A Pilot Clinical Study Evaluating the Effect of Parathyroid Hormone (PTH) Lowering On Erythropoietin Consumption in Calcitriol-Resistant Patients

• Sponsor: AbbVie (prior sponsor, Abbott) (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01506947
• Collaborator: (none)
• Enrollment: 65
• Arm: 1
• Actual Duration (Months): 46.9

Study Details

Study Description

Brief Summary

To evaluate the effect of PTH lowering on erythropoietin consumption in calcitriol-resistant patients with stage 5 chronic kidney disease.

Condition or Disease	Intervention/Treatment	Phase
Moderate to Severe Secondary Hyperparathyroidism; Stage 5 Chronic Kidney Diseases	Drug: Paricalcitol; Drug: Darbepoetin alfa	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 65 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Prospective, Non-randomised, Single-arm, Open-Label Pilot Clinical Study Evaluating the Effect of PTH Lowering on Erythropoietin Consumption in Calcitriol-Resistant Patients
• Actual Study Start Date: May 10, 2012
• Actual Primary Completion Date: Apr 7, 2016
• Actual Study Completion Date: Apr 7, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Paricalcitol Participants received paricalcitol intravenously during hemodialysis until serum intact parathyroid hormone (iPTH) levels were below 150 pg/mL or for up to 6 months. Paricalcitol dose was based on iPTH levels and was titrated to maintain iPTH levels between 150-300 pg/mL. Participants may have also received routine darbepoetin alfa to treat anemia.

Drug: Paricalcitol; Paricalcitol was administered by intravenous bolus. The initial dose was calculated according to the following formula: [Paricalcitol (µg) = iPTH (pg/mL) / 80]. Subsequent doses were determined based on iPTH, calcium and phosphorus levels.; Other Names: ABT-358 Zemplar ; Drug: Darbepoetin alfa; Routine darbepoetin alfa use was allowed when transferrin saturation (TSAT) was ≥ 20% and ferritin ≥ 200 μg/L, and hemoglobin level < 11.5 g/dL. The initial dose was 0.25 to 0.75 µg/kg/week, and the maintenance dose was 0.13 to 0.35 µg/kg/week. Target hemoglobin level was between 10 to 11.5 g/dL.

Outcome Measures

Primary Outcome Measures

1. Mean Erythropoietin Dose Per Visit [Baseline and Months 1, 2, 3, 4, 5 and 6]

   The requirement of erythropoietin (EPO) treatment to maintain serum hemoglobin levels between 10 to 11.5 g/dL during the study was assessed by analysis of the dose of darbepoetin alfa used at baseline and during each month of the study. The mean EPO dosage per injection for each study month is reported.

Secondary Outcome Measures

1. Mean Scores of Short Form Health Survey 36 (SF-36) Questionnaire [Baseline and Month 6]

   The Medical Outcome Study Short Form 36-Item Health Survey (SF-36) is a self-administered questionnaire that measures the impact of disease on overall quality of life and consists of 36 questions in eight domains. The domains include physical (physical functioning, role limitations due to physical health (role-physical), general health perceptions and pain) and mental domains (energy/fatigue (vitality), social functioning, emotional well-being (mental health), and role limitations due to emotional problems (role emotional)). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning.

2. Mean Intact Parathyroid Hormone (iPTH) Level at Baseline and Month 6 [Baseline and Month 6]

3. Mean Calcium Level at Baseline and Month 6 [Baseline and Month 6]

4. Mean Phosphorus Level at Baseline and Month 6 [Baseline and Month 6]

5. Mean Alkaline Phosphatase Level at Baseline and Month 6 [Baseline and Month 6]

6. Vitamin B12 Levels [Baseline and month 6]

   Vitamin B12 levels were categorized according to the following laboratory reference ranges: Low: < 200 pg/mL Normal: 200 - 950 pg/mL High: > 950 pg/mL

7. Folic Acid Levels [Baseline and month 6]

   Folic acid levels were categorized according to the following laboratory reference ranges: Low: < 4.6 ng/mL Normal: 4.6 - 18.7 ng/mL High: > 18.7 ng/mL

8. Mean High Sensitivity C-reactive Protein (hsCRP) Level at Baseline and Month 6 [Baseline and Month 6]

9. Mean Fibroblast Growth Factor-23 (FGF-23) Level at Baseline and Month 6 [Baseline and Month 6]

10. Number of Participants With Adverse Events [From the time of study drug administration until 4 weeks after the discontinuation of the study drug; up to 7 months.]

    Serious adverse events were any adverse events meeting any of the following criteria: An event that resulted in the death of a participant; An event that, in the opinion of the investigator, would have resulted in immediate fatality if medical intervention had not been taken (life-threatening); Resulted in an admission to the hospital for any length of time or prolonged hospital stay; An anomaly detected at or after birth, or any anomaly that results in fetal loss; An event that resulted in a condition that substantially interfered with the activities of daily living; An important medical event that may not be immediately life-threatening or result in death or hospitalization, but based on medical judgment may have jeopardized the participant and may have required medical or surgical intervention to prevent any of the outcomes listed above. Adverse events were assessed by the investigator for possible relationship to study drug.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria: A subject will only be included if all the following entry criteria are met:

• Patients ≥ 18 years of age

• Stage 5 chronic kidney disease (CKD) patients receiving hemodialysis and with moderate to severe secondary hyperparathyroidism (SHPT)

• Patients with anemia due to renal insufficiency but who are iron replete:; Transferrin saturation (TSAT) > 20% and Ferritin levels > 200 ng/mL and requiring treatment with erythropoietin (EPO)

• Patients with vitamin B levels > lower limit of normal (LLN) and folic acid levels > LLN

• Patients treated only with intravenous calcitriol for at least 6 months

• Patients with serum intact parathyroid hormone (iPTH) level > 500 pg/mL

• Patients with calcium phosphate product (Ca × PO4) < 65 mg²/dL²

• Patients willing to sign "written informed consents" before participating in any the study related activity.

• Patients with phosphorus levels < 6.5 mg/dL and calcium levels < 11.2 mg/dL

Exclusion Criteria:

A subject will be excluded from the study if he/she meets any of the following criteria:

• Patients who have known hypersensitivity and/or toxicity to vitamin D metabolites and/or to paricalcitol and/or to other product ingredients.

• Patients who have participated in a clinical study within the last month.

• Patients whose previous concomitant medication and laboratory data for 6 months prior to the baseline visit are not available.

• Patients with known contraindication to selective Vitamin D receptor activators (VDRAs) according to the Summary of Product Characteristics (SmPC).

• Pregnancy, breast-feeding or planning a pregnancy within next 6 months after enrollment. Sexually active female patients not accepting appropriate contraceptive methods during the course of the study will also be excluded.

• Hypertensive and diabetic patients who are not on an optimal and steady medication regimen for more than 30 days.

• Patients with microcytic (mean corpuscular volume [MCV] < 80 fL) and macrocytic (MCV > 100 fL) anemia at screening that may be caused by diseases such as for microcytic anemias - Iron Deficiency, Thalassemias, Anemia of Chronic Disease, Copper Deficiency, Zinc poisoning, Sideroblastic Anemia, macrocytic anemias -ethanol abuse, myelodysplastic syndromes, acute myeloid leukemias, reticulocytosis, drug induced anemia, liver disease.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• AbbVie (prior sponsor, Abbott)

Investigators

• Study Director: Mahmut Gücük, MD, AbbVie

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

• Poordad F, Landis CS, Asatryan A, Jackson DF 3rd, Ng TI, Fu B, Lin CW, Yao B, Kort J. High antiviral activity of NS5A inhibitor ABT-530 with paritaprevir/ritonavir and ribavirin against hepatitis C virus genotype 3 infection. Liver Int. 2016 Aug;36(8):1125-32. doi: 10.1111/liv.13067. Epub 2016 Feb 3.

• Responsible Party: AbbVie (prior sponsor, Abbott)
• ClinicalTrials.gov Identifier: NCT01506947
• Other Study ID Numbers: W12-645
• First Posted: Jan 10, 2012
• Last Update Posted: Jul 30, 2021
• Last Verified: Jul 1, 2021

• Keywords provided by AbbVie (prior sponsor, Abbott): Hemodialysis; Chronic kidney disease; Secondary hyperparathyroidism,
• Additional relevant MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Hyperparathyroidism; Hyperparathyroidism, Secondary; Darbepoetin alfa

Study Results

Participant Flow

Recruitment Details	This study was conducted at 7 centers in Turkey.

Arm/Group Title	Paricalcitol
Arm/Group Description	Participants received paricalcitol intravenously during hemodialysis until serum intact parathyroid hormone (iPTH) levels were below 150 pg/mL or for up to 6 months. Paricalcitol dose was based on iPTH levels and was titrated to maintain iPTH levels between 150-300 pg/mL. Participants may have also received routine darbepoetin alfa to treat anemia.
Period Title: Overall Study
STARTED	65
COMPLETED	49
NOT COMPLETED	16

Baseline Characteristics

Arm/Group Title	Paricalcitol
Arm/Group Description	Participants received paricalcitol intravenously during hemodialysis until serum intact parathyroid hormone (iPTH) levels were below 150 pg/mL or for up to 6 months. Paricalcitol dose was based on iPTH levels and was titrated to maintain iPTH levels between 150-300 pg/mL. Participants may have also received routine darbepoetin alfa to treat anemia.
Overall Participants	48
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49.6 (16.7)
Sex: Female, Male (Count of Participants)
Female	26 54.2%
Male	22 45.8%

Outcome Measures

1. Primary Outcome

Title	Mean Erythropoietin Dose Per Visit
Description	The requirement of erythropoietin (EPO) treatment to maintain serum hemoglobin levels between 10 to 11.5 g/dL during the study was assessed by analysis of the dose of darbepoetin alfa used at baseline and during each month of the study. The mean EPO dosage per injection for each study month is reported.
Time Frame	Baseline and Months 1, 2, 3, 4, 5 and 6

Outcome Measure Data

Analysis Population Description

Per-protocol analysis set with EPO dosage available at all visits.

Arm/Group Title	Paricalcitol
Arm/Group Description	Participants received paricalcitol intravenously during hemodialysis until serum intact parathyroid hormone (iPTH) levels were below 150 pg/mL or for up to 6 months. Paricalcitol dose was based on iPTH levels and was titrated to maintain iPTH levels between 150-300 pg/mL. Participants may have also received routine darbepoetin alfa to treat anemia.
Measure Participants	45
Baseline	35.8 (15.0)
Month 1	22.2 (20.0)
Month 2	22.7 (21.3)
Month 3	4.7 (4.5)
Month 4	7.2 (6.2)
Month 5	17.3 (19.5)
Month 6	21.8 (19.7)

2. Secondary Outcome

Title	Mean Scores of Short Form Health Survey 36 (SF-36) Questionnaire
Description	The Medical Outcome Study Short Form 36-Item Health Survey (SF-36) is a self-administered questionnaire that measures the impact of disease on overall quality of life and consists of 36 questions in eight domains. The domains include physical (physical functioning, role limitations due to physical health (role-physical), general health perceptions and pain) and mental domains (energy/fatigue (vitality), social functioning, emotional well-being (mental health), and role limitations due to emotional problems (role emotional)). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

Per-protocol analysis set

Arm/Group Title	Paricalcitol
Arm/Group Description	Participants received paricalcitol intravenously during hemodialysis until serum intact parathyroid hormone (iPTH) levels were below 150 pg/mL or for up to 6 months. Paricalcitol dose was based on iPTH levels and was titrated to maintain iPTH levels between 150-300 pg/mL. Participants may have also received routine darbepoetin alfa to treat anemia.
Measure Participants	48
Physical Function - Baseline	51.7 (26.3)
Physical Function - Month 6	51.5 (30.1)
Role Physical - Baseline	38.5 (45.2)
Role Physical - Month 6	44.3 (46.5)
Role Emotional - Baseline	52.8 (46.0)
Role Emotional - Month 6	54.2 (47.0)
Vitality - Baseline	47.4 (16.5)
Vitality - Month 6	45.2 (17.0)
Mental Health - Baseline	54.5 (12.6)
Mental Health - Month 6	52.7 (15.2)
Social Functioning - Baseline	59.6 (20.7)
Social Functioning - Month 6	55.5 (26.3)
Pain - Baseline	61.3 (26.6)
Pain - Month 6	60.5 (25.0)
General Health - Baseline	47.0 (16.9)
General Health - Month 6	44.4 (22.3)

3. Secondary Outcome

Title	Mean Intact Parathyroid Hormone (iPTH) Level at Baseline and Month 6
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

Per-protocol analysis set with available data at each time point.

Arm/Group Title	Paricalcitol
Arm/Group Description	Participants received paricalcitol intravenously during hemodialysis until serum intact parathyroid hormone (iPTH) levels were below 150 pg/mL or for up to 6 months. Paricalcitol dose was based on iPTH levels and was titrated to maintain iPTH levels between 150-300 pg/mL. Participants may have also received routine darbepoetin alfa to treat anemia.
Measure Participants	48
Baseline	918.0 (585.9)
Month 6	692.5 (413.4)

4. Secondary Outcome

Title	Mean Calcium Level at Baseline and Month 6
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

Per-protocol analysis set with available data at each time point.

Arm/Group Title	Paricalcitol
Arm/Group Description	Participants received paricalcitol intravenously during hemodialysis until serum intact parathyroid hormone (iPTH) levels were below 150 pg/mL or for up to 6 months. Paricalcitol dose was based on iPTH levels and was titrated to maintain iPTH levels between 150-300 pg/mL. Participants may have also received routine darbepoetin alfa to treat anemia.
Measure Participants	48
Baseline	8.81 (0.95)
Month 6	9.29 (0.86)

5. Secondary Outcome

Title	Mean Phosphorus Level at Baseline and Month 6
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

Participants who completed the study with available data at each time point.

Arm/Group Title	Paricalcitol
Arm/Group Description	Participants received paricalcitol intravenously during hemodialysis until serum intact parathyroid hormone (iPTH) levels were below 150 pg/mL or for up to 6 months. Paricalcitol dose was based on iPTH levels and was titrated to maintain iPTH levels between 150-300 pg/mL. Participants may have also received routine darbepoetin alfa to treat anemia.
Measure Participants	48
Baseline	4.87 (1.11)
Month 6	5.47 (1.22)

6. Secondary Outcome

Title	Mean Alkaline Phosphatase Level at Baseline and Month 6
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

Per-protocol analysis set with available data at each time point.

Arm/Group Title	Paricalcitol
Arm/Group Description	Participants received paricalcitol intravenously during hemodialysis until serum intact parathyroid hormone (iPTH) levels were below 150 pg/mL or for up to 6 months. Paricalcitol dose was based on iPTH levels and was titrated to maintain iPTH levels between 150-300 pg/mL. Participants may have also received routine darbepoetin alfa to treat anemia.
Measure Participants	48
Baseline	225.7 (170.1)
Month 6	172.9 (147.6)

7. Secondary Outcome

Title	Vitamin B12 Levels
Description	Vitamin B12 levels were categorized according to the following laboratory reference ranges: Low: < 200 pg/mL Normal: 200 - 950 pg/mL High: > 950 pg/mL
Time Frame	Baseline and month 6

Outcome Measure Data

Analysis Population Description

Per-protocol analysis set with available data at each time point.

Arm/Group Title	Baseline	Month 6
Arm/Group Description
Measure Participants	48	46
Low	2 4.2%	0 NaN
Normal	13 27.1%	22 NaN
High	33 68.8%	24 NaN

8. Secondary Outcome

Title	Folic Acid Levels
Description	Folic acid levels were categorized according to the following laboratory reference ranges: Low: < 4.6 ng/mL Normal: 4.6 - 18.7 ng/mL High: > 18.7 ng/mL
Time Frame	Baseline and month 6

Outcome Measure Data

Analysis Population Description

Per-protocol analysis set with available data at each time point.

Arm/Group Title	Baseline	Month 6
Arm/Group Description
Measure Participants	48	46
Low	1 2.1%	4 NaN
Normal	25 52.1%	25 NaN
High	22 45.8%	17 NaN

9. Secondary Outcome

Title	Mean High Sensitivity C-reactive Protein (hsCRP) Level at Baseline and Month 6
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

Per-protocol analysis set with available data at each time point.

Arm/Group Title	Paricalcitol
Arm/Group Description	Participants received paricalcitol intravenously during hemodialysis until serum intact parathyroid hormone (iPTH) levels were below 150 pg/mL or for up to 6 months. Paricalcitol dose was based on iPTH levels and was titrated to maintain iPTH levels between 150-300 pg/mL. Participants may have also received routine darbepoetin alfa to treat anemia.
Measure Participants	48
Baseline	11.8 (14.1)
Month 6	14.4 (20.7)

10. Secondary Outcome

Title	Mean Fibroblast Growth Factor-23 (FGF-23) Level at Baseline and Month 6
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

Per-protocol analysis set with available data at each time point.

Arm/Group Title	Paricalcitol
Arm/Group Description	Participants received paricalcitol intravenously during hemodialysis until serum intact parathyroid hormone (iPTH) levels were below 150 pg/mL or for up to 6 months. Paricalcitol dose was based on iPTH levels and was titrated to maintain iPTH levels between 150-300 pg/mL. Participants may have also received routine darbepoetin alfa to treat anemia.
Measure Participants	46
Baseline	6267 (5967)
Month 6	11340 (13450)

11. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	Serious adverse events were any adverse events meeting any of the following criteria: An event that resulted in the death of a participant; An event that, in the opinion of the investigator, would have resulted in immediate fatality if medical intervention had not been taken (life-threatening); Resulted in an admission to the hospital for any length of time or prolonged hospital stay; An anomaly detected at or after birth, or any anomaly that results in fetal loss; An event that resulted in a condition that substantially interfered with the activities of daily living; An important medical event that may not be immediately life-threatening or result in death or hospitalization, but based on medical judgment may have jeopardized the participant and may have required medical or surgical intervention to prevent any of the outcomes listed above. Adverse events were assessed by the investigator for possible relationship to study drug.
Time Frame	From the time of study drug administration until 4 weeks after the discontinuation of the study drug; up to 7 months.

Outcome Measure Data

Analysis Population Description

The safety population included all participants who enrolled.

Arm/Group Title	Paricalcitol
Arm/Group Description	Participants received paricalcitol intravenously during hemodialysis until serum intact parathyroid hormone (iPTH) levels were below 150 pg/mL or for up to 6 months. Paricalcitol dose was based on iPTH levels and was titrated to maintain iPTH levels between 150-300 pg/mL. Participants may have also received routine darbepoetin alfa to treat anemia.
Measure Participants	65
Non-serious adverse events	9 18.8%
Serious adverse events	11 22.9%
Treatment-related adverse events	0 0%
Fatal adverse events	3 6.3%

Adverse Events

Time Frame	6 months
Arm/Group Title	Paricalcitol
Arm/Group Description	Participants received paricalcitol intravenously during hemodialysis until serum intact parathyroid hormone (iPTH) levels were below 150 pg/mL or for up to 6 months. Paricalcitol dose was based on iPTH levels and was titrated to maintain iPTH levels between 150-300 pg/mL. Participants may have also received routine darbepoetin alfa to treat anemia.
All Cause Mortality
	Paricalcitol
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Paricalcitol
	Affected / at Risk (%)	# Events
Total	11/65 (16.9%)
Blood and lymphatic system disorders
Haemoconcentration	1/65 (1.5%)
Cardiac disorders
Cardio-respiratory arrest	1/65 (1.5%)
Acute coronary syndrome	1/65 (1.5%)
Palpitations	2/65 (3.1%)
Cardiac valve disease	1/65 (1.5%)
Arrhythmia	1/65 (1.5%)
Mitral valve incompetence	1/65 (1.5%)
Gastrointestinal disorders
Ascites	1/65 (1.5%)
Abdominal pain upper	1/65 (1.5%)
Stools watery	1/65 (1.5%)
Faeces discoloured	1/65 (1.5%)
Gastric ulcer	1/65 (1.5%)
Upper gastrointestinal haemorrhage	1/65 (1.5%)
General disorders
Asthenia	2/65 (3.1%)
Fatigue	1/65 (1.5%)
Pyrexia	2/65 (3.1%)
Chest Pain	1/65 (1.5%)
Infections and infestations
Soft tissue infection	1/65 (1.5%)
Lung infection	1/65 (1.5%)
Respiratory Tract Infection	1/65 (1.5%)
Injury, poisoning and procedural complications
Arteriovenous fistula site complication	1/65 (1.5%)
Arteriovenous fistula thrombosis	2/65 (3.1%)
Investigations
Haemoglobin decreased	1/65 (1.5%)
Haemoglobin increased	1/65 (1.5%)
Metabolism and nutrition disorders
Hyperkalaemia	1/65 (1.5%)
Nervous system disorders
Loss of consciousness	1/65 (1.5%)
Somnolence	1/65 (1.5%)
Cerebrovascular Accident	1/65 (1.5%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	1/65 (1.5%)
Productive cough	1/65 (1.5%)
Cough	1/65 (1.5%)
Dyspnoea	4/65 (6.2%)
Acute Respiratory distress syndrome	1/65 (1.5%)
Respiratory arrest	1/65 (1.5%)
Skin and subcutaneous tissue disorders
Erythema	1/65 (1.5%)
Diabetic foot	1/65 (1.5%)
Surgical and medical procedures
Nephrectomy	1/65 (1.5%)
Parathyroidectomy	1/65 (1.5%)
Renal transplant	2/65 (3.1%)
Other (Not Including Serious) Adverse Events
	Paricalcitol
	Affected / at Risk (%)	# Events
Total	1/65 (1.5%)
Ear and labyrinth disorders
Vertigo	1/65 (1.5%)
Gastrointestinal disorders
Abdominal pain upper	1/65 (1.5%)
Nausea	1/65 (1.5%)
Gastric haemorrhage	1/65 (1.5%)
General disorders
Chest pain	1/65 (1.5%)
Pain	1/65 (1.5%)
Infections and infestations
Nasopharyngitis	1/65 (1.5%)
Injury, poisoning and procedural complications
Arteriovenous fistula site haemorrhage	1/65 (1.5%)
Musculoskeletal and connective tissue disorders
Myalgia	1/65 (1.5%)
Nervous system disorders
Headache	1/65 (1.5%)
Dizziness	1/65 (1.5%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	1/65 (1.5%)
Dyspnoea	1/65 (1.5%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	1/65 (1.5%)
Vascular disorders
Arteriovenous fistula	1/65 (1.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

AbbVie requests that any investigator or institution that plans on presenting/publishing results disclosure, provide written notification of their request 60 days prior to their presentation/publication. AbbVie requests that no presentation/publication will be instituted until 12 months after a study is completed, or after the first presentation/publication whichever occurs first. A delay may be proposed of a presentation/publication if AbbVie needs to secure patent or proprietary protection.