Monocentric STUDY, Randomised Double Blinded (Healthy Subjects, or Transversal (Patients With Gitelman Syndrome) (DEPROGE)

Progesterone is needed to permit adaptation of the kidney to limit potassium loss in the urines. The investigators wonder whether progesterone or other adrenal hormon play the same role. The investigators will investigate surrenal hormone production in healthy subjects under a 7-day potassium depleted diet and in patients chronically hypokalaemic due to a renal loss of potassium.

Study Overview

• Status: Completed
• Conditions: Gitelman Syndrome; Potassium Depletion
• Intervention / Treatment: Dietary supplement: Potassium depletion

Detailed Description

The investigators will study the adaptation of steroidogenesis to potassium depletion in healthy volunteer, and the role of progesterone in renal adaptation to potassium depletion. Practically, healthy volunteers will be submitted twice to two periods of normal Na+/ high K+ diet (control period) followed by a normal Na+/ low K+ diet sustained by a pharmacological treatment with Kayexalate (K+-depleted condition). The subjects will be treated with either RU486 or a placebo, according to a randomization. The adrenal response will be evaluated after stimulation by Synacthen at baseline and at the end of each experimental period. A Synacthen test will be also done in 10 patients suffering of chronic hypokalemia linked to a hereditary tubulopathy inducing renal K+ leak called Gitelman syndrome and their plasma steroid profile will be established.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 4

Contacts and Locations

Study Locations

• France
  • Paris, France, 75015
    • European George Pompidou Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria for healthy subjects:

• Caucasian male subject
• 18-35 yrs-old
• BMI between 18 and 30 Kg/m2
• Normal biological pattern (sodium, potassium, eGFR >60mL/min/1.73 m2, SGOT and SGPT < 2.5 normal value)
• Non smoker subjects or less than 5 cigarettes a day
• No drug abuse
• No active viral B or C hepatitis, no positive HIV serology
• No treatment except paracetamol
• Normal EKG
• Inform consent given
• Affiliation to French Medicare assurance

Inclusion Criteria for patients :

• 18-75 Years old subjects
• genetically proven Gitelman syndrome
• Normal EKG
• Inform consent given
• Affiliation to French Medicare assurance

Non inclusion Criteria for healthy subjects:

• History of cardiac arrythmia or abnormal EKG
• Recent or chronic diarrhea
• Spontaneous low potassium intakes
• Biological abnormality : SGOT or SGPT > 2.5 N, fasting hyperglycemia (> 6.5 mmol/l, anemia (hemoglobin< 12g/dL)
• Single or functionally solitary kidney
• Any severe allergies, or allergic history to any drug.
• Predicted Difficulty monitoring and compliance.
• Blood donation for less than 2 months.
• Persons directly involved in the implementation of the Protocol.
• Person in exclusion period in biomedical research.
• Protected Person (person under guardianship, deprived of liberty, ...).
• Taking medication in the previous 7 days (except paracetamol).
• Chronic adrenal insufficiency.
• Known allergy to any of the excipients of the RU 486 (colloidal anhydrous silica, maize starch, povidone, microcrystalline cellulose, magnesium stearate).
• Severe asthma not controlled by treatment.
• Porphyria hereditary.

Non inclusion Criteria for Gitelman patients:

• People that did not give their consent or unable to understand the protocol.
• Anemia (Hg <10 g / dL).
• Clinically significant abnormality on the EKG.
• Any severe allergies, or allergic history to any drug.
• Treatment with corticosteroids.
• Patient in exclusion period in biomedical research.
• Protected Person (patient trust, deprived of liberty, ...)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RU 486 (mifepristone); Subjects will receive 400 mg once a day of RU486	Dietary supplement: Potassium depletion; Healthy subjects will be submitted twice at 15-30 day interval, to a low potassium diet (20mmol/day)
Placebo Comparator: Placebo; Subjects will receive placebo once a day	Dietary supplement: Potassium depletion; Healthy subjects will be submitted twice at 15-30 day interval, to a low potassium diet (20mmol/day)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of potassium depletion on plasma progesterone (Change from Baseline of progesterone)	Healthy subjects : Change from Baseline of progesterone in response to synacthen at day 8 in subject treated by placebo. Patients with Gitelman syndrome: Change from Baseline of progesterone in response to synacthen	Day 1 and Day 8 of placebo period of treatment (healthy subjects) or once (Gitelman patients)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
effect of RU 486 on renal adaptation to potassium depletion (Plasma potassium and kaliuresis will be monitored )	Plasma potassium and kaliuresis will be monitored during the 7-days potassium depletion in subjects treated by RU486 or placebo, according randomization	Day 1 and day 8 of each period of treatment
Effect of potassium depletion on pulse pressure velocity (Pulse wave velocity and central blood pressure)	Pulse wave velocity and central blood pressure are measured before and after 7 days of potassium deprivated diet.	At Day 1 and Day 8 of each period of treatment
Effect of potassium depletion on plasma progesterone under RU486 (Change from Baseline of progesterone)	Healthy subjects : Change from Baseline of progesterone in response to synacthen at day 8 in subject treated by RU486.	Day 1 and Day 8 of placebo period of treatment (healthy subjects) or once (Gitelman patients)

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Anne Blanchard, MD, PhD, Assistance Publique - Hopitaux de Paris

Publications and helpful links

General Publications

• Elabida B, Edwards A, Salhi A, Azroyan A, Fodstad H, Meneton P, Doucet A, Bloch-Faure M, Crambert G. Chronic potassium depletion increases adrenal progesterone production that is necessary for efficient renal retention of potassium. Kidney Int. 2011 Aug;80(3):256-62. doi: 10.1038/ki.2011.15. Epub 2011 Feb 16.
• Blanchard A, Brailly Tabard S, Lamaziere A, Bergerot D, Zhygalina V, Lorthioir A, Jacques A, Hourton D, Azizi M, Crambert G. Adrenal adaptation in potassium-depleted men: role of progesterone? Nephrol Dial Transplant. 2020 Nov 1;35(11):1901-1908. doi: 10.1093/ndt/gfz135.

Study record dates

Study Major Dates

• Study Start: July 1, 2014
• Primary Completion (Actual): September 1, 2015
• Study Completion (Actual): September 1, 2015

Study Registration Dates

• First Submitted: October 29, 2014
• First Submitted That Met QC Criteria: November 20, 2014
• First Posted (Estimate): November 21, 2014

Study Record Updates

• Last Update Posted (Estimate): October 1, 2015
• Last Update Submitted That Met QC Criteria: September 30, 2015
• Last Verified: September 1, 2015

More Information

Terms related to this study

• Keywords: Progesterone; Potassium intake; steroidogenesis; RU486; Synachtene test
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Kidney Diseases; Urologic Diseases; Disease; Nutrition Disorders; Genetic Diseases, Inborn; Deficiency Diseases; Malnutrition; Renal Tubular Transport, Inborn Errors; Water-Electrolyte Imbalance; Syndrome; Hypokalemia; Gitelman Syndrome; Potassium Deficiency
• Other Study ID Numbers: P120906