Back to resultsStudy to Assess the Efficacy of an Extended Injection Interval Schedule of Lanreotide Autogel in Acromegalic Subjects (LEAD)
Primary Purpose
Acromegaly
Status
Completed
Phase
Phase 4
Locations
International
Study Type
Interventional
Intervention
Lanreotide Autogel 120 mg
Sponsored by
About this trial
This is an interventional treatment trial for Acromegaly
Eligibility Criteria
Inclusion Criteria:
- The subject has given written informed consent prior to any study-related procedures
- The subject is male or female and is over 18 years of age
- The subject must have had documentation supporting the diagnosis of acromegaly, based on elevated IGF-1 and/or GH levels
- The subject has been receiving octreotide LAR (10 or 20 mg) treatment for at least six months and is biochemically controlled. Control is defined as normal (age and sex adjusted) IGF 1 levels for two consecutive measurements (at least two months apart) preceding study entry
- If the subject is receiving dopamine agonist therapy, treatment should be stable for at least four months, and no change in their dopamine-agonist medication is expected during the entire study period
Exclusion Criteria:
- The subject has received radiation therapy to the pituitary gland before study entry
- The subject has a history of hypersensitivity to lanreotide or drugs with a similar chemical structure
- The subject has received a growth hormone receptor antagonist (pegvisomant) therapy within three months before study entry
- The subject has undergone treatment with any other investigational drug in the 30 days before study entry or is scheduled to receive an investigational drug, other than lanreotide 120 mg, during the course of the study
- The subject has received any unlicensed drug within the 30 days prior to the baseline visit or is scheduled to receive an unlicensed drug during the course of the study
Sites / Locations
- Universidade Federal do Rio de Janeiro - Department of Internal Medicine - Section of Endocrinology - Neuroendocrine Research Center
- Hospital das Clínicas de São Paulo - Internal Medicine - Neuroendocrine Unit - Division of Endocrinology and Metabolism
- Arhus University Hospital - Department of Medicinsk AVd M
- Righospitalet - University Department of Endocrinology & Internal Medicine P
- Odense University Hospital - Department of Endocrinology
- Helsinki University Central Hospital - (HUCH) Division of Endocrinology - Department of Medicine
- Kuopio University Hospital - Department of Medicine, Internal Medicine/Endocrinology and Diabetology Division
- CHU Besançon - Hôpital Jean Minjoz
- Hôpital Avicenne - Bâtiment Madeleine Breis
- Hôpital Neurologique - Pierre Wertheimer
- Hôpital du Bocage Sud - Service d'Endocrinologie
- CH La Rochelle - Hopital Saint Louis - Service de Médecine interne - Endocrinologie - Maladies Métaboliques- Nutrition
- Hôpital Du Cluzeau - Service de Médecine B
- Hôpital Archet 1 - Service d'Endocrinologie
- CHU de Nîmes - Hôpital Caremeau
- Hôpital Lariboisière - Service Médecine Interne - Endocrinologie - Nutrition
- Hopital Pitié-Salpêtrière - Service d'Endocrinologie
- Hôpital Cochin - Saint-Vincent-de-Paul - La-Roche-Guyon
- Hôpital Haut Lévêque - Unité de soins normalisés
- Hôpital Robert Debré
- Hôpital de Hautepierre, Service de Médecine Interne et Nutrition
- CHU de Tours - Hopital Bretonneau - Service Endocrinologie-Diabétologie Medecine B
- Evangelismos Hospital - Department of Endocrinology
- Polykliniki Hospital - Department of Endocrinology
- Metaxa Hospital - Department of Endocrinology
- B IKA Panagia Hospital - Department of Endocrinology
- Seoul National University hospital, 28 Yongon-dong Chongno-gu
- Yonsei University Severance Hospital - Department of Endocrinology and Metabolism
- Sungkyunkwan University Samsung Medical Center
- P. Stradins Clinical University Hospital - Department of Endocrinology
- Erasmus Medical Centre - Department of Endocrinology
- UMC Utrecht - Department of Endocrinology, Heidelberglaan 100
- Department of Medicine, Haukeland Hospital Jonas Lies
- Swietorkryskie Centrum Onkologii, UL. Artwinskiego 3 - Department of endocrinology and Nuclear Medecine
- University Hospital in Krakow, Dept. of Endocrinology, Kopernika Str. 17
- Samodzielny Publiczny Szpital Kliniczny nr 1, Ul. Pasteura 4
- University of Medicine and Pharmacy Iuliu Hatieganu
- Federal State Institution "Endocrinology Research Centre - Federal agency of high-tech medical care" - Neuroendocrinology & Osteopathy Department
- I.M. Sechenov Moscow Medical Academy - Endocrinology Department
- Clinical Centre of Serbia - Institute for Endocrinology, Diabetes and Metabolic Diseases, - Dr Subotica Street n°13
- Clinic for Endocrinology, Diabetes and Metabolic Disorders, Clinical Center of Vojvodina, Hajduk Veljkova 3-9
- EM-Kliniken, Universitetssjukhuset
- Skane University Hospital, Department of Endocrinology
- Karolinska University Hospital, Dpt of Endocrinology, Metabolism & Diabetology, Solna
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Lanreotide Autogel 120 mg
Arm Description
Outcomes
Primary Outcome Measures
Percentage of Subjects Having Maintained Their Injection Interval Schedule of Six Weeks or Increased Their Injection Interval to Eight Weeks Whilst Keeping Their Normalised Insulin Growth Factor (IGF-1) Levels (Age and Sex Adjusted)
A subject was responder if he maintained his injection interval schedule of 6 weeks or increased his injection interval to eight weeks whilst keeping his normalised IGF-1 level (age and sex adjusted) at the end of the study (Week 48)
Secondary Outcome Measures
Percentage of Subjects With Normalised IGF-1 Levels (Age and Sex Adjusted)
The criterion for a subject is satisfied if he has a normalised IGF-1 level (age and sex adjusted) at week 24.
Percentage of Subjects Having Maintained an Injection Interval of Six Weeks or Increasing Their Injection Interval to Eight Weeks
The criterion for a subject is satisfied if he maintained an injection interval of six weeks or increasing his injection interval to eight weeks during Phase 2 of the study.
Percentage of Subjects Who Extend Their Injection Interval to Eight Weeks During Phase 2 of the Study, Whilst Maintaining Normalised IGF-1 Levels
The criterion for a subject is satisfied if he extended his injection interval to eight weeks during Phase 2 of the study, whilst maintaining normalised IGF-1 levels at Week 48.
Mean Change From Baseline in IGF-1 Values [Expressed as % of Upper Limit of Normal (ULN)], Overall and by Injection Interval
IGF-1 change from Baseline to Week 48 = Mean IGF-1 level at Week 48 - Mean IGF-1 level at Baseline
Treatment Group (A, B or C) Mean Baseline IGF-1 Levels (Expressed as % of ULN) in Subjects Who Maintained Normalised IGF-1 Values at Week 48. Comparisons Will be Made as Follows: A Versus B, A Versus C, A Versus (B+C) and B Versus C
Mean Baseline IGF-1 Levels (Expressed as % of ULN) in All Groups (A, B and C) Versus Mean Baseline IGF-1 Levels (Expressed as % of ULN) in Subjects With Uncontrolled IGF-1 Levels at Week 24
Symptoms of Acromegaly (Headache, Excessive Perspiration, Fatigue, Soft Tissue Swelling and Arthralgia)
Acromegaly symptoms were assessed by the patients using the Patient Assessed Acromegaly Symptom Questionnaire (PASQ) scale ranging from 0 (No symptoms) to 8 (Severe, incapacitating symptoms).
Mean Changes From Baseline in Quality of Life Scores (AcroQoL)
AcroQoL score groups 22 components: Eight physical, Seven psychological appearance and Seven psychological personal relations, adjusted to a scale of 100, where a score of 100 corresponds to the best possible QoL and 0 to the worst.
Mean Changes From Baseline in Quality of Life Scores (SF-36)
Short Form-36 questionnaire (SF-36) score comprises eight components: Physical function, role-physical, bodily pain, general health, vitality, social functioning, role-emotional and mental health on a scale of 100, where a score of 100 corresponds to the best possible QoL and 0 to the worst.
Percentage of Subjects With Normalized IGF-1 Levels (Age and Sex Adjusted), Without Any Worsening of the AcroQoL Change Score Between Inclusion and Week 48
The criterion for a subject is satisfied if he had a IGF-1 level (age and sex adjusted) without any worsening of the AcroQoL change score between Inclusion and Week 48.
Correlation Between the Changes From Baseline in Quality of Life (AcroQoL) With the Corresponding Changes in IGF-1 Level (Expressed as % of ULN) at Each Visit
AcroQoL change from Baseline to Week 24 (48) = AcroQoL at Week 24 (48) - AcroQoL at Baseline.
IGF-1 change from Baseline to Week 24 (48) = IGF-1 at Week 24 (48) - IGF-1 at Baseline.
Correlation presented is a Spearman correlation (non parametric).
Serum Growth Hormone (GH) Levels
Percentage of Subjects With GH Level Less Than or Equal to 2.5 ng/mL
Subject Treatment Schedule Preference
At week 24, the preference assessed between Octreotide Long Acting Repeatable intramuscular injection (Oct-LAR IM) every 4 weeks and Lanreotide Autogel 120 mg subcutaneous injection (SC) every 6 weeks.
At week 48, the preference is assessed between Oct-LAR IM every 4 weeks and Lanreotide Autogel 120 mg SC either injected every 4, 6 or 8 weeks (as injected during Phase II of the study).
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00701363
Brief Title
Study to Assess the Efficacy of an Extended Injection Interval Schedule of Lanreotide Autogel in Acromegalic Subjects
Acronym
LEAD
Official Title
A Prospective, International, Multi-centric, Open-label Study to Assess the Efficacy of an Extended Injection Interval Schedule of Lanreotide Autogel 120 mg in Acromegalic Subjects Who Are Biochemically Controlled on the Long Term Treatment With Octreotide LAR 10 or 20 mg
Study Type
Interventional
2. Study Status
Record Verification Date
January 2019
Overall Recruitment Status
Completed
Study Start Date
October 2008 (undefined)
Primary Completion Date
March 2013 (Actual)
Study Completion Date
May 2013 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Ipsen
4. Oversight
5. Study Description
Brief Summary
The purpose of the study is to assess the efficacy of an extended injection interval schedule of lanreotide Autogel 120 mg in acromegalic subjects who are biochemically controlled on long term treatment with octreotide LAR 10 or 20 mg
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acromegaly
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
124 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Lanreotide Autogel 120 mg
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Lanreotide Autogel 120 mg
Intervention Description
120mg, injections every 6 weeks, then depending on IGF-1 results at Week 24
Primary Outcome Measure Information:
Title
Percentage of Subjects Having Maintained Their Injection Interval Schedule of Six Weeks or Increased Their Injection Interval to Eight Weeks Whilst Keeping Their Normalised Insulin Growth Factor (IGF-1) Levels (Age and Sex Adjusted)
Description
A subject was responder if he maintained his injection interval schedule of 6 weeks or increased his injection interval to eight weeks whilst keeping his normalised IGF-1 level (age and sex adjusted) at the end of the study (Week 48)
Time Frame
At week 48 (End of Study)
Secondary Outcome Measure Information:
Title
Percentage of Subjects With Normalised IGF-1 Levels (Age and Sex Adjusted)
Description
The criterion for a subject is satisfied if he has a normalised IGF-1 level (age and sex adjusted) at week 24.
Time Frame
At week 24
Title
Percentage of Subjects Having Maintained an Injection Interval of Six Weeks or Increasing Their Injection Interval to Eight Weeks
Description
The criterion for a subject is satisfied if he maintained an injection interval of six weeks or increasing his injection interval to eight weeks during Phase 2 of the study.
Time Frame
During phase 2 of the study (up to week 48)
Title
Percentage of Subjects Who Extend Their Injection Interval to Eight Weeks During Phase 2 of the Study, Whilst Maintaining Normalised IGF-1 Levels
Description
The criterion for a subject is satisfied if he extended his injection interval to eight weeks during Phase 2 of the study, whilst maintaining normalised IGF-1 levels at Week 48.
Time Frame
At week 48
Title
Mean Change From Baseline in IGF-1 Values [Expressed as % of Upper Limit of Normal (ULN)], Overall and by Injection Interval
Description
IGF-1 change from Baseline to Week 48 = Mean IGF-1 level at Week 48 - Mean IGF-1 level at Baseline
Time Frame
Baseline (visit 1) and week 48
Title
Treatment Group (A, B or C) Mean Baseline IGF-1 Levels (Expressed as % of ULN) in Subjects Who Maintained Normalised IGF-1 Values at Week 48. Comparisons Will be Made as Follows: A Versus B, A Versus C, A Versus (B+C) and B Versus C
Time Frame
Baseline (visit 1)
Title
Mean Baseline IGF-1 Levels (Expressed as % of ULN) in All Groups (A, B and C) Versus Mean Baseline IGF-1 Levels (Expressed as % of ULN) in Subjects With Uncontrolled IGF-1 Levels at Week 24
Time Frame
Baseline (visit 1)
Title
Symptoms of Acromegaly (Headache, Excessive Perspiration, Fatigue, Soft Tissue Swelling and Arthralgia)
Description
Acromegaly symptoms were assessed by the patients using the Patient Assessed Acromegaly Symptom Questionnaire (PASQ) scale ranging from 0 (No symptoms) to 8 (Severe, incapacitating symptoms).
Time Frame
At baseline, week 24 and week 48
Title
Mean Changes From Baseline in Quality of Life Scores (AcroQoL)
Description
AcroQoL score groups 22 components: Eight physical, Seven psychological appearance and Seven psychological personal relations, adjusted to a scale of 100, where a score of 100 corresponds to the best possible QoL and 0 to the worst.
Time Frame
At weeks 24 and 48
Title
Mean Changes From Baseline in Quality of Life Scores (SF-36)
Description
Short Form-36 questionnaire (SF-36) score comprises eight components: Physical function, role-physical, bodily pain, general health, vitality, social functioning, role-emotional and mental health on a scale of 100, where a score of 100 corresponds to the best possible QoL and 0 to the worst.
Time Frame
At weeks 24 and 48
Title
Percentage of Subjects With Normalized IGF-1 Levels (Age and Sex Adjusted), Without Any Worsening of the AcroQoL Change Score Between Inclusion and Week 48
Description
The criterion for a subject is satisfied if he had a IGF-1 level (age and sex adjusted) without any worsening of the AcroQoL change score between Inclusion and Week 48.
Time Frame
At week 48 (End of Study)
Title
Correlation Between the Changes From Baseline in Quality of Life (AcroQoL) With the Corresponding Changes in IGF-1 Level (Expressed as % of ULN) at Each Visit
Description
AcroQoL change from Baseline to Week 24 (48) = AcroQoL at Week 24 (48) - AcroQoL at Baseline.
IGF-1 change from Baseline to Week 24 (48) = IGF-1 at Week 24 (48) - IGF-1 at Baseline.
Correlation presented is a Spearman correlation (non parametric).
Time Frame
At weeks 24 and 48
Title
Serum Growth Hormone (GH) Levels
Time Frame
At Baseline, week 24 and week 48
Title
Percentage of Subjects With GH Level Less Than or Equal to 2.5 ng/mL
Time Frame
At weeks 24 and 48
Title
Subject Treatment Schedule Preference
Description
At week 24, the preference assessed between Octreotide Long Acting Repeatable intramuscular injection (Oct-LAR IM) every 4 weeks and Lanreotide Autogel 120 mg subcutaneous injection (SC) every 6 weeks.
At week 48, the preference is assessed between Oct-LAR IM every 4 weeks and Lanreotide Autogel 120 mg SC either injected every 4, 6 or 8 weeks (as injected during Phase II of the study).
Time Frame
At weeks 24 and 48
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
The subject has given written informed consent prior to any study-related procedures
The subject is male or female and is over 18 years of age
The subject must have had documentation supporting the diagnosis of acromegaly, based on elevated IGF-1 and/or GH levels
The subject has been receiving octreotide LAR (10 or 20 mg) treatment for at least six months and is biochemically controlled. Control is defined as normal (age and sex adjusted) IGF 1 levels for two consecutive measurements (at least two months apart) preceding study entry
If the subject is receiving dopamine agonist therapy, treatment should be stable for at least four months, and no change in their dopamine-agonist medication is expected during the entire study period
Exclusion Criteria:
The subject has received radiation therapy to the pituitary gland before study entry
The subject has a history of hypersensitivity to lanreotide or drugs with a similar chemical structure
The subject has received a growth hormone receptor antagonist (pegvisomant) therapy within three months before study entry
The subject has undergone treatment with any other investigational drug in the 30 days before study entry or is scheduled to receive an investigational drug, other than lanreotide 120 mg, during the course of the study
The subject has received any unlicensed drug within the 30 days prior to the baseline visit or is scheduled to receive an unlicensed drug during the course of the study
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ipsen Medical Director
Organizational Affiliation
Ipsen
Official's Role
Study Director
Facility Information:
Facility Name
Universidade Federal do Rio de Janeiro - Department of Internal Medicine - Section of Endocrinology - Neuroendocrine Research Center
City
Rio de Janeiro
Country
Brazil
Facility Name
Hospital das Clínicas de São Paulo - Internal Medicine - Neuroendocrine Unit - Division of Endocrinology and Metabolism
City
Sao Paulo
Country
Brazil
Facility Name
Arhus University Hospital - Department of Medicinsk AVd M
City
Arhus C
ZIP/Postal Code
DK 8000
Country
Denmark
Facility Name
Righospitalet - University Department of Endocrinology & Internal Medicine P
City
Copenhagen
ZIP/Postal Code
DK-2100
Country
Denmark
Facility Name
Odense University Hospital - Department of Endocrinology
City
Odense C
ZIP/Postal Code
DK-5000
Country
Denmark
Facility Name
Helsinki University Central Hospital - (HUCH) Division of Endocrinology - Department of Medicine
City
Helsinki
ZIP/Postal Code
00290
Country
Finland
Facility Name
Kuopio University Hospital - Department of Medicine, Internal Medicine/Endocrinology and Diabetology Division
City
Kuopio
ZIP/Postal Code
70210
Country
Finland
Facility Name
CHU Besançon - Hôpital Jean Minjoz
City
Besançon
ZIP/Postal Code
25030
Country
France
Facility Name
Hôpital Avicenne - Bâtiment Madeleine Breis
City
Bobigny
ZIP/Postal Code
93009
Country
France
Facility Name
Hôpital Neurologique - Pierre Wertheimer
City
Bron
ZIP/Postal Code
69677
Country
France
Facility Name
Hôpital du Bocage Sud - Service d'Endocrinologie
City
Dijon
ZIP/Postal Code
21079
Country
France
Facility Name
CH La Rochelle - Hopital Saint Louis - Service de Médecine interne - Endocrinologie - Maladies Métaboliques- Nutrition
City
La Rochelle
ZIP/Postal Code
17019
Country
France
Facility Name
Hôpital Du Cluzeau - Service de Médecine B
City
Limoges
ZIP/Postal Code
87042
Country
France
Facility Name
Hôpital Archet 1 - Service d'Endocrinologie
City
Nice
ZIP/Postal Code
06200
Country
France
Facility Name
CHU de Nîmes - Hôpital Caremeau
City
Nîmes
ZIP/Postal Code
30029
Country
France
Facility Name
Hôpital Lariboisière - Service Médecine Interne - Endocrinologie - Nutrition
City
Paris
ZIP/Postal Code
75010
Country
France
Facility Name
Hopital Pitié-Salpêtrière - Service d'Endocrinologie
City
Paris
ZIP/Postal Code
75013
Country
France
Facility Name
Hôpital Cochin - Saint-Vincent-de-Paul - La-Roche-Guyon
City
Paris
ZIP/Postal Code
75074
Country
France
Facility Name
Hôpital Haut Lévêque - Unité de soins normalisés
City
Pessac
ZIP/Postal Code
33604
Country
France
Facility Name
Hôpital Robert Debré
City
Reims
ZIP/Postal Code
51092
Country
France
Facility Name
Hôpital de Hautepierre, Service de Médecine Interne et Nutrition
City
Strasbourg
ZIP/Postal Code
67098
Country
France
Facility Name
CHU de Tours - Hopital Bretonneau - Service Endocrinologie-Diabétologie Medecine B
City
Tours
ZIP/Postal Code
37044
Country
France
Facility Name
Evangelismos Hospital - Department of Endocrinology
City
Athens
Country
Greece
Facility Name
Polykliniki Hospital - Department of Endocrinology
City
Athens
Country
Greece
Facility Name
Metaxa Hospital - Department of Endocrinology
City
Piraeus
Country
Greece
Facility Name
B IKA Panagia Hospital - Department of Endocrinology
City
Thessaloniki
Country
Greece
Facility Name
Seoul National University hospital, 28 Yongon-dong Chongno-gu
City
Seoul
ZIP/Postal Code
110-744
Country
Korea, Republic of
Facility Name
Yonsei University Severance Hospital - Department of Endocrinology and Metabolism
City
Seoul
ZIP/Postal Code
120-752
Country
Korea, Republic of
Facility Name
Sungkyunkwan University Samsung Medical Center
City
Seoul
ZIP/Postal Code
135-710
Country
Korea, Republic of
Facility Name
P. Stradins Clinical University Hospital - Department of Endocrinology
City
Riga
ZIP/Postal Code
1002
Country
Latvia
Facility Name
Erasmus Medical Centre - Department of Endocrinology
City
Rotterdam
ZIP/Postal Code
NL-3015 CE
Country
Netherlands
Facility Name
UMC Utrecht - Department of Endocrinology, Heidelberglaan 100
City
Utrecht
ZIP/Postal Code
NL-3584 CX
Country
Netherlands
Facility Name
Department of Medicine, Haukeland Hospital Jonas Lies
City
Bergen
ZIP/Postal Code
N-5009
Country
Norway
Facility Name
Swietorkryskie Centrum Onkologii, UL. Artwinskiego 3 - Department of endocrinology and Nuclear Medecine
City
Kielce
ZIP/Postal Code
25-734
Country
Poland
Facility Name
University Hospital in Krakow, Dept. of Endocrinology, Kopernika Str. 17
City
Krakow
ZIP/Postal Code
31501
Country
Poland
Facility Name
Samodzielny Publiczny Szpital Kliniczny nr 1, Ul. Pasteura 4
City
Wroclaw
ZIP/Postal Code
50-367
Country
Poland
Facility Name
University of Medicine and Pharmacy Iuliu Hatieganu
City
Cluj-Napoca
Country
Romania
Facility Name
Federal State Institution "Endocrinology Research Centre - Federal agency of high-tech medical care" - Neuroendocrinology & Osteopathy Department
City
Moscow
Country
Russian Federation
Facility Name
I.M. Sechenov Moscow Medical Academy - Endocrinology Department
City
Moscow
Country
Russian Federation
Facility Name
Clinical Centre of Serbia - Institute for Endocrinology, Diabetes and Metabolic Diseases, - Dr Subotica Street n°13
City
Belgrade
ZIP/Postal Code
11000
Country
Serbia
Facility Name
Clinic for Endocrinology, Diabetes and Metabolic Disorders, Clinical Center of Vojvodina, Hajduk Veljkova 3-9
City
Novi Sad
ZIP/Postal Code
21000
Country
Serbia
Facility Name
EM-Kliniken, Universitetssjukhuset
City
Linkoping
ZIP/Postal Code
581 85
Country
Sweden
Facility Name
Skane University Hospital, Department of Endocrinology
City
Lund
ZIP/Postal Code
221 85
Country
Sweden
Facility Name
Karolinska University Hospital, Dpt of Endocrinology, Metabolism & Diabetology, Solna
City
Stockholm
ZIP/Postal Code
17176
Country
Sweden
12. IPD Sharing Statement
Learn more about this trial
Study to Assess the Efficacy of an Extended Injection Interval Schedule of Lanreotide Autogel in Acromegalic Subjects
We'll reach out to this number within 24 hrs