Omega-3 and Vitamin D Supplements in Childhood T1D

• Sponsor: Azienda Ospedaliero Universitaria Maggiore della Carita (Other)
• Overall Status: Completed
• CT.gov ID: NCT03911843
• Collaborator: University of Eastern Piedmont (Other)
• Enrollment: 64
• Arms: 2
• Actual Duration (Months): 24

Study Details

Study Description

Brief Summary

The study was conducted in 64 patients with T1D of which 26 had the onset in 2017, and 38 in 2016, 2015 and 2014. All received vitamin D 1000 IU /day since disease's onset. Moreover in the 2017 group omega-3 were supplemented, starting within 3 and 6 months from the disease's outbreak, and those were considered cases; the other 38 were enrolled as controls. Four cases and one control dropped out. Finally in 59/64 were compared data of glycosylated hemoglobin percentage (HbA1c%), average insulin daily requirement (IU/Kg/day), and IDAA1c [Insulin Daily dose Adjusted for HbA1c, a surrogate index of residual endogen insulin secretion, calculated as insulin daily dose (IU/Kg/24 h) x 4 + HbA1c%] at recruitment (T0), and 3 (T3), 6 (T6), 12 (T12) months after. T0 in cases was at the start of supplementation of omega-3, and consequently 3, 6 and 12 months after; in controls were found data in clinical records of outpatient beginning from the 3rd month and 3-6-12 months thereafter. Then 22 cases and 37 controls were compared.

Condition or Disease	Intervention/Treatment	Phase
Type 1 Diabetes Mellitus	Drug: omega-3 supplementation; Drug: Vitamin D supplementation	Phase 2/Phase 3

Detailed Description

Was assessed the comparability of cases and controls at baseline for gender, age, body weight, HbA1c% and device for insulin therapy.

The preparation of omega-3 administered was a highly purified fish oil to avoid pollutants, containing a mixture of omega-3 long chain fatty acids standardized for contents of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in a 2: 1 ratio, in capsules or in liquid form. The liquid preparation was used in the case of difficulties in swallowing capsules or concomitant celiac disease because it was certified as gluten-free (Ener Zone Omega 3 RX® Equipe Enervit). The preparations contained antioxidants to preserve omega-3 LCFA, tocopherol (1 mg in 1 g of omega-3 LCFA), palmitate, and rosemary extract. EPA and DHA were administered at 50-60 mg/kg/day for 12 months. The investigation of Arachidonic Acid (AA)/EPA ratios was performed in cases on recruitment (T0), and repeated after 3 (T3), 6 (T6), and 12 months (T12).

Cholecalciferol supplementation was fixed at 1000 IU/day (25 mcg/day), both in cases and controls. Vitamin D level was determined as 25(OH)D level at the clinical onset of T1D, at T0, T3, T6, and T12 in cases, and at clinical onset of controls.

Study Design

• Study Type: Interventional
• Actual Enrollment: 64 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: A cohort study was performed in 2017, in all T1D patients 1-18 years old with onset in the years 2014-2017. Supplementation with omega3 was proposed to all subjects with onset in 2017. Patients with onset in 2014-2015-2016 were enrolled only as control subjects. The work was performed on retrospectively collected data in medical records for patients with start of the disease in 2014-2016. Patients enrolled since 2017 have been studied prospectively.A cohort study was performed in 2017, in all T1D patients 1-18 years old with onset in the years 2014-2017. Supplementation with omega3 was proposed to all subjects with onset in 2017. Patients with onset in 2014-2015-2016 were enrolled only as control subjects. The work was performed on retrospectively collected data in medical records for patients with start of the disease in 2014-2016. Patients enrolled since 2017 have been studied prospectively.
• Masking: None (Open Label)
• Primary Purpose: Supportive Care
• Official Title: Omega 3 Long Chain Polyunsaturated Fatty Acids, Enriched Mediterranean Diet and Vitamin D Supplementation in Childhood Type 1 Diabetes: One Year Case-cohort Study
• Actual Study Start Date: Jan 1, 2017
• Actual Primary Completion Date: Dec 31, 2018
• Actual Study Completion Date: Dec 31, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CASES Of eligible subjects, 26/64 started an intervention program with Ω-3 (CASES). The intervention consisted in supplementation with highly purified Ω-3, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) at a dose of 50-60 mg/kg/day for 12 months	Drug: omega-3 supplementation; Supplementation with Ω-3, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) at a dose of 50-60 mg/kg/day for 12 months, currently underway or completed after 12 months of omega-3 administration, in 22/64 T1D children; Other Names: Ener Zone Omega 3 RX® Equipe Enervit ; Drug: Vitamin D supplementation; Cholecalciferol 1000 IU/die
Active Comparator: CONTROLS Others 38/64 subjects joined to the study as data contributors, and were entered as controls (CONTR).	Drug: Vitamin D supplementation; Cholecalciferol 1000 IU/die

Outcome Measures

Primary Outcome Measures

1. Daily Insulin Need (IU/Kg/Day) and Daily Insulin Pre-meal Demand (Pre-meal IU/Kg/Day) at 12 Months [12 months]

   The Daily Insulin Needs (IU/Kg/day), and the Daily Insulin Pre-meal Demand (Pre-meal IU/Kg/day) respectively represent the average total (sum of boluses and basal) and average pre-meal (sum of pre-meal boluses) insulin doses administered in one day to each patient. They have been calculated over a week, and were expressed in International Units / Kg of weight, higher values mean a worse outcome.

2. HbA1c Percentage [12 months]

   percentage of glycated hemoglobin measured through the high-performance liquid chromatography (HPLC).

3. Number of Participants With Insulin Demand Adjusted for HbA1c %(IDAA1c) <9 [12 months]

   The IDAA1c (insulin daily dose adjusted for glycosylated hemoglobin percentage) was calculated as HbA1c percentage + average daily insulin dose (IU/kg/24 h) x 4. A score <9 meet definition of partial remission and Residual Endogenic Insulin Secretion (REIS). IDAA1c represents a surrogate index of insulin secretion and of metabolic control. In a scale from 5 to 12, higher score mean a worse outcome (e.g. <5.5 is expected in a normal individual, <9 in an individual in partial remission. See reference).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• All T1D patients aged 1-18 years whose disease onset had been in 2017, 2016, 2015, 2014 affering to the Pediatric Diabetology of AOU Novara (Italy)

• written consents of parents

• without assumption of omega 3 supplementation before 2017

Exclusion Criteria:

• renal cysts

• sarcoidosis

• histoplasmosis

• hyperparathyroidis

• lymphoma

• tuberculosis

• Patients treated with drugs that could affect immunity or glucose metabolism, including corticosteroids, ciclosporin and tacrolimus

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Azienda Ospedaliero Universitaria Maggiore della Carita
• University of Eastern Piedmont

Investigators

• Principal Investigator: Francesco Cadario, MD, Pediatric Clinic of AOU Novara

Study Documents (Full-Text)

• Study Protocol - Jan 1, 2017
• Statistical Analysis Plan - Jan 1, 2017
• Informed Consent Form - Jan 1, 2017

More Information

Additional Information:

• Pilot Study of OMEGA-3 and Vitamin D in High-Dose in Type I Diabetic Patients (POSEIDON)

Publications

• Baidal DA, Ricordi C, Garcia-Contreras M, Sonnino A, Fabbri A. Combination high-dose omega-3 fatty acids and high-dose cholecalciferol in new onset type 1 diabetes: a potential role in preservation of beta-cell mass. Eur Rev Med Pharmacol Sci. 2016 Jul;20(15):3313-8.
• Cadario F, Savastio S, Ricotti R, Rizzo AM, Carrera D, Maiuri L, Ricordi C. Administration of vitamin D and high dose of omega 3 to sustain remission of type 1 diabetes. Eur Rev Med Pharmacol Sci. 2018 Jan;22(2):512-515. doi: 10.26355/eurrev_201801_14203.

• Responsible Party: Francesco Cadario, MD, MD Division of Pediatrics, Azienda Ospedaliero Universitaria Maggiore della Carita
• ClinicalTrials.gov Identifier: NCT03911843
• Other Study ID Numbers: AOU Novara
• First Posted: Apr 11, 2019
• Last Update Posted: Apr 19, 2021
• Last Verified: Mar 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Keywords provided by Francesco Cadario, MD, MD Division of Pediatrics, Azienda Ospedaliero Universitaria Maggiore della Carita: omega3; T1D remission period; honeymoon period; AA/EPA ratio
• Additional relevant MeSH terms: Diabetes Mellitus, Type 1; Vitamin D

Study Results

Participant Flow

Recruitment Details

The recruitment started 03/17/2017 with the enrollment of the first patient, and ended on 06/08/2019 with the end of the omega-3 supplementation period of the last enrolled patient. All participants were introduced since the beginning of T1D to tailored insulin therapy, to Mediterranean diet (according to a standardized item detailed in reference), and received 1000 IU/day of vitamin D supplementation.

Arm/Group Title	CASES New T1D Onsets 2017	CONTROLS Previous T1D Onsets
Arm/Group Description	All the New T1D Onsets 2017 received a further supplementation of ultra refined fish oil, enriched in LC-PUFA omega 3, containing standardized concentrations EPA + DHA (2:1), at 60 mg/kg/day. The supplementation with omega 3 started within 3th and 6th months after the clinical T1D onset and lasted one year.	All Previous T1D Onsets (2014-2016) receiving vitamin D and Mediterranean diet without omega 3 supplementation, were continuously recruited. Retrospectively their available data from 3th and 6th months from the clinical onset to T1D, for the following year, were compared.
Period Title: Overall Study
STARTED	26	38
COMPLETED	22	37
NOT COMPLETED	4	1

Baseline Characteristics

Arm/Group Title	CASES	CONTROLS	Total
Arm/Group Description	The T1D onsets were eligible subjects, of which 26/64 new onsets started an intervention program with Ω-3 (CASES). The intervention consisted in supplementation with highly purified Ω-3, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) at a dose of 60 mg/kg/day for 12 months. The supplementation with omega 3 started within 3th and 6th months of T1D clinical onset and lasted one year. They had been introduced to the Mediterranean diet according to a standardized item and received 1000 IU/day of vitamin D supplementation since the beginning of T1D	The Previous T1D onsets, 38/64 subjects joined to the study as controls (CONTROLS). They received vitamin D supplementation 1000 IU/day and Mediterranean diet according to a standardized item since the onset of T1D, without omega 3; retrospectively their available data from 3th and 6th months of overt disease for the following year, were compared	Total of all reporting groups
Overall Participants	26	38	64
Age (Count of Participants)
<=18 years	26 100%	38 100%	64 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	8.7 (4.6)	8.8 (3.6)	8.75 (4)
Sex: Female, Male (Count of Participants)
Female	14 53.8%	20 52.6%	34 53.1%
Male	12 46.2%	18 47.4%	30 46.9%
Race/Ethnicity, Customized (Count of Participants)
Italian	20 76.9%	33 86.8%	53 82.8%
North Africa	4 15.4%	4 10.5%	8 12.5%
Albania	1 3.8%	1 2.6%	2 3.1%
Pakistan	1 3.8%	0 0%	1 1.6%
Region of Enrollment (participants) [Number]
Italy	26 100%	38 100%	64 100%

Outcome Measures

1. Primary Outcome

Title	Daily Insulin Need (IU/Kg/Day) and Daily Insulin Pre-meal Demand (Pre-meal IU/Kg/Day) at 12 Months
Description	The Daily Insulin Needs (IU/Kg/day), and the Daily Insulin Pre-meal Demand (Pre-meal IU/Kg/day) respectively represent the average total (sum of boluses and basal) and average pre-meal (sum of pre-meal boluses) insulin doses administered in one day to each patient. They have been calculated over a week, and were expressed in International Units / Kg of weight, higher values mean a worse outcome.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	CASES New T1D Onsets 2017	CONTROLS Previous T1D Onsets
Arm/Group Description	All the New T1D Onsets 2017 received a further supplementation of ultra refined fish oil, enriched in LC-PUFA omega 3, containing standardized concentrations EPA + DHA (2:1), at 60 mg/kg/day. The supplementation with omega 3 started within 3th and 6th months after the clinical T1D onset and lasted one year.	All Previous T1D Onsets (2014-2016) receiving vitamin D and Mediterranean diet without omega 3 supplementation, were continuously recruited. Retrospectively their available data from 3th and 6th months from the clinical onset to T1D, for the following year, were compared.
Measure Participants	22	37
Daily insulin need	0.49 (0.2)	0.63 (0.1)
Daily Insulin Pre-meal Demand	0.22 (0.1)	0.34 (0.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CASES New T1D Onsets 2017, CONTROLS Previous T1D Onsets
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments	the p-value of significance was calculated using the analysis system
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.14
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	CASES New T1D Onsets 2017, CONTROLS Previous T1D Onsets
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.14
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	HbA1c Percentage
Description	percentage of glycated hemoglobin measured through the high-performance liquid chromatography (HPLC).
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	CASES New T1D Onsets 2017	CONTROLS Previous T1D Onsets
Arm/Group Description	All the New T1D Onsets 2017 received a further supplementation of ultra refined fish oil, enriched in LC-PUFA omega 3, containing standardized concentrations EPA + DHA (2:1), at 60 mg/kg/day. The supplementation with omega 3 started within 3th and 6th months after the clinical T1D onset and lasted one year.	All Previous T1D Onsets (2014-2016) receiving vitamin D and Mediterranean diet without omega 3 supplementation, were continuously recruited. Retrospectively their available data from 3th and 6th months from the clinical onset to T1D, for the following year, were compared.
Measure Participants	22	37
Mean (Standard Deviation) [percentage of HbA1c]	7.4 (1)	7.8 (1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CASES New T1D Onsets 2017, CONTROLS Previous T1D Onsets
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

3. Primary Outcome

Title	Number of Participants With Insulin Demand Adjusted for HbA1c %(IDAA1c) <9
Description	The IDAA1c (insulin daily dose adjusted for glycosylated hemoglobin percentage) was calculated as HbA1c percentage + average daily insulin dose (IU/kg/24 h) x 4. A score <9 meet definition of partial remission and Residual Endogenic Insulin Secretion (REIS). IDAA1c represents a surrogate index of insulin secretion and of metabolic control. In a scale from 5 to 12, higher score mean a worse outcome (e.g. <5.5 is expected in a normal individual, <9 in an individual in partial remission. See reference).
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	CASES New T1D Onsets 2017	CONTROLS Previous T1D Onsets
Arm/Group Description	All the New T1D Onsets 2017 received a further supplementation of ultra refined fish oil, enriched in LC-PUFA omega 3, containing standardized concentrations EPA + DHA (2:1), at 60 mg/kg/day. The supplementation with omega 3 started within 3th and 6th months after the clinical T1D onset and lasted one year.	All Previous T1D Onsets (2014-2016) receiving vitamin D and Mediterranean diet without omega 3 supplementation, were continuously recruited. Retrospectively their available data from 3th and 6th months from the clinical onset to T1D, for the following year, were compared.
Measure Participants	22	37
Count of Participants [Participants]	12 46.2%	7 18.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CASES New T1D Onsets 2017, CONTROLS Previous T1D Onsets
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	Chi-squared
	Comments

Adverse Events

Time Frame	The observation interval of side effects was in each case into the period of omega-3 supplementation (T0-T12), lasting 12 months, and into a comparable period in the controls.
Adverse Event Reporting Description	Chronic diarrhea lasting 2 weeks of duration in a female case. The administration of supplementation with omega 3 was interrupted Isolated thyrotropine deficiency, in a teenager girl with pre-existing autoimmune thyroiditis. The administration of supplementation with omega 3 was interrupted Activated partial thromboplastin time (observable entity) without clinical symptoms observed. At the end of the study, one year after the start of omega 3 supplementation
Arm/Group Title	CASES New T1D Onsets 2017		CONTROLS Previous T1D Onsets
Arm/Group Description	All the New T1D Onsets 2017 received Mediterranean diet, vitamin D 1000 IU/day, and a further supplementation of ultra refined fish oil, enriched in LC-PUFA omega 3, containing standardized concentrations EPA + DHA (2:1), at 60 mg/kg/day. The supplementation with omega 3 started within 3th and 6th months after the clinical T1D onset and lasted one year.		All Previous T1D Onsets (2014-2016) receiving vitamin D and Mediterranean diet without omega 3 supplementation, were continuously recruited. Retrospectively their available data from 3th and 6th months from the clinical onset to T1D, for the following year, were compared.
All Cause Mortality
	CASES New T1D Onsets 2017		CONTROLS Previous T1D Onsets
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		0/37 (0%)
Serious Adverse Events
	CASES New T1D Onsets 2017		CONTROLS Previous T1D Onsets
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		0/37 (0%)
Other (Not Including Serious) Adverse Events
	CASES New T1D Onsets 2017		CONTROLS Previous T1D Onsets
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/26 (3.8%)		0/38 (0%)
Blood and lymphatic system disorders
an extension of the aPTT clotting	1/26 (3.8%)	1	0/38 (0%)	0
Endocrine disorders
transient suppression of TRH	1/26 (3.8%)	1	0/38 (0%)	0
Gastrointestinal disorders
persistent diarrhea	1/26 (3.8%)	1	0/38 (0%)	0

Limitations/Caveats

The study was not randomized and Controls were retrospective, whereby the comparability between Cases and Controls concerned only HbA1c percentage, Daily Insulin Needs (IU/Kg/day) and IDAA1c, indirect indices of residual endogen insulin secretion (REIS)

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.