Recombinant Human rhPTH(1-34) VS Association Alfacalcidol/Hydrochlorothiazide in Severe Primary Hypoparathyroidism (ACTICAS)
Primary Purpose
Autosomal Dominant Hypocalcemia OR Primary Hypoparathyroidism Related to Other Cause But Complicated by Hypercalciuria Under Treatment
Status
Completed
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Teriparatide
Thiazide
Potassium sparing diuretic
Alfacalcidol
Sponsored by
About this trial
This is an interventional treatment trial for Autosomal Dominant Hypocalcemia OR Primary Hypoparathyroidism Related to Other Cause But Complicated by Hypercalciuria Under Treatment focused on measuring Hypoparathyroidism, PTH(1-34), Thiazides, Hypercalciuria, Calcium sensing receptor
Eligibility Criteria
Inclusion criteria :
- Patients aged from 18 to 80 years, of both sexes
- Patient with primary hypoparathyroidism related to a genetically proven ADH OR primary hypoparathyroidism related to other cause but complicated by hypercalciuria under treatment
- Affiliated to a French health insurance system, and who have consented to the study.
Exclusion criteria :
- Pregnant and breastfeeding women;
- Women of childbearing age without contraception;
- For men aged from 18 to 20 years, presence of cartilage of growth on X-ray of left knee;
- Anuria;
- Kidney failure with plasmatic creatinine >125 mmol/l and urea >10 mmol/l;
- Long QT interval : QTc > 450 ms (men) or 470 ms (women);
- Hepatic failure;
- Metabolic bone diseases (Paget's disease of bone) other than primary osteoporosis or glucocorticoid-induced osteoporosis;
- Association to other potassium sparing diuretics;
- Hypokalemia (<3.5 mmol/l) without diuretic therapy;
- Hyperkalemia (>5.5 mmol/l);
- Hyponatremia (<135 mmol/l) without diuretic therapy;
- Hypercalcemia (>2.6 mmol/l);
- Severe hypomagnesemia (≤ 0.5 mmol/l);
- Vitamin D deficiency (25OH vit D < 20 ng/mL);
- Unexplained increase in alkaline phosphatase (>2N);
- Intolerance to sulfamide;
- Intolerance to amiloride or other component of the drug;
- Hypersensitivity to any active substance or excipient of one of the experimental drugs;
- Gluten intolerance;
- Bone break history within the three previous months;
- History of radiotherapy of the skeleton;
- History of bone cancer or metastasis.
- Personnal or familial (first degree relatives) of skin cancer
Sites / Locations
- AP-HP Hopital Europeen Georges Pompidou
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
rh PTH(1-34)
Thiazide + potassium sparing diuretic
Arm Description
40 µg/day rhPTH(1-34) (teriparatide or FORSTEO® 20 µg twice daily) over 7 to 8 weeks (52±3 days).
hydrochlorothiazide 25 mg/day (ESIDREX®) + amiloride 5 mg/day (MODAMIDE®) + 0.5 µg/day alfacalcidol (ALFACALCIDOL®) over 7 to 8 weeks (52±3 days).
Outcomes
Primary Outcome Measures
Plasma calcium concentration
Mean of two measures at 30-min interval of Ionized serum calcium concentration
Secondary Outcome Measures
Ambulatory calcium concentration
Ambulatory measurement of serum calcium level
Calciuria
24h-urinary calcium excretion (expressed as mmol/24h and mmol/mmol creatinine)
Plasma calcium x phosphate product
Blood pressure
Tolerance of thiazides and amiloride
Serum sodium level
Tolerance of thiazides and amiloride
Serum potassium level
Tolerance of thiazides and amiloride
Estimated GFR using MDRD formula
Tolerance of thiazides and amiloride
Serum renin level
Tolerance of thiazides and amiloride
Serum aldosterone level
Tolerance of thiazides and amiloride
24h-urinary sodium excretion
Tolerance of thiazides and amiloride
24h-urinary potassium excretion
Tolerance of thiazides and amiloride
24h-urinary aldosterone excretion
Tolerance of thiazides and amiloride
Serum 25 OH vitamin D level
Tolerance of thiazides and amiloride
Serum 1,25(OH)2 vitamin D level
Tolerance of thiazides and amiloride
Serum magnesium level
Tolerance of thiazides and amiloride
24h-urinary magnesium excretion
Tolerance of thiazides and amiloride
Calcium/citrate ratio measured on spot urines
Assessment of stone formation risk
Calcium/creatinine ratios measured on spot urines
Assessment of stone formation risk
Crystalluria
Assessment of stone formation risk
Alkaline phosphatase level
Evaluation of the impact of rhPTH(1-34) on bone
Number of episodes of cramps
Other tolerance
Number of episodes of paresthesia
Other tolerance
Number of episodes of tetany
Other tolerance
Number of episodes of seizure
Other tolerance
SF36 self-administered questionnaire
Evaluation of the impact on quality of life
Full Information
NCT ID
NCT02824718
First Posted
July 1, 2016
Last Updated
June 23, 2021
Sponsor
Assistance Publique - Hôpitaux de Paris
Collaborators
Ministry of Health, France
1. Study Identification
Unique Protocol Identification Number
NCT02824718
Brief Title
Recombinant Human rhPTH(1-34) VS Association Alfacalcidol/Hydrochlorothiazide in Severe Primary Hypoparathyroidism
Acronym
ACTICAS
Official Title
A Randomized Crossover TrIal to Compare Recombinant Human rhPTH(1-34) to the ASsociation Alfacalcidol/Hydrochlorothiazide in the Treatment of Severe Primary Hypoparathyroidism
Study Type
Interventional
2. Study Status
Record Verification Date
June 2021
Overall Recruitment Status
Completed
Study Start Date
June 6, 2017 (Actual)
Primary Completion Date
May 28, 2020 (Actual)
Study Completion Date
May 28, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris
Collaborators
Ministry of Health, France
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
Hypoparathyroidism is a rare condition in which the parathyroid glands fail to produce sufficient amount of parathyroid hormone or the parathyroid hormone produced lacks biologic activity. The most common cause of hypoparathyroidism is damage to or removal of the parathyroid glands due to neck surgery for another condition. Occurrence of hypercalciuria under treatment is a frequent concern in primary hypoparathyroidism, limiting correction of hypocalcemia.
Hypoparathyroidism can also be caused by an autoimmune process. In rare cases, hypoparathyroidism may occur as a genetic disorder inherited as an autosomal recessive, autosomal dominant or X-linked recessive trait. The autosomal dominant hypocalcemia (ADH) is mainly caused by heterozygous activating mutations in the CASR gene encoding CaSR). As other severe presentation of primary hypothyroidism, ADH is characterized by the increased risk to develop hypercalciuria and nephrolithiasis. The purpose of the study is to compare two therapeutic approaches in severe hypoparathyroidism in order to limit the risk of nephrocalcinosis and renal failure when attempting to correct hypocalcemia: rhPTH(1-34) vs association of active vitamin D and hydrochlorothiazide. The European Society of Endocrinology Clinical has indeed recently published guidelines for the treatment of chronic hypoparathyroidism in adults. These guidelines suggest considering treatment with a thiazide diuretic In a patient with hypercalciuria and replacement therapy with PTH in patients who do not stably and safely maintain their serum and urinary calcium in the target range.
Detailed Description
The design consists in a five-periods, two-treatments, open-label, randomized, crossover study with blind end-point evaluation.
Patients will come for an inclusion visit and will receive treatment with 0.5 µg/day alfacalcidol for 4 weeks (28±3 days, run-in). They will be instructed to maintain dietary calcium intakes (1 g/day) for the duration of the study and will be supplemented throughout the study with native vitamin D in order to maintain the concentration of 25OH vitamin D ≥ 40 ng/L. Magnesium supplementation (100 mg/day) will be maintained throughout the study.
At inclusion, patients will be randomly assigned to receive at the end of run-in period, in cross-over either an association hydrochlorothiazide 25 mg/day (ESIDREX®) + amiloride 5 mg/day (MODAMIDE®) + 0.5 µg/day alfacalcidol (ALFACALCIDOL®) or 40 µg/day rhPTH(1-34) (teriparatide or FORSTEO® 20 µg twice daily) over 7 to 8 weeks (52±3 days).
After a washout period of 28±3 days under 0.5 µg alfacalcidol /day, the patients will follow the second period of treatment. The study will end with a final period of 28±3 days under 0.5 µg alfacalcidol /day. Patients will ambulatory monitor serum calcium, sodium, potassium, and creatinine levels at days 15 of run in and run out periods and at day 7 and day 28 of each treatment period.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Autosomal Dominant Hypocalcemia OR Primary Hypoparathyroidism Related to Other Cause But Complicated by Hypercalciuria Under Treatment
Keywords
Hypoparathyroidism, PTH(1-34), Thiazides, Hypercalciuria, Calcium sensing receptor
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
16 (Actual)
8. Arms, Groups, and Interventions
Arm Title
rh PTH(1-34)
Arm Type
Experimental
Arm Description
40 µg/day rhPTH(1-34) (teriparatide or FORSTEO® 20 µg twice daily) over 7 to 8 weeks (52±3 days).
Arm Title
Thiazide + potassium sparing diuretic
Arm Type
Active Comparator
Arm Description
hydrochlorothiazide 25 mg/day (ESIDREX®) + amiloride 5 mg/day (MODAMIDE®) + 0.5 µg/day alfacalcidol (ALFACALCIDOL®) over 7 to 8 weeks (52±3 days).
Intervention Type
Drug
Intervention Name(s)
Teriparatide
Other Intervention Name(s)
FORSTEO
Intervention Description
human recombinant parathormone
Intervention Type
Drug
Intervention Name(s)
Thiazide
Other Intervention Name(s)
ESIDREX
Intervention Description
Diuretic
Intervention Type
Drug
Intervention Name(s)
Potassium sparing diuretic
Other Intervention Name(s)
MODAMIDE
Intervention Description
Diuretic
Intervention Type
Drug
Intervention Name(s)
Alfacalcidol
Other Intervention Name(s)
UN-ALFA
Intervention Description
Belongs to the class of vitamin D and analogues
Primary Outcome Measure Information:
Title
Plasma calcium concentration
Description
Mean of two measures at 30-min interval of Ionized serum calcium concentration
Time Frame
two months of treatment
Secondary Outcome Measure Information:
Title
Ambulatory calcium concentration
Description
Ambulatory measurement of serum calcium level
Time Frame
days 7 an 28 of treatment by rhPTH(1-34) and association alfacalcidol/hydrochlorothiazide and at day 14 of non-treatment periods (run in, wash out, run out).
Title
Calciuria
Description
24h-urinary calcium excretion (expressed as mmol/24h and mmol/mmol creatinine)
Time Frame
Inclusion, weeks 4 (end of the run-in period), 7-8 (end of the first treatment period), 11-12 (end of the wash-out period), 18-20 (end of the second treatment period), 202 (end of the wash-out period)
Title
Plasma calcium x phosphate product
Time Frame
Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period)
Title
Blood pressure
Description
Tolerance of thiazides and amiloride
Time Frame
Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period)
Title
Serum sodium level
Description
Tolerance of thiazides and amiloride
Time Frame
Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period)
Title
Serum potassium level
Description
Tolerance of thiazides and amiloride
Time Frame
Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period)
Title
Estimated GFR using MDRD formula
Description
Tolerance of thiazides and amiloride
Time Frame
Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period)
Title
Serum renin level
Description
Tolerance of thiazides and amiloride
Time Frame
Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period)
Title
Serum aldosterone level
Description
Tolerance of thiazides and amiloride
Time Frame
Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period)
Title
24h-urinary sodium excretion
Description
Tolerance of thiazides and amiloride
Time Frame
Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period)
Title
24h-urinary potassium excretion
Description
Tolerance of thiazides and amiloride
Time Frame
Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period)
Title
24h-urinary aldosterone excretion
Description
Tolerance of thiazides and amiloride
Time Frame
Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period)
Title
Serum 25 OH vitamin D level
Description
Tolerance of thiazides and amiloride
Time Frame
Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period)
Title
Serum 1,25(OH)2 vitamin D level
Description
Tolerance of thiazides and amiloride
Time Frame
Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period)
Title
Serum magnesium level
Description
Tolerance of thiazides and amiloride
Time Frame
Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period)
Title
24h-urinary magnesium excretion
Description
Tolerance of thiazides and amiloride
Time Frame
Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period)
Title
Calcium/citrate ratio measured on spot urines
Description
Assessment of stone formation risk
Time Frame
Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period)
Title
Calcium/creatinine ratios measured on spot urines
Description
Assessment of stone formation risk
Time Frame
Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period)
Title
Crystalluria
Description
Assessment of stone formation risk
Time Frame
Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period)
Title
Alkaline phosphatase level
Description
Evaluation of the impact of rhPTH(1-34) on bone
Time Frame
Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period)
Title
Number of episodes of cramps
Description
Other tolerance
Time Frame
Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period)
Title
Number of episodes of paresthesia
Description
Other tolerance
Time Frame
Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period)
Title
Number of episodes of tetany
Description
Other tolerance
Time Frame
Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period)
Title
Number of episodes of seizure
Description
Other tolerance
Time Frame
Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period)
Title
SF36 self-administered questionnaire
Description
Evaluation of the impact on quality of life
Time Frame
Inclusion, days 28 (end of the run-in period), 80 (end of the first treatment period), 108 (end of the wash-out period), 160 (end of the second treatment period), 202 (end of the wash-out period)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria :
Patients aged from 18 to 80 years, of both sexes
Patient with primary hypoparathyroidism related to a genetically proven ADH OR primary hypoparathyroidism related to other cause but complicated by hypercalciuria under treatment
Affiliated to a French health insurance system, and who have consented to the study.
Exclusion criteria :
Pregnant and breastfeeding women;
Women of childbearing age without contraception;
For men aged from 18 to 20 years, presence of cartilage of growth on X-ray of left knee;
Anuria;
Kidney failure with plasmatic creatinine >125 mmol/l and urea >10 mmol/l;
Long QT interval : QTc > 450 ms (men) or 470 ms (women);
Hepatic failure;
Metabolic bone diseases (Paget's disease of bone) other than primary osteoporosis or glucocorticoid-induced osteoporosis;
Association to other potassium sparing diuretics;
Hypokalemia (<3.5 mmol/l) without diuretic therapy;
Hyperkalemia (>5.5 mmol/l);
Hyponatremia (<135 mmol/l) without diuretic therapy;
Hypercalcemia (>2.6 mmol/l);
Severe hypomagnesemia (≤ 0.5 mmol/l);
Vitamin D deficiency (25OH vit D < 20 ng/mL);
Unexplained increase in alkaline phosphatase (>2N);
Intolerance to sulfamide;
Intolerance to amiloride or other component of the drug;
Hypersensitivity to any active substance or excipient of one of the experimental drugs;
Gluten intolerance;
Bone break history within the three previous months;
History of radiotherapy of the skeleton;
History of bone cancer or metastasis.
Personnal or familial (first degree relatives) of skin cancer
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Anne Blanchard, MD, PhD
Organizational Affiliation
Assistance Publique - Hôpitaux de Paris
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Agnes Linglart, MD, PhD
Organizational Affiliation
Assistance Publique - Hôpitaux de Paris
Official's Role
Study Director
Facility Information:
Facility Name
AP-HP Hopital Europeen Georges Pompidou
City
Paris
ZIP/Postal Code
75015
Country
France
12. IPD Sharing Statement
Learn more about this trial
Recombinant Human rhPTH(1-34) VS Association Alfacalcidol/Hydrochlorothiazide in Severe Primary Hypoparathyroidism
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