Clinical Research on Acute Intermittent Porphyria and the Use of Carbohydrate-Rich Diet as a Treatment

The main aim of this clinical trial is to learn about the effect of carbohydrate-rich diet as a treatment for AIP (acute intermittent porphyria).

Aim: Investigate the diet's impact on tissue and serum glucose, plasma insulin, cytokine levels, amino acids, and gut microbiota in AIP, and their correlation with PBG (Porphobilinogen).

Aim: Assess the diet's effect on AIP symptoms and health status in AIP. Aim: Measure the effect of a high-carbohydrate diet on mitochondrial activity in AIP Aim: Map and detect potential mutations in mitochondrial genomic DNA in AIP Aim: Discover new markers in AIP through RNA sequencing and machine learning.

Participants will follow two diet plans, a 4-week intervention with 60-65 E% carbohydrates and a 4 week intervention with 40-45 E% carbohydrates.

Study Overview

• Status: Recruiting
• Conditions: Porphyria, Acute Intermittent
• Intervention / Treatment: Other: Carbohydrates

Detailed Description

Acute intermittent porphyria (AIP) is an inherited disease that leads to the accumulation of porphobilinogen (PBG), resulting in severe abdominal pain, paralysis, fatigue, low-grade inflammation, and an increased risk of kidney failure and liver cancer. Studies at the cellular level and in mice have shown that elevated levels of glucose and insulin can affect heme synthesis, potentially reducing PBG levels. The investigators have previously demonstrated that individuals with AIP consume less carbohydrate (E% 40) than recommended. The investigators aim to conduct a crossover study involving 50 participants with AIP, where 50% will be subjected to a 4-week intervention with 60-65 E% carbohydrates, while the other half will consume 40-45 E% carbohydrates for 4 weeks. After a 4-week intervention-free period, the two groups will switch to the respective carbohydrate percentages. Symptoms, PBG levels, continuous tissue glucose, plasma/serum insulin, glucose, cytokines, amino acid levels, microbiota in the gut, body composition, and physical activity measured using accelerometers will be assessed before and after each intervention and compared. Mitochondrial activity will be assessed at the cellular level as oxidative activity. Mutations in mitochondrial DNA and RNA will also be examined since defects in oxidative energy metabolism are known to be associated with inflammation and cancer. The work will be carried out at Nordland Hospital and at the University of Oslo. The study will be coordinated and conducted by the Postdoc and partners at Nordland Hospital, the University of Oslo, the Arctic University of Tromsø, and Nord University. Clinical nutritionists will create dietary plans, and bioengineers will perform analyses. Stay abroad for postdoc, and research cooperation, with porphyria researchers at UTMB, Texas and MGH, Boston, US.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Elin Storjord, MD PhD; Phone Number: 97072484; Email: elin.storjord@nordlandssykehuset.no
• Study Contact Backup: Name: Hilde Thunhaug, Nurse; Phone Number: 95057864; Email: hilde.thunhaug@nordlandssykehuset.no

Study Locations

• Norway
  • Nordland
    • Bodø, Nordland, Norway, 8092
      • Recruiting
      • Nordland Hospital Trust
      • Contact: Elin Storjord, MD PhD; Phone Number: +4797072484; Email: elin.storjord@nordlandssykehuset.no
      • Contact: Hilde Thunhaug, IC nurse; Phone Number: +47 95057864; Email: hilde.thunhaug@nordlandssykehuset.no
      • Principal Investigator: Elin Storjord, MD PhD
      • Sub-Investigator: Amy Dickey, MD
      • Sub-Investigator: Bjørn Steen Skålhegg, PhD, Prof.
      • Sub-Investigator: Bård O. Karlsen, PhD
      • Sub-Investigator: Elin Røst, Master
      • Sub-Investigator: Erik Knutsen, PhD
      • Sub-Investigator: Hilde Thunhaug, Bachelor
      • Sub-Investigator: Jonas Aakre Wik, PhD
      • Sub-Investigator: Andersen Karl, MD, Prof.
      • Sub-Investigator: Pettersen Kristin, Bachelor
      • Sub-Investigator: Marlene B. Karlsen, Master
      • Sub-Investigator: Nina Lorentsen, Master
      • Sub-Investigator: Ole-Lars Brekke, MD,PhD,Prof
      • Sub-Investigator: Randolf Hardersen, MD, PhD
      • Sub-Investigator: Rita Laastad, Bachelor
      • Sub-Investigator: Steinar Daae Johansen, PhD, Dean
      • Sub-Investigator: Tor Erik Jørgensen, PhD
      • Sub-Investigator: Vegar Rangul, PhD
      • Sub-Investigator: Åse Emblem, PhD
      • Sub-Investigator: Fredrik Ellefsrud, MD
      • Sub-Investigator: Tor Claudi, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of AIP

Exclusion Criteria:

• Not having diagnosis of AIP
• Undergoing treatment as part of other clinical research on AIP
• Pregnancy
• Diabetes
• Below 18 years of age

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 60-65 E% Carbohydrates; Diet plan A with 60-65 E% Carbohydrates in 4 weeks	Other: Carbohydrates; Half of the patients will initially follow Diet Plan A with 60-65 E% carbohydrates for 4 weeks, followed by a 4-week washout period, and then Diet Plan B with 40-45 E% carbohydrates for 4 weeks. The other half will start with Diet Plan B for 4 weeks, followed by a 4-week washout period, and then Diet Plan A for 4 weeks . Diet Plans A and B contain recommended and adequate nutrients according to the Nordic Nutrition Recommendations 2023 (NNR2023) for maintaining a stable weight.
Active Comparator: 40-45% Carbohydrates; Diet plan B with 40-45 E% Carbohydrates in 4 weeks	Other: Carbohydrates; Half of the patients will initially follow Diet Plan A with 60-65 E% carbohydrates for 4 weeks, followed by a 4-week washout period, and then Diet Plan B with 40-45 E% carbohydrates for 4 weeks. The other half will start with Diet Plan B for 4 weeks, followed by a 4-week washout period, and then Diet Plan A for 4 weeks . Diet Plans A and B contain recommended and adequate nutrients according to the Nordic Nutrition Recommendations 2023 (NNR2023) for maintaining a stable weight.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Urine Porphobilinogen/creatinine	AIP biochemical disease activity. First morning Urine Porphobilinogen/creatinine. Change from baseline before diet A to immediately after diet A, and change from baseline before diet B to immediately after diet B	Baseline before diet A and immediately after the 4 weeks of diet A, baseline before diet B and immediately after the 4 weeks of diet B
Urine Porphobilinogen/creatinine concentration, percentage change of repeated measurements	AIP biochemical disease activity, repeated measurements Percentage change in the median of repeated measurements of Urine Porphobilinogen/creatinine concentrations between Diet A and Diet B The repeated measurements in urine analyzed in urine samples from Day 1 ,4, 8, 11, 15, 18, 22, 25 and 29 of Diet A and of Diet B, and calculated median of Urine Porphobilinogen/creatinine concentration for diet A and median for diet B	Day 1 ,4, 8, 11, 15, 18, 22, 25 and 29 of Diet Intervention A and of Diet Intervention B

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Hospitalizations,sick leaves, and doctor visits due to AIP	Using questionnaire counting Number of hospitalizations, sick leaves, and doctor visits due to AIP; In the 4 weeks before Diet A, measured at baseline immediately before Diet A; In the 4 weeks of Diet A, measured immediately after Diet A.; In the 4 weeks before Diet B, measured at baseline immediately before Diet B; in the 4 weeks of Diet B, measured immediately after Diet B	Baseline before diet A and immediately after the 4 weeks of diet A, baseline before diet B and immediately after the 4 weeks of diet B
Health status	A standardized questionnaire assessing health (RAND-36) with a 4-week time frame from 0 (worst functioning) to 100 (best functioning), where 2 to 5 points represent a clinically meaningful difference based on data from other chronic diseases.	Baseline before diet A and immediately after the 4 weeks of diet A, baseline before diet B and immediately after the 4 weeks of diet B
Plasma Glucose level	Plasma glucose concentration	Baseline before diet A and immediately after the 4 weeks of diet A, baseline before diet B and immediately after the 4 weeks of diet B
Interstitial fluid glucose level	Glucose measured in the interstitial fluid (ISF) Measuring is performed continuously by ISF glucose sensor FreeStyle Libre 3 in the 4 weeks of Diet A and in the 4 weeks of Diet B. Outcome is percentage change in the mean of repeated measurements between Diet A and Diet B. Each tissue glucose sensor lasts 14 days, and hence the outcome measure will be assessed each 14 days, and read in the LibreView program. The sensor is placed on the back of the participants upper arm	Day 15 and 29 of diet A and day 15 and 29 of diet B
Number of hypoglycemic events	Tissue glucose measured continuously by tissue glucose sensor FreeStyle Libre 3 (Abbott) in the 4 weeks during diet A and in the 4 weeks of diet B. Counting number of hypoglycemic events during the 4 weeks of diet A and comparing to counted number of hypoglycemic events during the 4 weeks of diet B. Each tissue glucose sensor lasts 14 days, and hence the outcome measure will be assessed each 14 days, and read in the LibreView program. Assessing is performed day 15 and day 29 of diet A and day 15 and 29 of diet B.	Day 15 and 29 of diet A and day 15 and 29 of diet B
Amino acid profile	Levels of amino acids measured	Baseline before diet A and immediately after the 4 weeks of diet A, baseline before diet B and immediately after the 4 weeks of diet B
Plasma insulin, glucose, c-peptide	Concentration levels measured in plasma	Baseline before diet A and immediately after the 4 weeks of diet A, baseline before diet B and immediately after the 4 weeks of diet B
HOMA score	HOMA score (Homeostatic Model Assessment) including estimated beta cell function, HOMA%B (%B), insulin sensitivity, HOMA%S (%S), and insulin resistance HOMA-IR (IR), calculated from insulin, glucose and C-peptide in plasma, using an Excel spreadsheet from the University of Oxford.	Baseline before diet A and immediately after the 4 weeks of diet A, baseline before diet B and immediately after the 4 weeks of diet B
HbA1c	Concentration levels measured in blood	Baseline before diet A and immediately after the 4 weeks of diet A, baseline before diet B and immediately after the 4 weeks of diet B
Cytokines in plasma	Cytokines, chemokines and growth factors measured using Multiplex assay from BioRad Lab, Bio-Plex 27-plex kit: Interleukin (IL)-1β, IL-1RA (IL-1 receptor antagonist), IL-2, IL-4, IL-5, IL-6, IL-7, chemokine (C-X-C) motif 8 (CXCL8), IL-9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, chemokine (C-C motif) ligand 5 (CCL5), chemokine ligand 11 (CCL11), basic fibroblast growth factor (FGF), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-γ, CXCL10, CCL2, CCL3, CCL4, platelet-derived growth factor-BB (PDGF-BB), tumour necrosis factor (TNF) and vascular endothelial growth factor (VEGF).	Baseline before diet A and immediately after the 4 weeks of diet A, baseline before diet B and immediately after the 4 weeks of diet B
Intestinal microbiota composition	Sequencing of fecal samples, Gut Health Panel from Bio-Me, covering 100 different bacterias	Baseline before diet A and immediately after the 4 weeks of diet A, baseline before diet B and immediately after the 4 weeks of diet B
Physical activity	Accelerometer (AX3 Axivity Newcastle, UK), attached to the thigh and worn for 7 consecutive days in the first week of diet A and in the first week of diet B. Moderate to vigorous physical activity (MVPA) is detected in 5-second intervals. Measuring time (min/day) spent in MVPA during the first week of diet A and during the first week of diet B.	Immediately after one week of Diet A, and immediately after one week of Diet B
Blood pressure	20 min measurement	Baseline before diet A and immediately after the 4 weeks of diet A, baseline before diet B and immediately after the 4 weeks of diet B
Body composition, metabolic age	Tanita Body Composition Analyzer	Baseline before diet A and immediately after the 4 weeks of diet A, baseline before diet B and immediately after the 4 weeks of diet B
Mitochondrial oxygen consumption rate	SeaHorse, mononuclear cells in peripheral blood	Baseline before diet A and immediately after the 4 weeks of diet A, baseline before diet B and immediately after the 4 weeks of diet B
ALAS1mRNA	TaqMan gene expression assay	Baseline before diet A and immediately after the 4 weeks of diet A, baseline before diet B and immediately after the 4 weeks of diet B
Urine-ALA/creatinine & urine-porphyrins	level measurement of concentration in urine	Baseline before diet A and immediately after the 4 weeks of diet A, baseline before diet B and immediately after the 4 weeks of diet B
Mitochondrial function-related genes	Paxgen tubes, qPCR, Mitochondrial genome sequencing	At baseline immediately before each participants first diet intervention

Collaborators and Investigators

• Sponsor: Nordlandssykehuset HF
• Collaborators: University of Oslo; Norwegian University of Science and Technology; The University of Texas Medical Branch, Galveston; UiT The Arctic University of Norway; Nord University
• Investigators: Principal Investigator: Elin Storjord, MD PhD, Nordlandssykehuset HF

Study record dates

Study Major Dates

• Study Start (Actual): January 27, 2024
• Primary Completion (Estimated): October 31, 2027
• Study Completion (Estimated): December 31, 2037

Study Registration Dates

• First Submitted: February 8, 2024
• First Submitted That Met QC Criteria: February 16, 2024
• First Posted (Actual): February 22, 2024

Study Record Updates

• Last Update Posted (Actual): February 22, 2024
• Last Update Submitted That Met QC Criteria: February 16, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Metabolic Diseases; Skin Diseases; Liver Diseases; Genetic Diseases, Inborn; Skin Diseases, Genetic; Porphyrias, Hepatic; Porphyria, Erythropoietic; Porphyrias; Porphyria, Acute Intermittent
• Other Study ID Numbers: HNF1719-24

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Selected Individual participant data that underlie the results reported in published articles, can be accessed upon reasonable request to the principal investigator, but in each case the data will be deidentified, and the data can only be shared if it is considered that it will not be possible to reidentify persons from the data, and if in each case the data protection officer has advised it and the principal investigator has granted it.

Due to Norwegian law on sensitive data, raw data of this type cannot be submitted to public repositories, e.g DNA sequencing data.

Study protocol and the template for informed consent form is available upon reasonable request.

• IPD Sharing Time Frame: Immediately following each publication. Until 31 of December 2037
• IPD Sharing Access Criteria: Reasonable request
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

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