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Open-label Extension of Study 20130173 of Denosumab in Children and Young Adults With Osteogenesis Imperfecta

Primary Purpose

Osteogenesis Imperfecta (OI)

Status

Terminated

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Denosumab

Alternative osteoporosis medications

About this trial

This is an interventional treatment trial for Osteogenesis Imperfecta (OI) focused on measuring OI, Bone.

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Subject has provided informed consent/assent prior to initiation of any Study 20170534 specific activities/procedures. Subject's legally acceptable representative has provided informed consent when the subject is legally too young to provide informed consent and the subject has provided written assent based on local regulations and/or guidelines prior to any study-specific activities/procedures being initiated.
Subject is currently/was enrolled in Study 20130173 and
- completed the 20130173 End of Study (EOS) visit (regardless of completing or ending investigational product early) OR
- did not reconsent/reassent to transition to 3-month dosing regimen on Study 20130173 OR
- early terminated from Study 20130173 as a result of meeting bone mineral density (BMD) Z-score investigational product stopping criteria.

Exclusion Criteria:

Treatment with any prohibited proscribed medications while receiving denosumab. Eligibility into study treatment with alternative osteoporosis medication/s of investigator's choice, follow guidelines per the specific alternative osteoporosis medication/s selected. For subjects off-treatment (observation only), no prohibited medications apply.
Subjects currently receiving treatment in another investigational device or drug study other than Study 20130173. Other investigational procedures while participating in this study are excluded.
For subjects expected to receive investigational product (denosumab) at study day 1: Female subject is pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 5 months after the last dose of denosumab. Females of childbearing potential (Tanner Stage greater than or equal to 2) should only be included in the study after a negative highly sensitive urine or serum pregnancy test. For study treatment with alternative osteoporosis medication/s of investigator's choice, follow guidelines per the specific alternative osteoporosis medication/s selected. For Subjects off-treatment (observation only), no exclusion applies.
For subjects expected to receive investigational product (denosumab) at study day 1: Female subjects of childbearing potential unwilling to practice true sexual abstinence (refrain from heterosexual intercourse) or use 1 highly effective method of contraception during treatment and for an additional 5 months after the last dose of investigational product (denosumab). For study treatment with alternative osteoporosis medication/s of investigator's choice, follow contraception guidelines per the specific alternative osteoporosis medication/s selected. For subjects not receiving any investigational product (observation only), no contraception required.
History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.

Sites / Locations

Childrens Hospital of Los Angeles
Indiana University - Riley Hospital for Children
The Childrens Hospital at Westmead
Perth Childrens Hospital
Universite Catholique de Louvain Cliniques Universitaires Saint Luc
Childrens Hospital of Eastern Ontario
The Hospital for Sick Children
Shriners Hospital for Children
Fakultni nemocnice Plzen
Thomayerova nemocnice
Centre Hospitalier Universitaire de Bordeaux - Hopital Pellegrin
Hopital Necker Enfants Malades
Uniklinik Köln
Semmelweis Egyetem
Azienda Ospedaliera Policlinico Umberto I
SPZOZ Centralny Szpital Kliniczny Uniwersytetu Medycznego w Lodzi
Hospital Sant Joan de Deu
Hospital Universitari i Politecnic La Fe
Birmingham Childrens Hospital
Bristol Royal Hospital for Children
Royal Hospital for Children
Sheffield Childrens Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Other

Experimental

Arm Label

Alternative Medications / Observational

Denosumab 1 mg/kg Q6M

Denosumab 1 mg/kg Q3M

Arm Description

Participants who received non-denosumab alternative therapy during the study or who were not receiving any medication at baseline. Alternative osteoporosis medication(s) were determined at the investigator's discretion and per standard of care and local guidelines.

Participants who received at least 1 dose of 1 mg/kg denosumab administered once every 6 months (Q6M) by subcutaneous injection, but no Q3M denosumab during this study.

Participants who received at least one dose of 1 mg/kg denosumab administered once every 3 months (Q3M) by subcutaneous injection during this study.

Outcomes

Primary Outcome Measures

Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest

A Serious Adverse Event is defined as any untoward medical occurrence that met at least 1 of the following serious criteria: Resulted in death (fatal) Immediately life-threatening Required in-patient hospitalization or prolongation of existing hospitalization Resulted in persistent or significant disability/incapacity Was a congenital anomaly/birth defect Other medically important serious event that may have jeopardized the participant or require medical or surgical intervention to prevent 1 of the outcomes listed above. Adverse events of special interest included hypocalcemia, hypersensitivity, bacterial cellulitis, osteonecrosis of the jaw (ONJ), hypercalcemia, and typical osteogenesis imperfecta (OI) femur fractures.

Number of Participants With Anti-denosumab Antibodies

Blood samples were collected (from denosumab treated participants only) for the measurement of anti-denosumab binding antibodies. Samples positive for anti-denosumab binding antibodies were further tested for neutralizing antibodies.

Number of Participants With Clinical Laboratory Toxicities Grade ≥ 3

Laboratory abnormalities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. The grades refer to the severity of the finding: Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe or medically significant; Grade 4 = Life-threatening consequences, urgent intervention indicated.

Number of Participants With Clinically Significant Vital Sign Findings

Vital sign measurements included systolic and diastolic blood pressure, heart rate, respiratory rate, and temperature. The investigator assessed vital sign results and determined whether any abnormal changes represented a clinically significant change from the participant's baseline values.

Number of Participants With Metaphyseal Index Z-score Above Age-appropriate Normal Range

Anteroposterior radiographs of both knees (unless prohibited by the presence of hardware such as implants) were used to calculate the metaphyseal index Z-score of each knee in participants with open growth plates; the knee selected for assessment during the study was the knee with the higher Z-score at baseline. The metaphyseal index (MI) was calculated by the central imaging vendor as the ratio of femoral width over distal femoral growth plate width, and the Z-score for each participant, relative to the participant's age as: MI Z-score = (participant value - mean)/SD, where mean and standard deviation (SD) are the corresponding values based on a reference population for the participant's age group at the time of the assessment. Metaphyseal index Z-score above age-appropriate normal range is defined as a MI Z-score > 2.

Number of Participants With Abnormal Molar Eruption of the First or Second Molar Based on Radiological Findings

Participants underwent a visual inspection under natural light for the presence of the first and second molars. Participants were referred to a dentist to perform radiographic assessment of the unerupted molar(s) if: A participant was age 7 to 12 years and appeared to have an unerupted upper or lower first molar (ie, not all 4 first molars were visible/detectable). A participant was age 13 years or older and appeared to have an unerupted upper or lower (first or) second molar (ie, not all 4 first molars and all 4 second molars were visible/detectable). Abnormal molar eruptions includes the number of participants 7 to 12 years of age with 1st unerupted or partially erupted molars and participants 13 years of age or older with 2nd unerupted or partially erupted molars.

Percent Change From Baseline in Mandibular Shaping Parameters

Lateral cephalogram was performed to enable assessment of mandibular shaping. The lateral cephalogram is a profile X-ray of the skull and soft tissues and is used to assess the relation of the teeth in the jaws, the relation of the jaws to the skull, and the relation of the soft tissues to the teeth and jaws. The following anatomical angles and dimensions were measured to evaluate the correct proportions of the mandible and its position relative to the skull/maxilla: Gonial angle; Sella-Nasion-A Point Angle (SNA angle); Sella-Nasion-B Point Angle (SNB angle); and A Point - Nasion-B Point Angle (ANB Angle).

Secondary Outcome Measures

Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) Z-score

Bone densitometry assessments of the lumbar spine were performed using dual X-ray absorptiometry (DXA). The Z-score indicates the number of standard deviations away from the mean of an average person of the same age, sex, race, and weight. A Z-score of 0 is equal to the mean of the matched population, negative Z-scores indicate a BMD lower than the mean of the matched population, and positive Z-scores indicate a higher BMD than that of the matched population. A positive change from baseline indicates an improvement in lumbar spine BMD.

Change From Baseline in Total Hip BMD Z-score

Bone densitometry assessments of the hip were performed using dual X-ray absorptiometry (DXA). The Z-score indicates the number of standard deviations away from the mean of an average person of the same age, sex, race, and weight. A Z-score of 0 is equal to the mean of the matched population, negative Z-scores indicate a BMD lower than the mean of the matched population, and positive Z-scores indicate a higher BMD than that of the matched population. A positive change from baseline indicates an improvement in total hip BMD.

Change From Baseline in Femoral Neck BMD Z-score

Bone densitometry assessments of the femoral neck were performed using dual X-ray absorptiometry (DXA). The Z-score indicates the number of standard deviations away from the mean of an average person of the same age, sex, race, and weight. A Z-score of 0 is equal to the mean of the matched population, negative Z-scores indicate a BMD lower than the mean of the matched population, and positive Z-scores indicate a higher BMD than that of the matched population. A positive change from baseline indicates an improvement in femoral neck BMD.

Full Information

NCT ID

NCT03638128

First Posted

June 21, 2018

Last Updated

November 28, 2022

Sponsor

Amgen

1. Study Identification

Unique Protocol Identification Number

NCT03638128

Brief Title

Open-label Extension of Study 20130173 of Denosumab in Children and Young Adults With Osteogenesis Imperfecta

Official Title

Multicenter, Single-arm Open-label Extension Study to Assess Long-term Safety and Efficacy of Current or Prior Treatment With Denosumab in Children/Young Adults With Osteogenesis Imperfecta

Study Type

Interventional

2. Study Status

Record Verification Date

November 2022

Overall Recruitment Status

Terminated

Why Stopped

The study was stopped earlier than planned due to safety concerns about high levels of calcium in the blood of the participants

Study Start Date

July 26, 2018 (Actual)

Primary Completion Date

March 28, 2022 (Actual)

Study Completion Date

March 28, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Amgen

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

To evaluate long-term safety of denosumab in children/young adults with pediatric osteogenesis imperfecta (OI) who completed the prior study 20130173 (NCT02352753).

Detailed Description

All participants who completed the prior denosumab study 20130173 (NCT02352753) were offered participation in this study (20170534). Participants could continue to receive denosumab once every 3 months (Q3M) or could receive denosumab once every 6 months (Q6M) or off-treatment observation only at the investigator's discretion. The study design allowed subjects to discontinue denosumab, resume denosumab, initiate alternative osteoporosis medication, discontinue alternative osteoporosis medication, or receive no treatment (observation only) at any time. Therefore results of this study were analyzed according to both baseline treatment and subsequent treatment trajectories.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Osteogenesis Imperfecta (OI)

Keywords

OI, Bone.

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

75 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Alternative Medications / Observational

Arm Type

Other

Arm Description

Arm Title

Denosumab 1 mg/kg Q6M

Arm Type

Experimental

Arm Description

Participants who received at least 1 dose of 1 mg/kg denosumab administered once every 6 months (Q6M) by subcutaneous injection, but no Q3M denosumab during this study.

Arm Title

Denosumab 1 mg/kg Q3M

Arm Type

Experimental

Arm Description

Participants who received at least one dose of 1 mg/kg denosumab administered once every 3 months (Q3M) by subcutaneous injection during this study.

Intervention Type

Drug

Intervention Name(s)

Denosumab

Other Intervention Name(s)

Prolia

Intervention Description

Solution for injection

Intervention Type

Drug

Intervention Name(s)

Alternative osteoporosis medications

Intervention Description

Alternative osteoporosis medication/s at the discretion of the investigator.

Primary Outcome Measure Information:

Title

Number of Participants With Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest

Description

Time Frame

From enrollment to end of study, including 24 weeks after last dose of denosumab for participants who received denosumab; the maximum time on study was 24 months.

Title

Number of Participants With Anti-denosumab Antibodies

Description

Time Frame

From enrollment to end of study, including 24 weeks after last dose of denosumab for participants who received denosumab; the maximum time on study was 24 months

Title

Number of Participants With Clinical Laboratory Toxicities Grade ≥ 3

Description

Time Frame

From enrollment to end of study, including 24 weeks after last dose of denosumab for participants who received denosumab; the maximum time on study was 24 months

Title

Number of Participants With Clinically Significant Vital Sign Findings

Description

Time Frame

From enrollment to end of study, including 24 weeks after last dose of denosumab for participants who received denosumab; the maximum time on study was 24 months

Title

Number of Participants With Metaphyseal Index Z-score Above Age-appropriate Normal Range

Description

Time Frame

Baseline, month 12 and month 24

Title

Number of Participants With Abnormal Molar Eruption of the First or Second Molar Based on Radiological Findings

Description

Time Frame

Baseline, month 12, and month 24

Title

Percent Change From Baseline in Mandibular Shaping Parameters

Description

Time Frame

Baseline and month 12 and month 24

Secondary Outcome Measure Information:

Title

Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) Z-score

Description

Time Frame

Baseline and months 6, 12, and 24

Title

Change From Baseline in Total Hip BMD Z-score

Description

Time Frame

Baseline, months 6, 12, and 24

Title

Change From Baseline in Femoral Neck BMD Z-score

Description

Time Frame

Baseline and months 6, 12, and 24

10. Eligibility

Sex

All

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Subject has provided informed consent/assent prior to initiation of any Study 20170534 specific activities/procedures. Subject's legally acceptable representative has provided informed consent when the subject is legally too young to provide informed consent and the subject has provided written assent based on local regulations and/or guidelines prior to any study-specific activities/procedures being initiated. Subject is currently/was enrolled in Study 20130173 and completed the 20130173 End of Study (EOS) visit (regardless of completing or ending investigational product early) OR did not reconsent/reassent to transition to 3-month dosing regimen on Study 20130173 OR early terminated from Study 20130173 as a result of meeting bone mineral density (BMD) Z-score investigational product stopping criteria. Exclusion Criteria: Treatment with any prohibited proscribed medications while receiving denosumab. Eligibility into study treatment with alternative osteoporosis medication/s of investigator's choice, follow guidelines per the specific alternative osteoporosis medication/s selected. For subjects off-treatment (observation only), no prohibited medications apply. Subjects currently receiving treatment in another investigational device or drug study other than Study 20130173. Other investigational procedures while participating in this study are excluded. For subjects expected to receive investigational product (denosumab) at study day 1: Female subject is pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 5 months after the last dose of denosumab. Females of childbearing potential (Tanner Stage greater than or equal to 2) should only be included in the study after a negative highly sensitive urine or serum pregnancy test. For study treatment with alternative osteoporosis medication/s of investigator's choice, follow guidelines per the specific alternative osteoporosis medication/s selected. For Subjects off-treatment (observation only), no exclusion applies. For subjects expected to receive investigational product (denosumab) at study day 1: Female subjects of childbearing potential unwilling to practice true sexual abstinence (refrain from heterosexual intercourse) or use 1 highly effective method of contraception during treatment and for an additional 5 months after the last dose of investigational product (denosumab). For study treatment with alternative osteoporosis medication/s of investigator's choice, follow contraception guidelines per the specific alternative osteoporosis medication/s selected. For subjects not receiving any investigational product (observation only), no contraception required. History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Organizational Affiliation

Amgen

Official's Role

Study Director

Facility Information:

Facility Name

Childrens Hospital of Los Angeles

City

Los Angeles

State/Province

California

ZIP/Postal Code

90027

Country

United States

Facility Name

Indiana University - Riley Hospital for Children

City

Indianapolis

State/Province

Indiana

ZIP/Postal Code

46202

Country

United States

Facility Name

The Childrens Hospital at Westmead

City

Westmead

State/Province

New South Wales

ZIP/Postal Code

2145

Country

Australia

Facility Name

Perth Childrens Hospital

City

Nedlands

State/Province

Western Australia

ZIP/Postal Code

6909

Country

Australia

Facility Name

Universite Catholique de Louvain Cliniques Universitaires Saint Luc

City

Bruxelles

ZIP/Postal Code

1200

Country

Belgium

Facility Name

Childrens Hospital of Eastern Ontario

City

Ottawa

State/Province

Ontario

ZIP/Postal Code

K1H 8L1

Country

Canada

Facility Name

The Hospital for Sick Children

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M5G 1X8

Country

Canada

Facility Name

Shriners Hospital for Children

City

Montreal

State/Province

Quebec

ZIP/Postal Code

H4A 0A9

Country

Canada

Facility Name

Fakultni nemocnice Plzen

City

Plzen

ZIP/Postal Code

305 99

Country

Czechia

Facility Name

Thomayerova nemocnice

City

Praha 4

ZIP/Postal Code

140 59

Country

Czechia

Facility Name

Centre Hospitalier Universitaire de Bordeaux - Hopital Pellegrin

City

Bordeaux Cedex

ZIP/Postal Code

33076

Country

France

Facility Name

Hopital Necker Enfants Malades

City

Paris Cedex 15

ZIP/Postal Code

75743

Country

France

Facility Name

Uniklinik Köln

City

Köln

ZIP/Postal Code

50931

Country

Germany

Facility Name

Semmelweis Egyetem

City

Budapest

ZIP/Postal Code

1094

Country

Hungary

Facility Name

Azienda Ospedaliera Policlinico Umberto I

City

Roma

ZIP/Postal Code

00161

Country

Italy

Facility Name

SPZOZ Centralny Szpital Kliniczny Uniwersytetu Medycznego w Lodzi

City

Lodz

ZIP/Postal Code

91-738

Country

Poland

Facility Name

Hospital Sant Joan de Deu

City

Esplugues de Llobregat

State/Province

Cataluña

ZIP/Postal Code

08950

Country

Spain

Facility Name

Hospital Universitari i Politecnic La Fe

City

Valencia

State/Province

Comunidad Valenciana

ZIP/Postal Code

46026

Country

Spain

Facility Name

Birmingham Childrens Hospital

City

Birmingham

ZIP/Postal Code

B4 6NH

Country

United Kingdom

Facility Name

Bristol Royal Hospital for Children

City

Bristol

ZIP/Postal Code

BS2 8AE

Country

United Kingdom

Facility Name

Royal Hospital for Children

City

Glasgow

ZIP/Postal Code

G51 4TF

Country

United Kingdom

Facility Name

Sheffield Childrens Hospital

City

Sheffield

ZIP/Postal Code

S10 2TH

Country

United Kingdom

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.

IPD Sharing Time Frame

Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.

IPD Sharing Access Criteria

Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors. If not approved, a Data Sharing Independent Review Panel will arbitrate and make the final decision. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the URL below.

IPD Sharing URL

https://www.amgen.com/datasharing

Links:

URL

http://www.amgentrials.com

Description

AmgenTrials clinical trials website

Learn more about this trial

Open-label Extension of Study 20130173 of Denosumab in Children and Young Adults With Osteogenesis Imperfecta

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