NETwork of Linoleic Acid Supplementation in Cystic Fibrosis (NETLACF)

Double-blind Randomized Controlled Study of Linoleic Acid Supplementation for 1 Year in Patients With Cystic Fibrosis - Influence on Clinical Status and Metabolism

Undernutrition is a common problem in patients with cystic fibrosis (CF) despite international consensus that the patients shall be given 120-200% of energy recommendations. Studies imply that one problem might be that the patients are not compensated for the essential fatty acid deficiency (linoleic acid, LA), which is well known in these patients. This deficiency is shown not to be due to fat malabsorption, but related to an increased turnover of arachidonic acid, a transformation product of LA. This abnormality is related to mutations associated with a more severe clinical phenotype. The most common and typical symptom of LA deficiency is poor growth. Studies in animals have further indicated that many of the symptoms in CF are related to the deficiency. A series of recent prospective studies from Wisconsin corroborate the importance of LA for growth. In Sweden LA has been supplemented to most patients since the late 70´, and the condition of patients have been among the leading in the world regarding growth, pulmonary function and survival. Short-term studies have shown better effect of LA supplementation compared to similar supply of energy without including extra LA. There are few long-term studies, performed before the gene was identified, giving very heterogeneous patient groups in regard to genotype, but with some positive results on growth and physiology. It´s of interest that modern personalized extremely expensive therapy with correctors and potentiators for Cystic Fibrosis Transmembrane Conductance Regulator may influence lipid metabolism. LA might thus tentatively be a cheap adjuvant to this modern therapy, but this has to be specially studied.

The aim of the study is to find if there are differences in clinical and metabolic outcome between two groups, blindly given similar amount of extra calories, in one group consisting of linoleic acid.The benefit for the patients would be great if the expected positive effect can be proved in the planned study. The treatment will be cheap and without adverse effects. From socioeconomic point of view is would be a great advantage.

Study Overview

• Status: Enrolling by invitation
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Dietary supplement: linoleic acid supplementation; Dietary supplement: oleic acid supplementation

Detailed Description

Two group of matched children with CF were randomized to two type of oils given 20 g oil and 600 mg DHA daily for one year and anthropometry, pulmonary function, biochemistry, resting energy expenditure, lipid mediators, inflammatory and intestinal markers were studied at start and at 6 months and 1 year. Dietary intake was controlled and life quality recording at start and end of study.

• Study Type: Interventional
• Enrollment (Anticipated): 80
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Italy
  • Milan, Italy
    • Università degli Studi di Milan
  • Brescia - Lombardia
    • Brescia, Brescia - Lombardia, Italy, 25123
      • Centro Regionale di Supporto per la Fibrosei Cistica, ASST Spedali civili, Univ of Brescia
• Norway
  • Oslo, Norway
    • Norwegian Resourse Center for Cystic Fibrosis, Oslo University Hospital
• Poland
  • Poznań, Poland
    • Poznan University of Medical Sciences
• Sweden
  • Skåne
    • Lund, Skåne, Sweden, 22242
      • Center of Cystic fibrosis, Dept of Pediatrics, Lund University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 15 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Two mutations related to severe clinical status such as dF508, or other stop mutations or class II mutations. Severe status includes pancreatic insufficiency

Exclusion Criteria:

• Liver cirrhosis and/or portal hypertension, transplantation or on transplantation list, intake of lipid supplements the latest 2 months

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Linoleic; Linoleic acid 13 g and 600 mg algal docosahexaenoic acid (DHA)	Dietary supplement: linoleic acid supplementation; Oils given daily at morning meal with extra enzymes
Active Comparator: Oleic; Oleic acid 13 g and 600 algal DHA	Dietary supplement: oleic acid supplementation; Oils given at morning meal with extra enzymes

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Growth	change in BMI, standard deviation score (SDS)	1 year
Weight	change in SDS body weight	1 year
Height	change in SDS height	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pulmonary function	change in forced expiratory volume in one second (FEV1 % of predicted)	1 year
Quality of life, the patient experience of well being	Questionaire about health, physical activity, well being (8 items), CFQ-child + CFQ- parents (higher rates are better) The score changes are analysed.The CFQ considers the physical, image, digestive, respiratory, emotional, social, food, treatment, vitality, health, social role and weight domains. Each domain has a score and its sum generates the total score, whose values can vary from 0 to 100 The scores will also be related to measurements.	1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lipid mediators	change in lipid mediators in blood and urine, ion trap- Mass Spectrometry, picoMol (> 150 products of both the n-6 and n-3 series)	1 year
Clinical infectious status	change in number exacerbations compare to previous year,	1 year
Influence on sodium status	change in Sodium in sweat test, mol/L and urine (fractional sodium excretion)	1 year
Inflammatory markers	change in Cytokines, Proximity extension assays (PEA proteomics) picogram/ml	1 year
Metabolic marker	Change in serum insulin growth factor -1 (IGF-1, nanogram/ml)	1 year
Energy metabolism	Change in resting energy expenditure (REE/kg body weight)	1 year
Bone mineral density	Change in total bone mineral density by dual x-ray absorptiometry (DXA), gram/cm^2	1 year
Oral glucose tolerance	Measure of glucose and insuline after oral glucose loading	1 year

Collaborators and Investigators

• Sponsor: Karolinska Institutet
• Collaborators: European Society of Pediatric Gastroenterology, Hepatology and Nutrition
• Investigators: Principal Investigator: Jaroslaw Walkowiak, MD,PhD, University of Poznan, CF center, Poland; Principal Investigator: Carla Colombo, MD,PhD, University of Milan, CF center, Italy; Principal Investigator: Egil Bakkeheim, MD, PhD, University of Oslo, CF center, Norway; Principal Investigator: Raffaele Badolato, MD, PhD, University of Brescia, CF center, Italy; Principal Investigator: Christine Rönne-Hansen, Md, PhD, Lund University, CF center, Sweden

Publications and helpful links

General Publications

• Strandvik B. Fatty acid metabolism in cystic fibrosis. Prostaglandins Leukot Essent Fatty Acids. 2010 Sep;83(3):121-9. doi: 10.1016/j.plefa.2010.07.002. Epub 2010 Jul 31.
• Wheelock CE, Strandvik B. Abnormal n-6 fatty acid metabolism in cystic fibrosis contributes to pulmonary symptoms. Prostaglandins Leukot Essent Fatty Acids. 2020 Sep;160:102156. doi: 10.1016/j.plefa.2020.102156. Epub 2020 Jun 26.
• Strandvik B. Is the ENaC Dysregulation in CF an Effect of Protein-Lipid Interaction in the Membranes? Int J Mol Sci. 2021 Mar 8;22(5):2739. doi: 10.3390/ijms22052739.
• Strandvik B. Nutrition in Cystic Fibrosis-Some Notes on the Fat Recommendations. Nutrients. 2022 Feb 18;14(4):853. doi: 10.3390/nu14040853.

Study record dates

Study Major Dates

• Study Start (Actual): October 25, 2021
• Primary Completion (Anticipated): October 31, 2023
• Study Completion (Anticipated): January 31, 2024

Study Registration Dates

• First Submitted: August 18, 2020
• First Submitted That Met QC Criteria: August 26, 2020
• First Posted (Actual): August 28, 2020

Study Record Updates

• Last Update Posted (Actual): April 6, 2022
• Last Update Submitted That Met QC Criteria: March 28, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: growth; pulmonary function; cytokines; IGF-1; docosahexaenoic acid; lipid mediators; resting energy expenditure; arachidonic acid,
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis
• Other Study ID Numbers: 2020-02871

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The results will be anonymous and reported to peer review journals for publication. Beside the local PIs there will be other local staff involved and for the analyses also co-workers as shown in the study protocol which will be attached for review.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No