of the trial medication.
Additionally, the Full Analysis Set (FAS) will comprise all patients who received at least one dose of the trial medication and from whom at least one efficacy measurement is available after this dose. The Valid Case Set (VCAS) will comprise all patients in the FAS who did not show any major violations of the protocol including the violations of the requirements of study conduct.
All programming of tables, figures, listings and statistical analyses will be performed using a statistical software package (SAS® version 9.4). Statistics will be performed in accordance with the principles outlined by the guideline E9 of the International Conference on Harmonisation (ICH) and will be outlined in detail in the statistical analysis plan that will be finalized before close of database.
The primary analysis will be performed for the VCAS (FAS for sensitivity). No imputation will be performed. The t-test will compare the (one-sided) null hypothesis (H0: DT ≥ DS + d) against the alternative hypothesis (H1: DT < DS + d) on the level of 0.025, where DT and DS represent the increase of the primary endpoint upon T=test and S=standard, respectively. Non-inferiority (with non-inferiority margin σ=1.151) can be concluded, if the VCAS analysis yields an upper limit of the two-sided 95% confidence interval (or one-sided 97.5% confidence interval) for the treatment contrast of the primary endpoint lower than 1.151 and if this result is confirmed by the corresponding FAS analysis. Superiority of T vs S, i.e. H0: DT ≥ DS vs. H1: DT < DS, is demonstrated simultaneously, if the upper limit of the confidence interval is below zero for both the FAS analysis and the VCAS analysis.
Given non-inferiority of T vs. S, breakdown of the multiple primary endpoint to its components bilirubin, ALT and AST, will be performed . Further methods are descriptive statistics including standard procedures for the comparison of two groups (t-test, U test, c2 test).
Tests of secondary variables will be carried out in the area of exploratory data analysis. Therefore, corresponding p-values are to be regarded as exploratory ones and no adjustments for multiple testing will be made.
Data registration and Monitoring
All data obtained in the context of the clinical trial are subject to data protection. If personal data are stored and processed, the requirements of pertinent data protection legislation will be observed.
Every effort will be made to collect all data points in the study. The amount of missing data will be minimized by appropriate management of the trial, proper screening of subjects, and training of participating investigators and other authorized staff, monitors and study manager.
The data generated in this study will be recorded using a computerized system in accordance with applicable regulations. The system will generate an individual eCRF for each patient participating in the trial. The principal investigator of each study site must ensure the accuracy, completeness and timelines of the data entry in the system. The eCRF system will guarantee compliance with Code of Federal Regulations (CFR) 21 part 11, data safety, communication security, limited access, user roles and full audit trail.
Authorized, qualified Clinical Research Associates will visit investigational sites at regular intervals as defined in the monitoring plan to verify adherence to protocol and local legal requirements, to perform source data verification and to assist the investigator in his / her study related activities. Facilities that are involved in IP handling and dispensing will also be visited regularly for monitoring of IP accountability. In the case that unblinded IP is used at the facility, an additional unblinded monitor will perform these visits. An independent audit at the study site may take place at any time during or after the study.
Ethical and legal considerations
This clinical study will be conducted in accordance with the ethical principles described in the Declaration of Helsinki and in compliance with the protocol, good clinical practice (2001/20/EEC, CPMP/ICH/135/95), designated standard operating procedures, and with local legal and regulatory requirements in the countries in which the study will be conducted. Before the start of the trial, the trial protocol and all documents that are subject to review will be provided to the ethics committees/institutional review boards concerned, and to competent national and local authorities by the sponsor or the investigator in line with national provisions. All substantial protocol modifications will be submitted as substantial amendments to these committees and competent authorities.
Informed consent has to be obtained from all patients. The patients will be advised that they have the right to withdraw from the study at any time without prejudice, and may be withdrawn at the investigator's / sponsor’s discretion at any time, when this is considered to be in the interest of the patient.
Responsibilities of investigators, monitors and sponsor of the clinical trial regarding handling and storage of data, planning, assessment and quality assurance are regulated by the recommendations on ‘International Conference on Harmonisation Topic E6 Guideline for Good Clinical Practice’ and apply also to this clinical trial.
The costs necessary to perform the study have been agreed upon with each investigator and are documented in separate financial agreements which have been signed by the hospital administration, the investigator and the sponsor, prior to the study commencing.
The sponsor B. Braun Melsungen AG has taken out subject insurance for all patients taking part in the trial.
The sponsor and principal investigators shall agree on the final study report. It is intended that the results of the study may be published as scientific literature. In accordance with generally recognised principles of scientific collaboration, co-authorship with any sponsor personnel will be discussed before submission of a manuscript to a publisher. Results may also be used in submissions to regulatory authorities. Information developed in this clinical study may be disclosed as required to other investigators or any appropriate international regulatory authorities. The sponsor will be provided with complete test results and all data developed during this study.
The study protocol was registered in the ClinicalTrials.gov Protocol Registration and Results System, ClinicalTrials.gov ID: NCT03282955 on September 14, 2017.